Dyne Therapeutics Inc Aktie

All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here. It's my pleasure to introduce the team from Dyne Therapeutics. To my immediate left John Cox, President and CEO; and to his left is Erick Lucera, CFO. And just a reminder, the format for today is a fireside chat. But if anyone in the audience has a question, you can raise your hand, and we'll try and get it addressed during our discussion.

But before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative.

And with that, I'll hand it over to John to make some introductory comments before we jump into Q&A.

Terrific. Thanks, Mike. Well, I'll just mention a little bit about where we are at Dyne right now. It's an incredibly exciting time for us. This company over the last couple of years has been preparing for the moment right in front of us, which is to launch a very important medicine in DMD. And that's early next year, followed by DM1 the following year.

So we've been building a -- I guess I'd describe it as a pure-play neuromuscular stand-alone, fully integrated biotech. Over the last 1.5 years, we have built out our leadership team and brought in people that I think other people that know how to build a company like this. They've been part of this type of company in the past. The company we're building for the future. We know how to allocate capital, we know how to launch products, and we know how to commercialize. So we have -- we came here really, and I came here because we want to launch 2 really important medicines in neuromuscular diseases where there really is nothing that is helping these patients. So it's an extraordinary time. We've got a PDUFA date in January, and we are working hard to be ready to launch our first product.

Great. Thanks for that introduction.

I'm going to switch gears a little bit and start with DM1 because I think there's interest there for obvious reasons. But let's start Z-Basivarsen for DM1. Maybe to just set the stage for the discussion, give us a brief background on that program and highlight some of the key findings so far from the ACHIEVE study.

Well, DM1 is one of those diseases where there is really nothing for patients. And it affects tens of thousands of patients. There's probably 30-plus thousand individuals that suffer from that disease. It shortens their life by about 2 decades, and they struggle and they suffer. So our company had introduced Z-Basivarsen clinically some time ago in a trial called ACHIEVE. And that trial, we presented data that had shown, first of all, that we were getting at the core fundamental biology of the disease, and that's incredibly important. This is what's known as a nuclear spliceopathy disease. So it's in the nucleus.

And we had designed our platform, the FORCE platform to deliver broadly and deeply to tissue, but we also had attached to that platform an antisense oligonucleotide. And that antisense oligonucleotide gets to the nucleus. And so what we showed previously, importantly, related to that was that we saw DMPK knockdown, that's the mutant DMPK that's at the source of this issue. Knockdown of DMPK, we saw, as a result, a splicing correction. And I don't think anybody else has been able to show that where the missplicing is corrected. And we showed that in a dose-dependent way.

And then what we finally presented at the end of that multicending dose study was that we were seeing functional improvement across multiple measures. And that functional improvement was represented by things like 5x sit to stand. It also was represented by hand myotonia with vHOT. And it was even -- we even had shown improvement on patient-reported outcomes known as MDHI on 6 subscales that are arguably related to the CNS. And that disease has a CNS issue that's very significant.

Our targeting moiety, which targets TfR1 is an antibody fragment. And that fragment crosses the blood-brain barrier, and it also gets broadly and deeply to muscle. And I think it's got a very unique and differentiated distribution that's allowing us to see that kind of improvement across multiple measures.

Yes. Very exciting data so far. And I guess the question on a lot of people's minds is just what's the read-through from Novartis' recent HARBOR data. I know there weren't a lot of details there, so it's a little bit difficult to really understand what's happening, but maybe just share your thoughts on that and read through.

Yes. I mean that -- I think everybody knows, but their results indicated that they did not meet their primary endpoint on video hand opening time. We were surprised by that because vHOT tends to be an endpoint that moves very easily and it moves early. That's what we've seen. So we were surprised by that. But I would still come back to what I mentioned before, biology really matters here. Getting to the core pathobiology of the disease is key. And that particular medicine from Novartis uses an siRNA, which does not get to the nucleus. So I think we have to realize we have 2 very, very different molecules. So when we start talking about read-through, you need to start with -- even though we're both using TfR1 and going after the same disease, we have a completely different payload and our fab behaves very differently than the mAb that they use. So I would start there.

Now when we looked at our data, we had gotten to in the multi-ascending dose study to fairly high doses. In fact, we are at a much higher dose of oligonucleotide than the other sponsor is using much higher. And the reason for that is that we found at a low dose, we would move vHOT, but we weren't necessarily moving the other more clinically meaningful measures. And so we kept dose escalating to a much higher dose. And that dose escalation is largely possible because we use a fab. And with the fab, we do not get the dose-limiting toxicities of anemia that mAbs tend to see. So we could get to a higher dose, and we are well above where we think we need to be to move vHOT and even to move measures potentially into the CNS.

Makes sense. Maybe just talk about your view towards the different endpoints like a vHOT versus a 5x sit to stand. And I know you've had a lot of discussions with the FDA as well on this. So maybe share that view as well.

Yes. So listen, we see vHOT and we're using vHOT as an intermediate clinical endpoint. So our clinical development plan has been different than others. We -- and I think we have a very robust and fulsome clinical development plan as it's laying out. We're first doing accelerated approval, and we have a registrational expansion cohort in ACHIEVE with 71 patients, and we are using vHOT as an early indicator, in other words, an intermediate clinical endpoint at 6 months. And our data previously has shown at 6 months, you move vHOT meaningfully. And at later time points -- and at 6 months and at later time points, it is indicative and predictive of improvement on other endpoints.

vHOT in our conversations with the FDA and with clinicians is not such a clinically meaningful endpoint. It's just about being able to open your hand quicker or slower. There are other more clinically meaningful measures. And so in our Phase III, which is now enrolling, we're using what we think to be a very clinically meaningful endpoint of 5x sit to stand. We would not use vHOT as a primary endpoint for Phase III. We've always said that. It's just not clinically meaningful enough. Something like 5x sit to stand, followed by other measures is meaningful, and we can talk more about that.

I guess just given the data we've seen now from Novartis with vHOT, do you think that changes how the FDA views vHOT as like an intermediate sort of endpoint? Are they less favorable there now, you think? Or...

Well, I would not -- listen, the FDA doesn't talk to us about other sponsors. But if -- in my own view, if anything, this makes the case that it's an appropriate -- it's appropriate as an intermediate clinical endpoint, but not as a Phase III. And so I think we feel good and confident about how we've done this, how we've organized the registrational expansion cohort, how we have laid out the statistics around the endpoint. And then again, we followed up with a Phase III that will be very robust with a much more clinically meaningful endpoint.

Understood. You're going to share some updated data from ACHIEVE at a couple of medical meetings here. I think it's World Muscle and AANEM later this month or next month. But just give us a sense of what to expect there and how to think about those updates.

Yes. So we had -- we recently announced that we would introduce 12-month data at AANEM and also at World Muscle. And I'd tell you, Mike, the reason we organized this 12-month data, we went through some trouble to do that is we were anticipating that Novartis was going to be saying they hit on vHOT and present and then they would present other functional measures. And we want to give people a chance to compare on functional measures that really matter. We're going to go forward and present that. And that will be 25 patients -- we captured 25 patients from the ACHIEVE long-term extension study that have been on dose for at least 12 months. And we are also comparing that -- we'll be comparing that to baseline, and we'll be comparing that also to natural history where we've done a propensity matching. And we'll be looking again at multiple measures.

You'll recall that when we had presented before, we had shown at the registration expansion cohort of 6.8 mg per kg that we had moved on QMT, vHOT -- QMT, quantitative muscle testing, multiple time function tests and also on MDHI and on the CNS subscales. But it was only 6 patients. And so people were -- man, it's great data, but it's 6 patients. Well, we're going to be presenting now on 25 patients.

Okay. Great. So we look forward to seeing that. And I guess maybe just to follow the conversation, you'll still have your ACHIEVE registrational cohort data in 1Q and the primary endpoint there is vHOT at 6 months. I guess, what are your expectations for that data set?

Well, that data set, we have guided to Q1 of next year. So that will be the registration expansion cohort. That will be the set of data that we intend to submit to the FDA as part of an accelerated approval package. And so what we would hope to see with that and expect to see with that is that we expect to see that vHOT has responded appropriately, that it is an appropriate intermediate clinical endpoint. And then what we have to provide for accelerated approval is trends across other measures. And that data we showed from the MAD was very clear that there were trends on 5x sit to stand, 10-meter walk run, et cetera.

So that's what we would hope to see from that data set. And then we will rapidly put that together and submit it as an accelerated approval package.

Makes sense. If we just go back to the confirmatory study, the Phase III HARMONIA study and maybe talk a little bit more about the choice of the endpoint there, the 5x sit to stand versus some other functional endpoints which you could have chosen?

Mike, this disease, I think you're fully aware, has a lot of heterogeneity to it. For some people, it's a balance issue. It's a strength issue. For others, it can be general myotonia, GI issues. For others, it CNS issues. So identifying an endpoint, and there's no endpoint that's ever got a drug approved in the field. So establishing for the first time a meaningful endpoint is something we put a tremendous amount of work into. And that is also going back to the natural history data, working with all the top KOLs and then looking at our own data and talking to the FDA.

5x sit to stand, I think, will become the kind of benchmark definitive primary endpoint in this field. It looks at when you have to stand up and get up and down from the chair 5 times, that's telling you about strength. It's telling you about balance. It's telling you about coordination. There are mental aspects to it. It tells you about fatigue. And it's also about core truncal strength. And it relates to -- and it's been shown in other studies to be correlated with the likelihood of falls, which is obviously a very big deal in terms of morbidity.

So that endpoint is one that we feel very good about. We've looked at our study from the ACHIEVE study. We saw that we improved on 5x sit to stand and what would be considered an MCID. And so we think we've got a really good endpoint, and we think we have obviously a very good shot at hitting that.

Yes, for sure. And can you characterize your discussions with the FDA around that endpoint and kind of what their view was?

Well, we've provided the endpoint and the justification and the rationale. And so I think we're aligned with the FDA on what we're putting forward.

Yes. Makes sense. And then just HARMONIA is ongoing. Can you talk about just the pace of enrollment there versus your expectations? And are there ways to sort of accelerate that at all?

We're moving very quickly on HARMONIA. So HARMONIA is the Phase III confirmatory trial for the U.S., but it's also a trial that will enable us to go to Europe and Japan. So it's a global trial. It is essentially our global Phase III. And it is enrolling. We had announced that we had initiated it. Enrollment is happening. Enrollment, I think, is going quite well. There's a lot of interest in that study. There's always been interest because I think the field has understood that uniquely to our drug, we have the potential to get to the CNS. And with the ability to get to the CNS, when 50% or more of the patients have CNS issues, doctors have been holding patients for this drug. And so we're not having any issues in terms of moving on enrollment. In fact, just the opposite, and we're moving aggressively.

Great. Okay. I guess any risk with the top line results about to enrollment in the study at all? Or...

Well, risk to top line like 5x.

I just see an inability to enroll the study, maybe people are less -- they don't like vHOT for some reason or there's a question.

I think -- no, not at all. In fact, I think if -- with the recent news, even with the other drug, people will be encouraged to come to this trial. So we don't -- we see this as actually enrolling. In fact, at this point, I'll say, Mike, I think we're the only company with an active Phase III trial in DM1. That's both a registrational expansion cohort that's about to read out in Q1, and we're the only company with an active Phase III. So that puts us in a pretty good place, I think, in terms of market introduction.

Yes. Makes sense. Maybe we can shift gears now to Z-Rostudirsen, that's your DMD program, exon 51 currently under priority review, PDUFA date January. So maybe just highlight some of the key learnings there, points of differentiation, et cetera.

Well, Z-Rostudirsen is for DMD, and it is for those individuals that are amenable to exon 51 skipping. That's the most prevalent category of mutations or subpopulation within DMD. What is special about our medicine is, again, the delivery. People have known for years that you can skip exon 51. The challenge has been getting enough of the oligonucleotide broadly and deeply to the tissue. And as a reminder for people with this disease, it's a devastating disease. There's drugs out there, but nothing is stopping the inevitable outcome and progression.

And for these boys, and it's a recessive link mutation, so it's all boys. By the time they're 6 or 7, they start struggling to get up off the floor. By the time they're 11, 12, 13, they're in a wheelchair. And by the time they're in their late 20s or 30s, their heart fails or their diaphragm fails.

So getting distribution to all these different tissues, including the heart, the diaphragm and broadly the muscle is key. And what we have done is take a look at one key measure, many measures, but 6 functional measures, one being rise from floor velocity. And what we found in our study which was a registrational expansion cohort study is that we were improving on rise from floor velocity.

In other words, they were getting faster. We saw improvement, in fact, on all 6 key functional measures in DMD. That just isn't done or seen. Now that -- because of that, I think we're moving really well with the FDA. Everything is about getting this product launched. The community is engaged and excited for it. And we feel -- I mean, we feel a real responsibility to get this to patients as soon as we can.

Can you maybe talk about the surrogate endpoint, which is dystrophin expression, what you've seen there and how it evolves longer term, which I thought was pretty promising for durability.

Yes. Thanks for raising that. So generally, in this disease, people have looked at dystrophin levels in muscle biopsies as a biomarker. And in exon 51 patients, it's likely the most difficult exon to skip. There's a little bit of natural skipping depending on the mutation. They're virtually at about 0.4% or 0.5% of normal dystrophin if you take a biopsy, so almost none.

What we found was that when we adjusted for muscle content at 6 months, we were at roughly 5%, 5.5% dystrophin. We took some biopsies even longer term, 4 biopsies were voluntary biopsies that were not part of the original protocol. And we found that we had roughly tripled what you would see in terms of dystrophin levels. And all of that was consistent with what we were seeing longer term. So at 6 months, just 6 months, you would not have thought rise from floor velocity would improve in 6 months. You wouldn't expect Stride Velocity 95th Centile to improve at 6 months. It's a disease that people would have expected since it's fairly slowly progressing. You would see take time.

At 6 months, we're seeing it even at those dystrophin levels, which means we're getting broad deep distribution through the tissue. But longer term, then we presented the last MDA, 18 and 24 months across these measures, and you saw continued improvement, and we even saw stabilization of cardiac function and of lung function, which was really important. And we were seeing that across boys that were ambulatory and also non-ambulatory. So it really points to you are building dystrophin over time.

And the important piece is nobody has ever really understood how much dystrophin do you need to start seeing functional improvement. And people would always ask us that. And we would say, we're going to be the ones that just might have the answer. And now we've seen even at fairly low dystrophin levels, 4%, 5%, 6% at 6 months, you're actually seeing functional improvement, not slowing of decline, but functional improvement from baseline. It's remarkable, and we're excited about it, obviously.

Yes. And maybe you can just put some of that data you've just shared into the context of your currently available therapy in terms of the profile, like dosing maybe touch on that as well?

Well, the current therapy is EXONDYS, and that drug has been on the market for about 10 years. It was approved by accelerated approval. To date, it has not been able to show statistically that it's having functional improvement. So -- and it's dosed on a weekly basis. And so there's a lot of, I think, disappointment in that treatment and basically the current state of treatments. And so we are roughly 10x in terms of dystrophin production compared to what they had shown. And our dosing frequency is once a month. So it's an infusion once a month, much more convenient. It's really hard to -- it's hard to compare those drugs, honestly. And the reason is our oligonucleotide is attached to an antibody fragment that is delivering broadly and penetrating the tissue.

Can you maybe share what you've heard from some physicians on the profile?

Listen, we have met with -- we've worked with a lot of the physicians, and we've met with so many. Those who have used the drug in the clinical trials, they see this as a foundational therapy. The notion that they would keep somebody on one of the older therapies like EXONDYS, they're very clear. We're switching them. And so I think the receptivity among the clinicians they're sitting up and they're positive about it, and they're very excited about it. And then you've got the patient advocacy community as well, and they're fully aware and they're in tune and alert to it. So we're feeling very positive about successfully launching this drug next year.

Can you talk a little bit about the Phase III sort of confirmatory study and the choice of the endpoint there? You talked a little bit about it earlier and why it makes sense, but maybe just...

Ourselves and other sponsors of DMD clinical trials have kind of all come to the conclusion rise from floor velocity is a meaningful measure. It is something from -- in just in practical terms. As I mentioned, when you -- when people start -- when parents first realize their son is struggling to get up off the floor, they take them to the doctor and they get diagnosed. And then what they monitor is the time it takes for them to get up off the floor. And there gets to be a point in time, say, over 10 seconds where it starts to become very predictive, okay, when they hit that sad threshold, they're going to be in a wheelchair in a fairly short period of time.

So it's a -- there's no question of it's a very clinically meaningful measure. So that was selected as the primary. And then we have a number of secondaries. And dystrophin is not part of that. We've moved past dystrophin, done with biomarker. Now let's talk about efficacy. Rise from floor, Stride Velocity 95th Centile, NSAA, which is an ambulatory measure and others, pulmonary measures, cardiac measures, all of that will be part of and some patient-reported outcomes part of the Phase III. It's an 18-month endpoint and placebo controlled. And it's a global study.

Okay. Great. With the upcoming PDUFA date in January, I don't know if you can mention any kind of interaction so far with the FDA, your expectations around an AdCom?

Well, we're having the usual interactions that you would have getting to this point. We're not going to comment on those just to keep all of that out of respect to the process for the FDA. When we received the filing -- acceptance letter from the FDA, it was great. And that letter gave us priority review. And it also said that they did not expect an AdCom. So it was a positive. I like reading that list.

Yes. Great. Obviously, PDUFA date in January, you could be launching next year. So maybe touch on some of the launch preparations so far.

Well, listen, for launch, launching is for the first time as a company, and you need people that know how to do it, and they have to be on a mission, and we are. The areas of attention, regulatory execution, obviously, and that's happening. Other areas is manufacturing and supply chain execution. We brought in a team to do that, and we're executing on that and getting our inventories built and ready and scaling our processes.

And then the other big part is commercial. And we -- I've mentioned before, we brought in Johanna Friedl-Naderer to lead our commercial organization. Almost 2 years ago, she's been building and preparing that organization to launch a rare disease drug, which she and her entire team have done multiple times. So that preparation is in place. We've got the market access team in place. We've got patient services leadership in place. We have our medical affairs team in place. So market access preparations are kind of key at this point, and all that is moving per plan. It's a lot of work. It's a lot of fun, and it's happening.

Yes. Great. And can you talk a little bit about the strategy? I know it's -- you haven't quite fully gone there yet, but just your early thoughts on the strategy for the launch.

Well, listen, I think one of the beautiful things about doing this and being in rare diseases is that you can actually do it in a very capital-efficient way. And I'm going to let this guy to my left say a few words about that. So...

Yes. I think when you look at the Dyne portfolio, just taking a step back with the FORCE platform, it is something that is amenable to multiple products. So we have 7 products in the clinic with DM1, DMD, the other exons, FSHD. From that, we can scale a commercial organization that's largely seeing the same centers for all of these drugs and the manufacturing. We've got the same fab, same linker, oligochemistry. It's pretty much the same, just a few tweaks runway. So there's a lot of opportunities to scale a business unlike anything I've seen in the 30 years that I've been in biotech.

So from a capital and a resource standpoint, it's very capital efficient, and it's something that we think can provide patients and investors a trajectory of growth into the next decade that will be well above our peer average.

Makes sense. For the launch, do you expect sort of a pent-up demand just given the profile you've seen and the feedback you've gotten on it? Do you anticipate a lot of switching early? Or just how is that -- how do you think that all kind of plays out?

I think the demand is absolutely there without question. There is -- the unmet need is profound. So the demand is there. I think we're predicting this to be what you often will see in rare diseases in terms of the launch, meaning the first year is gated largely not so much by demand in this case, but gated more by coverage. It's just -- there's just -- it's kind of controlled -- the pace is controlled largely by the payers.

Now often in rare diseases, the challenge is finding the patients. DMD, the patients are known across the United States. It's about 1,600 they're known. The reimbursement pathways are there. So a lot of those kind of hurdles are not there. But you should see a launch that will be, I think, successful, but it will be a typical kind of rare disease affected by payers for a period of time, which we'll work through. And we should have a very good launch.

Yes. Makes sense. I wanted to ask you about your other exon skippers. You have several in the pipeline. John, you mentioned exon 51 is probably the most difficult to skip. You've had very promising data there. So how do we think about the rest of the pipeline, time lines, how fast can you move those forward?

Well, maybe I can let Erick start with how -- when he first joined the company, the first thing he did was start talking about, we've got to build a franchise in DMD. So maybe you can comment a little bit on.

Yes. I'd say for me, personally, I'm very excited about the DMD franchise. It's something that I noticed was a disconnect in the way the market viewed the stock. It is something that when you take all of the patients that we're targeting, you start with 51, that's 13% of the boys. You get the other 4 exons, that's 39% of the boys. So in terms of how we're going to get this to market, obviously, we found some money in the budget to get CMC and IND-enabling tox studies this year in advance of any discussions with the FDA. We did not want to lose any time getting these drugs to these boys. It's very important for us.

Obviously, the most important thing is to get exon 51 approved. Once we get that approved, we will then have discussions with the FDA about finding the appropriate development pathway forward. We think the best approach is to do some kind of a basket trial where you would have 4 actives and 1 placebo. I think if you were to try and do these on an individual basis, the incidence and prevalence probably isn't big enough to run randomized trials. You just would run out of patients. So a basket trial seems like a great way for us to get this to all the boys that we can, and we will have those discussions after we get approval and knock on wood for 51 next first quarter.

Mike, I really believe that we have a chance to be the leaders in DMD in the field. I think we've -- I think the exon 51 is step one and it has demonstrated that we actually can see functional improvement in places where people haven't seen before. we owe it to our shareholders and to the community to make that happen, and we're going to do our very best, and that is expand that franchise as rapidly as possible. And that will put us in a leadership position in DMD. And then right behind that, we'll obviously want an even bigger market.

Yes. And we'll have some data on preclinical work in a couple of weeks, put that press release out about 2 weeks ago. So looking forward to that.

Yes. And then maybe, Erick, you could just touch on since you have this efficient strategy going forward, just current cash and how far that gets you.

Yes. Right now, we have $1.3 billion of cash pro forma as of the end of the last quarter. We had a very successful raise, which you guys were instrumental in helping us get that done. So thank you very much. We believe that we have a unique opportunity to capitalize a company to do one build for multiple launches, and we are going to pursue that with the most capital-efficient means possible.

Great. Looks like we're just about out of time. So why don't we end it there. John and Erick, thanks so much. Really appreciate your time today.

Thank you.

Thank you.

All right. I guess we can get started. My name is Peyton Bohnsack. I'm the Vice President here on the biotech equity research team at TD Cowen. We're pleased to have here Erick Lucera, the CFO from Dyne, and we're looking forward to hearing all the exciting progress you guys have made.

Great. Thank you very much. We'll be making some forward-looking statements. So with that, here is the disclaimer. My name is Erick Lucera. I'm the CFO of Dyne Therapeutics, and I'm very excited to be here. I've been a client of Cowen's for almost 30 years now, 15 on the buy side and 15 as a CFO. I've been at Dyne for almost a year. And if you asked me, well, why did I come here? One is obviously to prepare for the commercial launch, and having been through a couple of other commercial launches, it's one of the best experiences you can have in your career. But also as a former investor, I still think like an investor, and when I saw the Dyne opportunity, I thought it was one of the most compelling opportunities I'd ever seen in those 30 years. So with that, I'm going to tell you the story as we see it here at Dyne.

We think we have a real unique opportunity to build an incredible and unique company really based on what we call the FORCE platform. There are not a lot of companies that I've seen in 30 years of biotech that have such a compelling platform, and we'll get into that through the course of this presentation. We think we have a company that can build a really long 10-year-plus run in rare disease and muscle based on the 8 programs that we have in our pipeline. One of the things that makes this such a unique platform is the commercial leverage that we're going to get from going to just muscle centers, seeing the same docs for all of our products. The fact that this platform, the FORCE platform is based on largely the same antibody fabs, largely the same linkers, very similar chemistry, so there's a lot of CMC and inventory leverage that this platform gives us.

If you were to think about 2025, it was really the year that we clinically validated our platform within -- with data within 2 programs, DMD and DM1. 2026 is going to be a great year for Dyne as we transition to a commercial company preparing for our launch of the DMD asset in the first quarter of next year. The next year, in 2028, we hope to be launching our second product in DM1. And then followed that with several other programs within FSHD, DMD and Pompe, which we think can extend the growth profile of the company in a very derisked way for a very long time. So we're very excited about the pipeline that we have based on this platform.

So what exactly is the FORCE platform? I think for those of you that have been in biotech as long as I have, the challenge in biotech has always been delivery of sufficient quantities of genetic medicine. Dyne was founded on the belief that a fab could do that without disrupting what we call the iron homeostasis and without causing anemia. And we can get these fabs to multiple tissues. And in rare diseases that affect the muscles, getting this broad and deep distribution to multiple tissues is what allows us to show the functional benefit and to do so without anemia. And as I mentioned, in 2025, we did this in 2 disease states, DMD and DM1.

So just real quickly, some of the preclinical data that we've shown many years ago shows the delivery of the oligonucleotide to multiple tissues that enable this functional benefit. You see the FORCE platform delivery versus a naked PMO, and you see significant differences in the ability for us to get to the diaphragm, to get to the heart and then get into the CNS areas in the cortex, the deep brain and the cerebellum. And we believe this penetration into the CNS tissue is what allows us to show some of the functional benefit that we're getting. And this makes the FORCE platform really unique in the biotech and so special and something that, again, that we validated in hundreds of patients in humans.

So the data that we've shown to date, and we'll get into it in a second, shows this broad distribution leading to functional improvement, validating our pipeline, not just in the 2 products that we've shown, but in all the others because they're all based on the same platform.

All right. So now let's get into some of the data here. All right. The first program that we're going to discuss is our DMD program, called Z-Rostudirsen for exon 51 skipping DMD patients. This is a devastating disease that despite some approved therapies, really has significant unmet need. Today's therapies that are on the market merely slow progression at best. At 6- to 7-year old, a lot of these kids that have this can't get off the floor. By 12 to 14, they're in a wheelchair. One of the largest causes of eventual morbidity and mortality then is what happens in the cardiac and in the diaphragm, the failure that will emerge in the 20s. And we've demonstrated that today already, and you'll see even more of that next week at the MDA conference.

In terms of what we're going after, exon 51 is one of many of these exons that's out there. It is the most prevalent mutation, and it's the toughest to skip. So that's why we went after it. We've never been afraid of a challenge. So we went after the hardest one and the biggest one. The first trial that we designed was called the DELIVER trial. It was a multiple ascending dose trial where we centered on our 20 mg dose. We're using this for accelerated approval, and then we'll be doing a confirmatory trial. This is set to be filed in the second quarter. We'll be filing our BLA and beginning the Phase III at the same time.

For the REC, dystrophin has been a surrogate marker for us, and we showed some data in December that I think was really quite compelling. We showed a sevenfold increase from baseline, very statistically significant, as we say, 0.00001 p-value. And then we showed a 10x difference from the current standard of care. Again, this is just dystrophin. But I think what made our data set really compelling was not just the change in dystrophin from baseline or versus standard of care, but the functional data that we showed along the way. We had 6 functional endpoints that we showed data on in December. And as we were leading up in this trial, we said the goal is to show statistical significance in dystrophin and trends in the functional data point. And what we ended up showing actually was 2 of these 6 endpoints. The all 6 showed a positive trend, 2 of them were even statistically significant, even though we didn't power the trial to show stat sig.

The first set of data that I'm going to show you here is Time to Rise Velocity and the 10-Meter Walk/Run test. And as you can see here, there's a significant improvement in Time to Rise Velocity versus placebo. You can see the placebo also dropping as expected while the patients on drug continue to show improvement. On the right-hand side of this, you'll see patients measured at 10-Meter Walk. And again, you'll see an increase in the drug arm versus a decline in the placebo. Again, this is data that no one has ever shown before with respect to functional improvement.

The next 2 graphs we're going to show are relative to ambulation. The North Star Ambulatory Assessment again shows an improvement with Z-Ros and a decline in the placebo. And then finally, on the right, SV95C shows another [indiscernible] of the drug versus the placebo. And in this case, the placebo did improve, but was biased by one patient. Otherwise, we'd have expected a decline.

Finally, the last set of data that we'll discuss is the PUL, Performance of Upper Limb, which again showed an improvement versus placebo. And finally, the Forced Vital Capacity. If there was one data set that I'm most excited about, it's the performance of FVC because this is really where the heart and the lung starts to impact the patients towards the end of their disease. And the fact that we've been able to stabilize this versus placebo is really profound.

So to recap the data on the simple chart here, this is really something that we're very proud of. We've got 6 measures here where we show improvement versus placebo at 6 months and the durability of this out to 24 months versus baseline. Again, we've got tissue penetration throughout the body. You've got 6 measures that measure multiple different arms, legs, organs, et cetera, and they're all showing improvement at 6 and 24 months. So this is really something that is truly unprecedented, and we do think will be transformative for patients.

When this data was released, our team was just inundated with messages from the field, from the patients, from the physicians. They've never seen anything like this. So we're really excited about this.

Finally, what about safety? Our safety continues to be very strong. Again, we're taking this for accelerated approval. In addition to the trends -- in addition to the stat sig dystrophin, the trends and function, we also need to show a favorable safety profile. And you see that here. The TEAs that we've seen have been mild to moderate, and we've got 1,400 doses that have been administered. In some patients, we've got safety out to 36 months. So very compelling.

And then finally, as we mentioned, we're pursuing accelerated approval, BLA to go in this quarter. What do we need? We think this will be a best-in-class drug. We think that we've shown a very robust and stat sig improvement in dystrophin, a very favorable safety profile, functional improvement across all 6 endpoints, favorable dosing. And as I said, we're on track to file in the second quarter. We're also on track to start a confirmatory Phase III. As you guys know, for accelerated approval, you have to do a confirmatory Phase III. That's all on track to start this quarter. And we think that getting this will be a major catalyst for this drug.

So in terms of the commercial opportunity, this is one of the best markets that you could hope to go into. The patients are identified. In fact, the advocacy is very strong. There's nothing more -- there's no patient advocacy group better than a DMD mom. We know where these patients are. The advocacy is strong. The advocacy groups are very strong. It's also a concentrated market. You can see here in the middle of the trial, we've got 80% of the patients are at about 100 different centers in the U.S. So that means we can have a very capital-efficient sales force. We're not going to need hundreds or thousands of people. We're not doing Super Bowl ads or anything like that. It's a very focused rare disease specialty pharma kind of sales force.

Reimbursement is also very well known. So again, another check in terms of what would be a great market to launch into. It's a great market when you have a very motivated patient population defined, you know where they are, reimbursement is in place. And we have a great team that is ready to launch this. I can say from my standpoint, being in biotech, we've got people throughout our organization who have done this before. And they've done it before at the same levels, right? A lot of times you see people at small companies, they get promoted into new titles. They have new responsibilities. We have an organization of folks that has all done this with the same title before. And this is why we're able to take on so many different drugs at the same time is that we have people that know what they're doing.

The team that we have from a commercial standpoint is led by Johanna Friedl-Naderer, who's been doing rare disease her whole career. She launched SPINRAZA at Biogen and has surrounded herself with a team of folks that have very specific rare disease launch, very specific commercial experience. They've been involved in SPINRAZA and other rare diseases. They know the physicians and they know how we get the reimbursement. They know how we get the patients on drugs.

The way we're now talking about DMD is a franchise. You may have seen on Monday, we announced that we're going to pursue 4 more exons beyond exon 51. So we truly view the DMD portion of the Dyne story as a franchise, not just exon 51, but 4 others. The movement into these 4 others will allow us to triple the total addressable market. There's about 1,600 patients with exon 51. With the other 4 exons, again, we're tripling that into the 4,000 to 5,000. Again, established reimbursement. The other thing about this is, from a product standpoint, it's the same fab, it's the same linker. The PMO chemistry is the same. The reimbursement is in place. It's the same doctors, the same centers, the diagnosis is the same. So getting from exon 51 to these other 4 products is a very high probability of success.

So we think this is much different than a traditional sort of preclinical program, and that we've really substantially derisked these other 4 exons, these other 4 programs with what we've done to date.

So how do we create shareholder value in DMD? Again, this is one of the most attractive markets that I've seen in 30 years. It is a significant unmet need. The population is identified. They're motivated. Reimbursement is in place. It's a concentrated population, which leads to capital efficiency for the commercial organization. Our assets are wholly owned. We think they have best-in-class profiles. And we think given the data that we've reduced -- or produced to date that it's all derisked.

All right. So let's move to the next asset. So beyond DMD, we have DM1, myotonic dystrophy, another large market opportunity. In this case, this is complete white space. There's really no treatments available. It is a similar size as the whole DMD franchise. So another very large untapped opportunity for us and something, again, with no approved therapies. DM1 is caused by DMPK mutations leading to missplicing of the RNA, then creating muscle weakness, myotonia and then there's CNS manifestations. And we believe where we're differentiated versus other potential products is with respect to CNS.

The ACHIEVE trial that we've been running has been designed for accelerated approval. We ran a MAD trial and then selected our dose going forward for the registrational cohort of 60 patients, which we're in the process of enrolling. We just released earnings on Monday, as some of you know, and we're still on track to wrap this enrollment up in the second quarter of this year. The primary endpoint is vHOT, video hand opening time. And we think that this is going to be a great endpoint for us.

So what did we have in the -- what data did we show in the MAD? We showed impact of changing DMPK, which is the foundational pathobiology and a reduction in that and a correlation of improvement in splicing. So you can see how strongly we did relative to placebo on Slide 25.

Slide 26. We showed robust improvement in vHOT, as I mentioned, at 6 months and again at 12 months. And vHOT is what we call an intermediate clinical endpoint for accelerated approval. It is very predictive of downstream functional improvement, and we've shown that to date.

So beyond vHOT, here on Slide 27, we show broad functional improvement, again, at 6 months and continued out at 12 months in areas of muscle strength, MDI, patient outcomes, et cetera. And each one of these, you can see an improvement versus placebo.

Finally, as I mentioned, the CNS component of this is very important. Here's a slide here that shows CNS-related MDI subscales. So again, in terms of sleep, fatigue, communication, behavior, pain, et cetera, we're all showing, again, sustained improvement in these CNS endpoints. And these are really important for driving the symptoms that the patients have. Our drug was designed to get to the CNS and designed to show these things. So we're not surprised to see them. And we believe when we're in the market that these will be a significant differentiator for us. Nobody else has shown these kind of CNS improvements.

And then again, like DMD, we have a very large safety database on DM1. We continue to show a very strong safety profile. We've had 1,000 doses on 93 patient years and no serious TEAs. So again, another very favorable safety profile. And again, this just shows the benefit of our platform.

Okay. So then just sort of hitting on some of the points that we mentioned before. In 2025, we validated our platform with clinical data in 2 diseases in human beings. This year, we're transitioning to a commercial company for the launch of DMD in 2027, and hopefully, the launch of DM1 in 2028. Beyond that, FSHD will be the next product that we put in the clinic. And then beyond that, we've got the 4 other exons and Pompe disease. So a total of 8 products, all wholly owned, all based on the same platform, all of which has been derisked.

And just wrapping up here on the pipeline here. Again, this just shows how things are going to play out over the next couple of years. The team is very excited, and I'm very excited to be here at Dyne so that's it.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tess Romero, and I'm one of the senior biotech analysts here at JPMorgan.

Our next presenting company is Dyne Therapeutics, and presenting on behalf of the company, we have President and CEO, John Cox. John, over to you.

Thank you, Tess. We'll be making some forward-looking comments. We move the slides forward.

I must say, I think there are very few biotech companies that can say they have 2 transformative late-stage assets, both in areas of significant unmet need, DMD in our case and DM1, that have near-term value drivers such as submitting our first BLA in 2026, completing our second registrational trial in 2026, launching our first commercial product in Q1 of 2027 and launching another product 1 year later. I think we can make an argument that we possess today the best-in-class platform for delivering genetic medicines to the tissues that matter in neuromuscular diseases. I'm going to show you data that I think supports that statement.

We have a balance sheet with a cash position of over $1 billion. And I'll remind you that we wholly own our assets. 2025 was the year that we clinically validated our platform in humans for neuromuscular diseases. 2026 will be the year we transform the company to become a fully integrated commercial biotech company. And I think we are now positioned to create value for our shareholders, not just for the near term but for the long term.

Now one of the great challenges in biotech has been the delivery of sufficient quantities of genetic medicines to muscle and to the CNS. The genetic sequences have been known. The issue has been delivery. Dyne was founded on a belief that you could take an antibody fragment, just a fragment of an antibody, target it to the transferrin receptor, a receptor that transports iron into cells, and use that Fab as a delivery vehicle to muscle, to CNS because that transferrin receptor which normally transports iron is found on all of those tissues.

It was founded on that belief. But a little bit more than that. So people had used monoclonal antibodies to target that same receptor, but it tends to bind that receptor for an extended period of time and disrupt the iron transport for a period of time, which causes anemia and limits the kind of dose that you can get to. So if you want to get sufficient doses of genetic medicines, our scientists have designed this type of Fab, which you see in the red and the blue, with a linker, both of which the Fab and linker are the platform. And below that, we have a payload. We can use any number of payloads, siRNA, ASOs, PMOs, even enzymes, to deliver those payloads with the same platform to a multitude of tissues, including CNS, cardiac, skeletal, diaphragm, the tissues that absolutely matter.

And last year, I believe, at the end of the year, in particular, we validated this platform as a delivery vehicle for -- in neuromuscular diseases for 2 different diseases and with 2 different genetic payloads.

Here, I just briefly want to highlight the distribution feature. We've shown this data in the past, but it is nonhuman primate data. And what you see here is oligonucleotide delivered with the FORCE platform to the diaphragm and the heart versus PMO oligonucleotide delivered without the FORCE platform. In the blue is obviously with the FORCE platform. Tremendous amounts of PMO delivered to these tissues. We've taken it further to show that kind of distribution profile into the CNS. And unlike intrathecal delivery using the 400 miles of vasculature in the brain and the transferrin receptor, we're able to deliver ASOs as you can see, profoundly deeply and broadly to the brain. It is about -- what makes this platform so special is the depth and distribution that it achieves across tissues.

We believe that what we showed in December was validating the platform in humans with our first medicine called Z-Rostudirsen. We had this foundational belief as a company, maybe a second foundational belief was that if you achieve the broad and deep distribution, you just might see, for the first time, functional improvement in some of the toughest neuromuscular diseases. And that is what we have seen with Z-Rostudirsen. It is validating of our platform. And frankly, we think is validating for every program in our pipeline. And I think it represents a new reality for DMD. And I think it's our historic time for neuromuscular diseases. And we're going to talk more about that data.

Let me touch on the pipeline. What is common about everything in this pipeline is that in order for you to address these diseases, you need broad, deep distribution. Our platform is designed to do that. And we think the data we show with Z-Rostudirsen applies now to DM1. It is a read-through. That is our second program. But it even is maybe even a more meaningful read through into the other exons that are in the pipeline. We think the probability of success has been improved across everything in the pipeline because every program is using the exact same platform.

You can see the other exons for DMD. Those are drug candidates that we have in place. It's the same platform, the same Fab, the same linker, the same manufacturing process, we're just changing the nucleotides. And what's important with adding those exons, we have a chance to create a franchise. And that franchise essentially triples the size of the market for DMD. Beyond that, the next program that we intend to have in the clinic is FSHD, and beyond that, Pompe disease.

Now let me spend a little bit more time specifically on DMD. And I want to talk about this disease. It's a devastating disease. I hope everybody knows about the disease Duchenne muscular dystrophy. Today's therapies, at best, offer a slowing of progression. And I -- and mostly, they fail to statistically demonstrate that. More practically in the disease, you're talking about muscle deterioration, but even to get more pragmatic about it, for these families and for these boys, what you see is by the time they're 6, 7, 8 years old, they are struggling or can no longer get up off the floor. By the time they receive -- get to 12, 13, 14, now they're in a wheelchair. And ultimately, what affects their life at the end, by the time they're in their late 20s or 30s, is the cardiac or the diaphragm failure. You have to get to all of these different tissues. There is no therapy that is meeting the needs of these patients today.

Exon 51 is one type of mutation that's most prevalent. It is the most prevalent in the DMD population. It also could arguably be called the toughest where you have very difficult time with exon skipping. That's why we took it up. We think it is the right challenge for our FORCE platform, and I want to show you data related to that.

We conducted a trial that we call the DELIVER trial. In that DELIVER trial, it consisted of a multi-ascending dose portion. We completed that and ultimately selected the 20 mg per kg dose to move forward with a registrational expansion cohort. It's a design for accelerated approval, followed by a confirmatory trial. The confirmatory trial will start in Q2 of this year, and the registrational expansion cohort has been completed. And so we are targeting Q2 of this year to file or to submit the data that I will be showing you shortly.

The bar for accelerated approval is dystrophin. That is the surrogate marker. That is what everybody has always used. I'll be brief on this because it's very straightforward. What we showed is a sevenfold increase from baseline. Whether you measure it muscle adjusted or not muscle adjusted, content adjusted, it doesn't matter. We have, far and away, hit the bar. And if you question that, just look at the p-value of 0.0001. The dystrophin levels at just 6 months are roughly 10x of the standard of care in the market today.

But what really matters to the patients is function. And I really believe this is maybe the first time in this field that in DMD, that people can move beyond talking about a surrogate marker and dystrophin and start talking about efficacy. It's a big moment in time.

Here are some functional measures, Time To Rise Velocity compared to placebo. Placebo declines, as you would expect. These patients are getting up off the floor faster. You don't see that in DMD. The same is true for the 10-Meter Walk/Run. If you take it further with ambulatory measures, NSAA, or Stride Velocity, in both cases, you see an improvement for those patients that are on drug. You don't see that in this disease. We see placebo decline in NSAA. I'll point out that placebo did not decline in Stride Velocity. We think that is biased by a single patient where we had an absolute remarkable increase in a particular placebo patient. Regardless, you see a Stride Velocity improvement.

And I should have pointed out on the previous slide that we actually had p-values of less than 0.05. The study is designed for accelerated approval. We just -- it wasn't designed for statistical significance, and yet that's what you saw. And we were even meeting the MCID on one of those measures and approaching it on another. None of that would have been expected.

And then there's a couple of measures that relate not just to ambulatory, but nonambulatory patients. Performance of upper limb function, you see an improvement against baseline as well. And very importantly, lung capacity is measured by Forced Vital Capacity. That is a measure that is extremely important, particularly as boys move into the wheelchair. Maintaining lung capacity and failure of pulmonary is often what leads to morbidity.

To see a stabilization of lung capacity is profound. You see the decline with placebo, but a stabilization. So all of those functional measures have moved.

And I just -- I really want to pause on this slide for just a moment because I don't think anybody has presented a table ever in DMD like this. We put on the left side the breadth of endpoints that were just covered in our top line data. All of these are critical measures for these patients. The breadth of the population, both ambulatory and nonambulatory that were covered; the breadth of muscle systems that have been included or captured by these endpoints. At 6 months, we saw functional improvement versus placebo in every single one of those measures. And it was durable. At 24 months, we had functional improvement versus baseline in every single measure.

People use the phrase unprecedented or transformational in our field all the time. This is unprecedented. I don't know what other people mean by it, but this is unprecedented, and I believe it will be transformational for this community.

The safety profile we should cover for accelerated approval, you need to show a favorable safety profile. I think we've done that. You can see that we've had 113 patient years of exposure; most related TEAs were mild or moderate; patients have been exposed up to 32 -- or 36 months; and well over 1,000 doses administered. So safety profile, we consider quite favorable.

I'll leave this with you in terms of having a compelling profile for accelerated approval. We think it meets the bar. We look forward to getting it in front of the FDA. And when you have time, take a look at the quote at the bottom. This is representative of how the physicians and the community are feeling about this important medicine.

So that leads us to we think we have a product here, and we believe we do, and we're preparing to commercialize and launch this product. We'll submit in Q2. We intend to launch in the first quarter of 2027. We've built a management team. And when introducing a rare medicine, I've done it a few times, virtually everybody on our team has done it, you typically run into certain challenges from commercialization. One is identification of patients. It's a rare disease. Another is there's very little advocacy or it's in its infancy. There's limited treatment centers for the disease, and the reimbursement pathways are not established. You have to do all of that.

Let's look at this disease and how we've characterized it. 1,600 patients with exon 51 skippable, minimal DMD, the patients are known. We can even categorize these patients. There is an active and educated patient community and a strong advocacy organization in place. Every single patient has an advocate. It's called a parent. And they want the best possible drug for their patients, for their boys. 80% of the DMD patients are at the top 100 centers. And then finally, the reimbursement pathway, it is known, and the pricing has been established at roughly $1 million a patient a year.

You just don't come into commercial markets with that kind of opportunity typically in rare diseases. And then I think that puts us in a position to create a capital-efficient commercial infrastructure designed to deliver this transformative therapy. We can build that. In 2025, we built a management team to do it. They know how to do it. We've got Johanna Friedl-Naderer here, who's our Chief Commercial Officer. She's done it many times in her career. And beyond that, a medical team, including Doug, who have done it as well. The initial field team members are in place. The CMC is in place, manufacturing is in place. We have the supply chain experience and expertise, and that is in place. And we are preparing for our first launch. We have all the ingredients, I believe, for a successful launch in 2027.

And I'll just quickly point out that the other exons, as I mentioned before, we have those as drug candidates. We're not stopping with exon 51. Our intent is to move those forward and create a franchise, and in so doing, we essentially triple the market size in DMD.

Now I think this leads to another slide that I really would love for you to hang on to. This slide is really meant to -- it's really meant for those interested in a not only near but long-term sustained value creation with DMD. These are the reasons to believe we can do that. You can see the attractive market characteristics. I just covered it. We are positioned wholly owned assets, best -- this is a best-in-class profile. We have a capital-efficient model. We've derisked the expansion opportunities, and we have the team in place to launch this product in early in Q1 of 2027, okay?

Now let me move on briefly to the second program because we're not stopping with DMD. DM1 is right behind that. And we think that, that is also being clinically validated, but let me talk a little bit about the disease.

It is a much larger market than DMD. There are no approved therapies whatsoever. It's caused by a mutation in the DMPK gene that leads to misplacing of RNA in the nucleus of cells. It's a nuclear spliceopathy, and that's important to remember that, and I'll explain why.

The result of all this misplacing is broad, clinical manifestations that include muscle weakness, myotonia, GI, cardiac, pulmonary issues and very importantly, CNS issues. Often, that is the biggest issue for these patients.

We selected an antisense oligonucleotide as the payload for Z-Basivarsen because of its ability to get to the nucleus. So to address the broad manifestations of DM1, one must deliver broadly to muscle and to the CNS and to the nucleus in the cells of those tissues. The FORCE platform with the ASO payload has been intentionally engineered to address the core pathobiology of DM1.

Our trial, the ACHIEVE study, I'll touch on that briefly. Like DELIVER, the ACHIEVE study was designed for accelerated approval. We started with a multi-ascending dose study to select the optimal dose. We dose escalated, saw proof of concept, not just in muscle, but in CNS at the 6.8 mg per kg dose. We selected it. Doug made that decision. And we initiated a registrational cohort that is in process of 60 patients. The primary endpoint is an intermediate clinical endpoint. We call video hand opening time, which represents myotonia, as well as -- and it also represents kind of early clinical benefit, which should be manifested in trends and other functional measures. And we're on track to complete enrollment of that study in Q2, early Q2 of 2026.

Here's a little bit of the data. DMPK knocked down 33%. This is at the 6.8 mg per kg, and splicing correction of 25%. I don't think you're going to see that data with other medicines out there. We are getting to the nucleus. This is addressing the core pathobiology, and that's the molecular evidence that we're doing that.

In terms of vHOT, that is an early marker. And you see at 3 months, we show improvement or a reduction in the time in video hand opening time. It increases further at 6 months and is sustained out to 12 months in our study so far.

But more important than that are the key critical functional measures. And this is what we highlight here. 5x sit to stand is an excellent time function test. It takes in the truncal strength, core strength, leg strength, et cetera. It is an important measure, and you see 5x sit to stand functional improvement relative to placebo and relative to baseline; 10-Meter Walk/Run the same story.

Quantitative muscle testing, which is a strength test, has really got people's attention because what you saw there is that at 6 months, we increased strength across upper and lower measures of the body by 10%. That is an unbelievable number. And then it increased to 20% at 12 months.

And then MDI is a patient-reported outcome, a total measure of kind of quality of life, but it also really has a set of -- a subset of measures that touch on CNS. It is the first place that we start to see some indications of CNS impact, and that's highlighted here.

MDI subscales, you can read the measurements. These are the types of CNS-related impacts that frankly affect their lives tremendously. At 6.8 mg and only when we were able to get to that dose did we see that kind of improvement across these measures. Now with 6 patients, what we want to see is do we see that in the registrational cohort and in the multi-ascending dose, long-term extension study. That's the data that doctors are really intrigued by, and I don't think anybody has ever presented data like that related to CNS improvement for these patients.

And then finally, I'll just touch on the safety as well. And with this study, we also saw a very favorable safety profile. The over 1,000 doses, 93 patient years. And no -- most TEAs were mild or moderate of intensity. So safety profile being a favorable one for this disease as well. Not surprising as we're using the same platform.

Now let me just touch a little bit on kind of a final couple of points. You can see the kinds of events in front of us. When I look at 2025, I see 2025 as the year that we validated our platform with absolutely unprecedented clinical data in 2 different diseases. In 2026, we will transform from an early biotech company to a late-stage, fully integrated commercial company. In 2027, we intend to transform the DMD market. And in 2028, we intend to do the same thing for DM1. We're determined to make a difference for these patients. And we're intent on creating long-term, sustained value for our shareholders. Thank you very much.

John, do you want to introduce your team members?

I do. Our Chief Medical Officer, Dr. Doug Kerr; and our Chief Financial Officer, Erick Lucera, are here with me today.

Great. Great. Well, thank you so much for the presentation. So we're going to dive into about -- let's see how much time I have -- about 15 minutes of Q&A.

So just to kind of talk a little bit big picture here to start. You talked a little bit about the strategic direction of the company, John. Is it fair to say that DM1 and DMD are equal priorities for Dyne? Has DMD kind of risen a little bit higher up in the priority list in terms of where you're going to really invest your capital? How should we be thinking about that?

Well, I think they're both absolutely high priority. And it's not either-or at all. I think you know, Tess, investors have been very focused on DM1 because of the market size and the unmet need there and there's nothing. We're very excited about DM1. And we just -- we've laid out the time line. DMD is the most near term. It's the most proximal in terms of commercial opportunity. And the unmet need there is so severe and I discussed it. So fortunately for us, we've -- with Erick and under his kind of leadership with finance and kind of capital raising and capital allocation, we have positioned ourselves to be able to fund both. So we're not going to do anything that's not a priority, both are our priority, and we're going to get them both done.

Okay. And can you talk a little bit about the manufacturing capabilities that you have at the company? And how this might need to evolve to support a commercial launch? And how should we be thinking about gross margins and overall spend there?

Yes. Let me start, and I'll turn it over a little bit on the margins to Erick. But -- so we have had a manufacturing supply chain in place. We have -- and it has been operating well. It's a global supply chain. That supply chain is something that we have been validating, and we've also been scaling. And we'll continue to scale up as the products are being introduced, and as you see the volume start to increase. It's all being done per plan. The CMC aspects of the business have been laid out with a program and a plan and an intent to have those prepared for the filing, and they're all on schedule to do that. Process validations, analytical method qualifications, all of that activity is in process or in place and ready and on time. As far as margins?

Yes. Thanks, John. We believe that at Dyne, we will have a very competitive gross margin profile, similar to what you see for other rare disease antibody companies. We have a great team in place that is working on continually finding ways to find efficiencies. And the other thing, most of our platform has the same Fab and same linker. So we're going to have a lot of ways to leverage the spending that we have on manufacturing across the pipeline over the years.

Okay. And you showed us the registrational expansion cohort data that you collected for Z-Rostudirsen in December. Has the pre-BLA meeting been planned with the FDA? And can you just remind us specifically when did the FDA sign off on dystrophin as a potential surrogate biomarker for AA of this product? And how much safety follow-up will you have to support the BLA?

Well, let me start that as well. I'll make a general statement about regulatory interactions. We generally -- we don't get into the kind of the play-by-play of the interactions, but I will tell you that we have had breakthrough designation. That opens up routine dialogue with the FDA. We've had breakthrough for both programs for DMD is what you're talking about. All of the usual activities are either done or active or in process, including pre-BLA and so on in various meetings. So everything is kind of on track for what we want to do regulatory-wise.

The view on accelerated approval, we have had -- we've had kind of consistent feedback with the FDA that accelerated approval is open. I know other sponsors have reported the same. So that's been -- and you can also see what we just described in terms of meeting the bar and accelerated approval. So we feel good about that as well. And then as far as kind of the safety piece, I'll let Doug kind of speak to that.

I mean only to say that we've had an ongoing dialogue. Our breakthrough designation was in August of this year. So I mean people have talked about kind of changes at the FDA. Our dialogue with them has been very consistent, same people at the review level, at the division level. There has been no change in the messaging. And we've received very good and consistent feedback in terms of what is the bar for accelerated approval, but also do we have sufficient safety. We feel very confident about all of that as we go forward towards our submission.

Okay. So how should we be thinking about the confirmatory Phase III study here and what that might look like and anticipated development time lines?

Well, so I think for both programs, we have a chance to set kind of field-defining Phase IIIs. And that really is about attention to endpoints. In DMD, nobody has met a functional endpoint for DMD, particularly not for exon 51. And we'll be defining -- and we have functional endpoints that we can select from. And it's going to be Doug making those decisions. And we will be walking people through what that protocol looks like soon because we're going to introduce that in Q2.

And DM1 is a similar story. I do not see for DM1 a Phase III that uses hand myotonia as the primary endpoint. We think it's great as an intermediate clinical endpoint for accelerated approval. We need something much more clinically meaningful. And I think we can choose from things like time function tests, 5x sit to stand and other measures, which will be Doug's -- which Doug is working through as we speak, and he'll be presenting that kind of data as well.

Okay. Okay. We'll get there in a moment here. But I just wanted to cover a couple of other topics on DMD. Is there a priority here for Dyne to move other exon skippers into the clinic relative to, say, I don't know, your efforts in FSHD. Like how does building like a pipeline in DMD really stack up from a priority list standpoint?

Well, FSHD, we expect that to be the next program in the clinic. I'll be clear about that. I think that is a really important opportunity in a very large market. The other exons, I highlighted them a couple of times in the presentation because we know they're important to the community. We think they've been enormously derisked with what we just presented on exon 51. So they are a priority.

Now the key with that is for us is we very much want to take advantage of the kind of platform designation as a way of streamlining the development of those programs. Step one is to get the first program approved. And then you can move forward with requests of a platform designation. So it's not either-or, but I do think FSHD will be the first, and we'll be pursuing the exons thereafter.

Okay. And turning to Z-Basivarsen and DM1, we saw the timing of the registrational expansion cohort data slip. Why has it slipped? What has really been the underlying driver of that? And can you just remind us, do you require there to be biopsies in the study? And is that slowing down your enrollment?

Okay. So the primary issue that we had described some time ago around a delay with that had been capacity. It was not an issue of patient demand. It was not an issue of taking biopsies. We do take biopsies because we think the splicing information as a marker of addressing that nuclear pathobiology, very important, and we want that data. But that's not the hindrance.

It was capacity. We had roughly 9 sites that were in Europe, ex U.S., mostly in Europe, that we had used to enroll the multi-ascending dose cohort. We moved into using those same sites, and we started finding that we were running into capacity. Capacity, meaning they needed additional staff or space. And we should have caught that earlier, but we didn't. And when we realized that, we started adding additional sites. We have increased the number of sites now to 16 sites. We've added sites in the United States, additional sites in Europe. So we think we've addressed that capacity problem. And as a result, we have a time line of which we have guided to of early Q2 to complete enrollment of the 60 patients.

Okay. Okay. And how much of the REC is enrolled at this point?

Well, we're not -- we haven't been giving kind of patient enrollment kind of updates. We'll tell you that we're enrolling. We've added the capacity, and we see a line of sight -- a clear line of sight to early Q2 for the 60.

Okay. And what has the back and forth been like with the FDA since you submitted the revised protocol with vHOT as the primary endpoint?

Doug, you want to jump in?

Yes. I mean, people will remember that we had explored CASI as splicing index as the basis for accelerated approval. The FDA was very keen on that because it reflects this foundational pathobiology because we know DM1 is a spliceopathy and no single clinical measure can capture the totality of that disease, whereas correction of splicing could.

It's still very valuable. But the FDA could not get their heads around this as a precedent setting surrogate endpoint for accelerated approval. So we had this ongoing dialogue back and forth with them. It was a very good dialogue. We ultimately made a switch where we proposed and had this discussion, which was a very good discussion about vHOT myotonia as an intermediate clinical endpoint.

And so we're very confident about that. We feel very good about that switch. We know it was a change to the community because we had been talking about splicing, but it could have taken us much longer to continue to fight that based on CASI. So we made the switch. It's our obligation to get this to patients as quickly as possible. It's very clear to us that vHOT can be that surrogate endpoint for accelerated approval in that it is a prognostic. It is -- it heralds improvement in other, more meaningful clinical measures. So we're very pleased about that. We're very pleased about the design. The execution is going well, and we'll read those data out in Q1 of '27.

Okay. And maybe we can talk a little bit about what you're working through and trying to optimize the confirmatory trial design. To me, it seems like you've been kind of thinking about this for some time. But like what are you still kind of wrestling with at this point? And when do you plan to provide more color around that?

Well, maybe let me just jump in for a moment, but we're not wrestling with it. We have data that we have presented across multiple measures, and it's been a matter of deciding on the -- on which functional measures would be primary or which one. We know what we want to do. We're going to initiate that trial this quarter. So -- and that's been the plan.

So we'll put that in front of people when we're ready. But it's not that we're stuck on something. In fact, we are like excited about it because I think we will have a field-defining kind of endpoint and a field-defining study. And that study, by the way, the way Doug has been laying this out, is that we're also going to have a chance to be really diving into some of the CNS aspects of this disease.

And what has the specific feedback been from regulators on the design and the tenor been on those discussions? Like what are they really hoping -- how are they kind of helping you decide on the most appropriate design?

Well, I think the message -- and Doug, you can jump in, but I think the message has been there has never been a drug approved in DM1. And the heterogeneity of the disease makes it difficult to pick a single endpoint that addresses all of these features. The FDA has been pretty clear. They want a clinical endpoint that is clinically meaningful. And by that, meaning it's meaningful to patients that you can have an MCID, that you can talk -- that it affects patient-reported outcomes and is absolutely clinically meaningful.

vHOT doesn't clearly fall into that category. And so the direction has been provide us with an endpoint that is meaningful and will tell us that you're improving the quality of life of these patients. We're pretty confident we got it.

We do. And I mean, I feel really good about these trials. We're going to come out with them publicly. We've had very good discussions. The breakthrough designation in the U.S. has been very helpful bidirectional discussions that have been very positive, very engaged. It also has been with Europe, and it also has been in Asia. So that's part of why we have aligned because we want an aligned Phase III protocol. We're ready to go, and we'll come out with it very soon. 43 seconds.

I don't know how much I can accomplish in 43 seconds. Okay. I think this might be a good spot to leave this conversation. Thanks so much to the entire Dyne team for being here. We really appreciate it. And thanks for all the listeners for hanging in and joining us.

Thank you.

Good morning, and welcome to the Dyne Therapeutics' call to review the top line clinical results from the DELIVER trial in Duchenne muscular dystrophy. Today's call will be hosted by John Cox, President and CEO; and Doug Kerr, Chief Medical Officer; CFO, Erick Lucera, will also be available to answer questions. I will now hand over to Mia Tobias to start our call.

Good morning, everyone. I'm Mia Tobias with Investor Relations. Thank you for joining us for today's event to review the positive top line results from the registrational expansion cohort of the DELIVER trial for z-rostudirsen in DMD. Before we get started, I'd like to remind everyone that we will be making forward-looking statements today that are subject to the safe harbor protections provided under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent Form 10-Q.

These statements represent Dyne's views as of today's date, and we disclaim any obligation to update these statements, except as required by law. For today's program, John Cox, Dyne's President and CEO, will first provide some opening comments. Dr. Doug Kerr, Dyne's Chief Medical Officer, will then review our latest data from the DELIVER trial, supporting the potential for U.S. accelerated approval. John will provide some closing remarks, and then we'll open the call for Q&A. Our CFO, Erick Lucera, will also be available to answer questions. I will now pass the call to John.

Thank you, Mia. At Dyne, we are on a mission to deliver functional improvement for people living with genetically driven neuromuscular diseases. And this morning, we are incredibly excited to share the positive top line results for z-rostudirsen from the DELIVER trial in boys with Duchenne muscular dystrophy amenable to exon 51 skipping, bringing us one step closer to our first potential commercial launch. The registrational expansion cohort, or REC, met its primary endpoint with compelling results that will form the basis of our BLA submission for U.S. accelerated approval, which is on track for Q2 of 2026. Specifically in the REC, treatment with z-rostudirsen led to a statistically significant and robust increase in dystrophin expression, replicating the same sevenfold change we observed in the MAD portion of the trial, and we saw a continued favorable safety profile.

Importantly, we also saw improvement across all 6 functional endpoints assessed in the top line readout of the REC at 6 months. These clinically validated outcome measures assess the critical manifestations of the disease, including ambulation, upper limb function and lung capacity and are widely used in DMD trials. Two of these generated nominal p-values less than 0.05, the time to rise velocity and the 10-meter walk run velocity, despite the study not being powered to demonstrate statistical significance in any of the functional measures. We were pleasantly surprised to also see preservation of lung function, a result that we did not expect in a short 6-month duration. This functional data was further supported by new positive results from the long-term portions of DELIVER, which showed sustained improvements from baseline across multiple functional endpoints out to 24 months.

It is also impressive that we have been able to observe these results in exon 51 skip amenable boys, a population that typically has lower baseline dystrophin with a faster progression of disease. Although our focus today will be on the positive data from DELIVER, I'd also like to highlight the positive read-through these results have for validating the potential of our FORCE platform to deliver payloads to targeted tissues with a favorable therapeutic window. This same platform is being used for our very promising program in DM1 as well as our early-stage pipeline in FSHD and Pompe disease.

And importantly, we now have the clinical validation to continue the development of our programs targeting other exons in DMD, which could roughly triple the addressable population of our franchise, all using the same basic PMO chemistry and Fab. With these results in hand, we are on track to finalize a BLA submission for U.S. accelerated approval in Q2 '26, which would set us up for our first potential U.S. launch in Q1 2027 if priority review is granted. We are also excited to initiate a robust Phase III study planned to start in Q2 2026, which will be designed to provide confirmatory evidence and also to support potential ex-U.S. submissions. We will provide more details on that study design as we get closer to study initiation.

Before we dig into the details, I'd like to reflect on what these results mean for the DMD community and our opportunity to potentially transform the quality of life for these families. For the first time, a potential therapy for exon 51 DMD has shown early and sustained functional improvement across multiple endpoints, including those that assess upper and lower limb function and importantly, preservation of lung function, the loss of which is a leading cause of mortality in DMD. We are honored to be able to make this announcement today and are proud to be working every day towards bringing these families the treatment that they have been waiting for and deserve. With that, I'll turn the call over to Doug to go through the DELIVER results in more detail.

Thanks, John. Before I dive in, let me start with a brief review of the unmet need in DMD and how we've designed z-rostudirsen to provide the kind of functional improvement that this community has been awaiting. As a reminder, DMD is a devastating progressive disease with significant unmet need. People with Duchenne lack the ability to make sufficient dystrophin protein, which leads to progressive muscle weakness, loss of lower and upper limb function, CNS-related symptoms and eventually cardiac and respiratory failure that are leading causes of death. Although the first therapy for exon 51 skip amenable DMD was approved almost 10 years ago, there remains serious unmet need for meaningful functional improvement.

Exon 51 skip amenable DMD represents the most prevalent mutation at approximately 13% of the entire DMD population, and this form of the disease is particularly challenging. These patients typically show greatly reduced or absent baseline dystrophin levels lower than most other DMD mutations. This results in a faster rate of functional decline and an earlier loss of ambulation. The current standard of care PMO for exon 51 has demonstrated limited dystrophin production, less than 1% and requires weekly administration due to the challenge of delivering enough active drug. This dosing burden is a frequently cited reason for treatment discontinuation or treatment avoidance by patients, with further patient burden often coming from the need to utilize an implantable venous access port for weekly dosing.

And questions remain around gene therapy due to the potential limited functionality of microdystrophin, unknown durability and an inability to redose and concerns around safety. In summary, despite some available options, there is a tremendous unmet need in Duchenne muscular dystrophy, particularly in addressing the underlying cause of the disease. As many of you know, z-rostudirsen was designed using our FORCE platform to overcome the challenge of targeted delivery. By conjugating a PMO designed to enable production of near full-length dystrophin to a Fab against TfR1, we have aimed to deliver a precise genetic medicine targeted to tissues that matter in DMD, namely muscle, including the diaphragm and heart as well as the CNS.

As a neurologist and neuroscientist, having spent much of my career taking care of patients living with DMD, I have seen this community waiting for decades to have a therapy that can meaningfully change the trajectory of the disease and provide functional improvement. The FORCE platform is why I joined Dyne because of the opportunity to transform DMD for patients and their families. And the data I will share with you today has the potential to bring us closer to that reality. Let me now turn to the exciting positive top line results we announced this morning from the DELIVER trial.

DELIVER was designed from the beginning to support a potential U.S. accelerated approval submission with both a multiple ascending dose portion, or MAD, to enable selection of an optimal dose and then a registrational expansion cohort, or REC to generate additional data at the go-forward dose of 20 mgs per kg Q4 weeks to support a potential BLA submission. DELIVER includes a total of 86 participants across a broad and representative population. The primary endpoints are change from baseline in dystrophin at 6 months as well as safety and tolerability. Although not powered for other endpoints, the trial also includes a number of functional assessments to gauge how these boys respond to treatment, including through the multiyear open-label extension and long-term extension, which I will collectively refer to as the long-term portions of the study.

It's first important to note that the baseline characteristics across the cohorts we'll discuss today were generally well balanced and demonstrate the broad population across ambulatory status studied in DELIVER. As we've discussed previously, the 20 mg per kg Q4-week cohort from the MAD was slightly older and more advanced in disease as compared to the younger 10 mg per kg Q4-week cohort. However, the 20 mg per kg Q4-week REC cohort and pooled placebo group were quite similar at baseline. Importantly, the overall safety and tolerability profile of z-rostudirsen 20 mgs per kg Q4 week remains favorable based on the additional data from the REC, along with all of the data from the MAD cohorts as well as the long-term portions of the study, including a total of 86 patients followed for up to 36 months. Most related TEAEs were mild or moderate and the most frequent related TEAEs were fever and headache.

No serious related TEAEs were observed during the placebo-controlled period for 20 mgs per kg Q4-week MAD and the REC. I will note that we have seen 2 new related serious TEAEs of fever and/or malaise at the 20 mg per kg Q4-week dose in the long-term portions of the study. Both participants fully recovered and have continued to receive z-rostudirsen without interruption. At our go-forward dose, no participants have demonstrated persistent related anemia and no participants at this dose have demonstrated persistent related thrombocytopenia. With over 1,400 doses of z-rostudirsen to date and 113 patient years of follow-up, we have a favorable long-term safety database to support BLA submission.

We are very excited to share that the registrational expansion cohort met its primary endpoint, demonstrating a statistically significant increase in dystrophin expression compared to baseline, reaching 5.46% at 6 months on a muscle content adjusted basis with a p-value of less than 0.0001. This robust increase is precisely what we wanted to see, and we are pleased with the strong statistical significance demonstrated here. In addition, we replicated in a cohort here of 24 boys, what we had seen previously in a smaller cohort from the MAD. Although the numerical results differ slightly between cohorts, including a lower baseline in the REC, we saw the same sevenfold change from baseline in muscle content adjusted dystrophin production in the REC that we saw previously in the MAD cohort with the same 20 mg per kg Q4-week dose, lending further support to the robustness of these data.

On an unadjusted basis, dystrophin expression in the REC increased to 2.87% at 6 months with a prespecified nominal p-value less than 0.0001 compared to baseline. This represents a greater fold increase than we observed in the corresponding MAD cohort, again supporting the robustness of these data. Looking at dystrophin production on an unadjusted basis can help facilitate comparisons to other studies with all of the usual caveats about cross-trial comparisons. Here, we show an approximately tenfold higher level of dystrophin production at 6 months than what has been reported in a Phase III study for the current standard of care for exon 51 with a significantly lower PMO dose administered 4x less frequently.

Although there is no indication that a statistically significant impact on function would be required for U.S. accelerated approval and the DELIVER study was not powered for these endpoints, we do believe the ultimate clinical value of z-rostudirsen will come from its ability to provide meaningful functional improvement for patients. To that end, we prespecified the analysis of a number of clinically validated outcome measures in DELIVER, including measures relevant to both ambulatory and non-ambulatory patients. Here, we will be showing data for time to rise and 10-meter walk run in terms of velocity, which was a prespecified method to analyze these data in our statistical analysis plan. We had made this adjustment based on precedent from the Phase III studies of other DMD therapies as well as the fact that using velocity is a statistically more rigorous approach.

Additionally, per the prespecified statistical analysis plan, placebo data were pooled from both the MAD and the REC for these functional assessments. We were incredibly excited to see improvement relative to placebo across all 6 of these endpoints at 6 months within the REC. The results from DELIVER continue to be unprecedented in exon 51 DMD. Let me start with the time to rise from floor here shown as velocity. Treatment with z-rostudirsen led to a meaningful improvement from baseline in TTR velocity compared to a decline on placebo. And the delta versus placebo exceeded the published MCID impressively at only 6 months. Put another way, the boys on drug got faster and those on placebo got slower. In a post-hoc analysis, the delta versus placebo generated a nominal p-value of less than 0.05, a compelling result given the sample size and short duration, which we attribute to the strength of the FORCE platform.

The 10-meter walk run test is another common timed function test used to assess the functional capabilities of DMD patients. And here, we have shown again a meaningful improvement from baseline with a benefit over placebo closely approaching the published MCID again at only 6 months. The boys on drug got faster. Those on placebo got slower. Just as with the time to rise in a post-hoc analysis, the delta versus placebo generated a nominal p-value of less than 0.05, again, impressive. The North Star Ambulatory Assessment is a 17-item scale measuring ambulatory function, which has been widely used in the DMD field. Here yet again, we saw functional improvement from baseline versus a decline on placebo and the delta of over 2 points versus placebo closely approaches the published MCID.

In a post-hoc analysis, the delta versus placebo generated a nominal p-value of 0.09. The stride velocity 95th centile is a digital outcome measure of the 5% fastest strides taken during everyday living. Here, we again saw improvement from baseline. I will note that the comparison to placebo is potentially confounded by a single placebo participant who achieved a surprising change from baseline of 0.46 meters per second at 6 months. Excluding this participant, the mean change from baseline at 6 months for the placebo group would have been much lower at 0.02 meters per second, more in line with what might be expected based on natural history. The magnitude of the impact of this patient on the placebo mean was augmented by the fact that the placebo sample size for SV95C was smaller.

Nevertheless, the increase from baseline with z-rostudirsen treatment represents an impressive improvement at only 6 months. Let me now turn to 2 additional functional measures that are included here because they assess whether z-rostudirsen impacts other aspects of DMD beyond lower extremity function and walking and therefore, can be assessed in both ambulatory and non-ambulatory boys and young men. We are excited to share data on these measures for the first time. Starting with upper extremity function, which is particularly relevant as it impacts the ability of boys living with DMD to do things like brush their teeth and take care of themselves. In the REC, treatment with z-rostudirsen led to an improvement from baseline and benefit over placebo in the performance upper limb scale, which is a 22-item scale measuring upper limb function.

The progressive loss of pulmonary function is unfortunately an inevitable and particularly debilitating aspect of DMD, starting with these boys having difficulty catching their breath and culminating in the use of respirators and eventually complete loss of pulmonary function, which is a leading cause of death. This is why we were particularly moved when we saw data indicating that z-rostudirsen could preserve this vital function. The cohorts shown here started in DELIVER with relatively high values for forced vital capacity, a global assessment of lung function at approximately 90% of predicted based on age, sex and height. Therefore, we believe it is quite compelling that treatment with z-rostudirsen led to preservation of lung function at 6 months as compared to the declines seen in the placebo group.

To summarize the top line results from the DELIVER registrational expansion cohort, we see a compelling and potentially transformational profile for z-rostudirsen, supporting the potential for U.S. accelerated approval and addressing the significant unmet need in DMD. We demonstrated a statistically significant and robust increase in dystrophin production at 6 months with levels well above the current standard of care. We have seen a favorable safety and tolerability profile with data out to 36 months. We have compelling results supporting the potential of z-rostudirsen to enable functional improvement across multiple clinical endpoints. Specifically, we saw improvement relative to placebo across all 6 of these diverse and validated clinical measures.

As I mentioned, a post-hoc statistical analysis comparing the data from the REC treatment group to pooled placebo at 6 months generated nominal p-values of less than 0.05 for 2 of these endpoints, the time to rise velocity and the 10-meter walk run velocity, a truly remarkable achievement that bodes well for the potential impact z-rostudirsen may have on this devastating disease. This is all in the context of a Q4-week dosing profile, which may help address the significant infusion burden of the current weekly standard of care. As a reminder, we had not set expectations to provide new data from the long-term portions of DELIVER in conjunction with the top line results from the REC. I am so thankful that our team was able to analyze and prepare these additional impressive long-term data while finalizing the comprehensive analysis required for the top line REC readout.

Let me now turn to these new long-term data from DELIVER, which showed sustained functional improvement across all 6 functional measures out to 24 months. This is a snapshot of our latest results in the long-term portions of the study. What's important here is that across 3 cohorts and 6 endpoints for a total of 18 assessments, we are showing sustained functional improvement from baseline in every measure out to 18 and 24 months. This is an unprecedented breadth and durability of effect in exon 51 DMD. From left to right, the cohorts include the original 20 mg per kg Q4-week cohort from the MAD now out to 18 months. And in the middle, a pooled analysis of both the 10 and 20 mg per kg MAD cohorts out to 18 months, followed by the 10 mg per kg MAD cohort, which then transitioned to 20 mgs per kg now out to 24 months.

I'd note that the final prespecified statistical analysis plan includes imputation for missing or out-of-range data, which was not done previously in order to maintain blinding. This is the way we have presented the data here and the way we will be presenting the data to regulators in our planned BLA submission. So in the context of a progressive disease where you would generally expect these measures to get worse over time. These patients showed actual functional improvement, not just a slowing of decline. Before I conclude, let me briefly discuss the broader positive implications we see from these data as they validate the potential of the FORCE platform.

Our platform was designed to leverage TfR1 to enable the targeted delivery of rationally selected payloads to address the underlying disease biology. In the case of z-rostudirsen, this has translated in the DELIVER trial into a statistically significant and robust increase in dystrophin production. In addition, our TfR1 binding Fab was designed to enable robust and widespread tissue distribution, which we believe is a key reason we've been able to show early and sustained functional improvement across multiple clinical endpoints. In terms of safety, our Fab was designed to not interfere with the natural biology of TfR1, specifically its role in iron homeostasis. In the DELIVER, we believe these features have contributed to the favorable safety and tolerability profile, including the lack of persistent related anemia or thrombocytopenia at the 20 mg per kg Q4-week dose.

And finally, our platform was designed to be redosable with less frequent dosing, enabling us to achieve these results for z-rostudirsen with only Q4 week dosing, which we believe is a significant patient advantage versus the standard of care weekly therapy. We believe the strength of these data bode well for our broader pipeline, including z-basivarsen in DM1, which is currently being evaluated in the registrational expansion cohort of the ACHIEVE trial as well as our earlier-stage pipeline in FSHD, Pompe disease and other exons for DMD, where we have the opportunity to build a portfolio leveraging the FORCE platform. Before I turn it back to John for some closing comments, I just want to express that I wish something like z-rostudirsen was available when I was treating DMD patients.

Thank you, Doug. With these positive results in hand, we are quickly turning our focus to executing on the compelling commercial opportunity we see with z-rostudirsen as we are poised to enter an established market with significant unmet need a little over a year from now, assuming priority review. We believe the data from DELIVER, including from the MAD, the REC and the long-term portions of the study demonstrate a strong value proposition for addressing the unmet need in DMD. We believe the robust increase in dystrophin production, the favorable safety and tolerability profile and the sustained functional improvement observed across multiple clinical measures all based on convenient Q4W dosing provide a compelling justification for patients to consider our therapy if approved. We are building a capital-efficient operating model to deliver on the potential for patients, our company and our shareholders.

We have a leadership team in place with the right expertise in rare muscular diseases and are taking a disciplined approach to building out our commercial organization with an eye toward expected future synergies with our opportunity in DM1 as well as the obvious overlap with our programs for other exons in DMD. At the same time, our CMC activities are on track to support our expected time lines for BLA submission and launch. As always, we plan to grow the company while ensuring disciplined capital allocation. In summary, we now have the data in hand to support a planned BLA submission for accelerated approval in Q2 of next year based on the positive results from the DELIVER trial, and we are more excited than ever about the broad opportunities for our pipeline based on the FORCE platform, which has enabled the positive results we announced today.

In addition to z-rostudirsen serving as our first potential launch, we remain on track with z-basivarsen in DM1 for a potential second launch roughly 1 year later. We continue to expect to complete enrollment in the registrational expansion cohort of the ACHIEVE trial in early Q2 of next year, and we look forward to presenting that data in Q1 2027. We would like to thank the DELIVER trial participants, their families and the Duchenne community for their trust and commitment as we continue to advance this promising therapy. As always, we remain steadfast in our mission to deliver functional improvement for those suffering from neuromuscular diseases. In doing so, we help to transform the lives of patients, their families and communities while also driving growth and tangible value for all stakeholders. Thank you for your attention. And with that, we will open it up for questions.

[Operator Instructions] Our first question comes from Paul Matteis from Stifel.

Can you hear me okay?

We can.

Congrats on the data. I really appreciate it. I just wanted to clarify a couple of things about the functional data, which looks super promising. Can you just clarify why all of this is referred to as post hoc and whether or not the analyses that you're showing us were, for lack of a better term, I guess, always the plan from just the endpoints and the methodology? And then second to that, as it relates to pooling the placebo arms, was that also always the plan? And I guess if you didn't pool it and you use the concurrent placebo, does anything change as it relates to the sort of effect sizes and the overall conclusion?

Yes. Let me -- Paul, thanks for the question. And also thanks for the Stifel report this morning. Let me turn it over to Doug. I think he can handle both of those.

Yes, Paul, it's a great question. Thanks for asking it. This was not a post-hoc analysis in the sense that you're probably used to seeing it. We prespecified the analysis of all of these functional endpoints, including the methods for imputation and how to pool the placebo group. The only thing on the functional data slides that was post hoc, if you will, is the statistical testing to generate the p-values because our prespecified SAP did not include an alpha-controlled hierarchical testing of any endpoint beyond dystrophin. The only endpoint formally analyzed from a statistical standpoint was the primary endpoint because that is the focus for accelerated approval. All we wanted to see from the functional endpoints was trends. As a reminder, the study was not designed to demonstrate efficacy on any functional measure. So we view these results, especially the nominal p-values as pure upside.

And on the pooling placebo question, Doug?

Yes. So we had prespecified, obviously, the pooling. We wanted to see a really robust measure assessing the functional outcome. That's better done with the pooled placebo from the MAD and the REC. That's why we set it up in the top line that way. So we're really more confident because of the pooling of that placebo gives us greater power to understand the difference between those 2 groups.

Our next question comes from Moritz Reiterer at Guggenheim.

Congrats on the data. I have 2 questions on the time function tests. First, could you elaborate on the precedents for using velocity instead of time for time to rise in the 10-meter walk run? And secondly, if you were to analyze your data from these endpoints based on time instead of velocity, would the results still be stat sig?

Doug?

Yes, great question. We made the adjustment to velocity based on precedent from the Phase III studies of other DMD therapies as well as the fact that using velocity is statistically more robust. So when you look at other recent studies and how the DMD field has moved. These include, for example, the Phase III givinostat study, Phase III REGENX microdystrophin, Phase III viltolarsen, Phase IIb vamorolone, they've all transitioned to velocity instead of time. There's a statistical basis for this. It creates a more robust assessment of the data. And importantly, the MCIDs are only available in velocity. That's why we did that. We've set that up in a prespecified way to increase the robustness of the analysis.

Our next question comes from Mike Ulz with Morgan Stanley.

Yes. Can you hear me?

Yes, Mike.

It's Avi Novick on the line for Mike. Congratulations on the data. So I guess just following up on the functional endpoints, I guess, have you done any market research that I guess as to which clinicians would find -- which of these endpoints clinicians would find most compelling? And do you think there's a possibility of driving switch from standard of care? And in addition, I guess, which of these do you see as, I guess, driving the highest probability -- or should we view as driving the highest probability of success in an eventual Phase III confirmatory study?

Maybe I'll touch on this. Doug can always add. But when we talk to clinicians, and by the way, Doug is one who has treated DMD patients, every one of these 6 top line measures is important. They're all clinically meaningful. The time to rise is particularly followed from a young age where they're trying to determine how long it takes for a child to get up and stand up from the floor. It is particularly predictive of how soon that boy will be in a wheelchair, for example. So that one is extremely important.

But the 10-meter walk run also has an MCID, also very important. We were particularly impressed with the lung function maintenance, the testing around FVC, that one appeared to preserve lung function, which is absolutely related to mortality with this disease. So I think all of these -- the fact that all 6 of those had moved in a direction that was compelling and favorable leads to answering the second part of your question, which is in terms of kind of the commercial opportunity, we do think that with this type of data, we have an opportunity to be first-in-class, best-in-class and become the standard of care in this field.

And maybe the only thing to add is we do know clinicians appreciate each of these measures. They have been used in DMD clinical trials. Importantly, they're measuring different aspects of the disease. So many of them are about ambulation and lower extremity strength, which is obviously important, but it's also important to assess the impact of drug on other aspects of DMD progression, including upper extremity strength and pulmonary function. And we had hoped to see that there was movement in a couple of these, but we've seen movement in all of them encompassing a diverse aspect of DMD disease progression. And that's what makes this so gratifying today.

Got it. And then I guess with respect to the upcoming Phase III, I guess, which of these do you see as most important for, I guess, confirming functional benefit?

Do you want to cover that one, Doug?

We're going to -- we've been thinking a lot about the Phase III. It's really important. It will start in Q2 of '26. So we're deep in the thinking about this. We have not externally discussed what the details are of that Phase III confirmatory trial. That's coming. That will come as we get closer to initiating that trial.

I might add, I think any number of these measures end up being very important in the Phase III. I think it's a chance for us and Doug to have a field-defining type of confirmatory trial that would apply for the United States for the first time, somebody showing an exon 51 actual efficacy and functional benefit in a confirmatory trial as well as having a trial that meets the requirements of ex U.S. such as the EMA.

Our next question comes from Andrew Tsai with Jefferies.

Congratulations on the very strong results. As we think about the path ahead, obviously, it's submitting for accelerated approval. So can you talk about your overall confidence in CMC manufacturing? 20 mgs per kg seems like a lot of drug to produce. So I just want to understand how derisked CMC and supply are at this juncture and how you're ensuring that won't be a risk during the FDA review.

Yes. Thank you, Andrew. Well, CMC is something that we have been working on for a long time, and we're prepared. So our tracking of time lines for CMC starts with ensuring that everything that needs to be done for the BLA, which is Q2 of this coming year is on track, and it is. That's process validations, analytical method qualifications, et cetera. So those activities are there. Our commercial supply chain has been established. That has been in place. And so we are preparing for a launch in Q2 -- I'm sorry, in early 2027. BLA submitted in Q2 of '26 and a launch in early '27. All of that is on track. So I think I'll leave it there, Andrew. We feel confident about CMC.

Our next question comes from Martin Auster with Raymond James.

Congratulations on the data this morning. I was wondering if you could talk a little bit more about the global commercial opportunity just in terms of how important that is. Right now, there's a drug approved in the U.S. but you address kind of how you see this opportunity sort of playing out globally? And then maybe touch on where you see the regulatory path and the requirements for gaining access, both in European as well as sort of rest of world markets.

Yes, Marty, thanks for the question. So the number of patients in the United States is roughly 1,500. There's at least that many in Europe and obviously many more throughout the world. I think with this data, there will absolutely be interest from regulators in different parts of the world. We are -- we have intention of being in Europe. And our intention right now, as I was mentioning before, base case is that we would be expected to complete a Phase III but we'll have conversations with the EMA based upon the data that we've had. We feel the same way about Japan. And there are plenty of other markets, for example, in the Middle East, where there will be interest in this type of medicine. So our plan is to be a global commercial organization, starting first in a very efficient way in the United States.

Our next question comes from Edward Tenthoff with Piper Sandler.

Can you hear me okay?

We can, Ted.

Excellent. Sorry. So firstly, congratulations, another big win for -- this is the second big win for DMD patients in just under a week. So really exciting to see these results. I was so impressed by the consistency of the data. Obviously, the focus is on z-ros but now with pivotal -- positive pivotal data in hand, how quickly do you think you could advance these other forced drugs that treat other exons into the clinic? And what do you think the regulatory path might be? Is there any chance that those move directly into registrational cohorts? Or do you think it would mirror the way you've advanced 251?

Yes. Ted, thanks for the question. Good to hear from you. We are -- we are very excited about the potential of building out a franchise here. I think you may have heard us talk a bit about the exons that we have in the pipeline. Moving those forward would roughly triple the market size and could do that fairly rapidly. We like the platform guidance that the FDA has put forth, we think is really ready-made for our particular type of platform. Every one of these different exons that we would go after use the same Fab, the same linker, the same manufacturing process, the same quality testing, same disease. It is just a handful of oligonucleotide changes. So it is kind of ready-made for a platform type of designation, and we would like to pursue that with the FDA. Our hope would be to get more to what you just pointed to would be a regulatory path that would include a basket type trial that would allow us to move rapidly. That's not set, but that is something that we would love to pursue with the help of the FDA based upon the data we've seen so far.

That makes a lot of sense. And again, congrats on the data and this really important work you're doing for these boys.

Our next question comes from Catherine Novack with JonesTrading.

I just wanted to ask a little bit about -- again, questions about the endpoints ideal for the registrational study. Do you expect to have a similar age group and mix of ambulant versus non-ambulant patients so we can get a sense of which endpoints would be more ideal, let's say, something that is more sensitive in a younger population versus those who are a bit older?

You're talking about for the confirmatory trial, Catherine?

For the confirmatory trial, yes.

Right. Doug, do you want to tackle that?

Well, we haven't really talked about the details. We are interested, obviously, in a very robust field-defining confirmatory trial. That will be initially in ambulatory patients. We're also interested in studying the impacts of the disease in non-ambulatory patients as well. Details of that and endpoints and size are coming, but we're not ready to externalize that at that point. We've done a lot of thinking about it. We're very excited about these trials, but we'll talk about that as we get closer to the initiation of that trial.

Got it. And then just on the commercial opportunity, do you have a sense that there's any kind of loyalty whatsoever to current exon skippers? Or is once a drug with superior dystrophin expression is available to patients? Is that -- is dystrophin alone something that would encourage providers to change treatment? And additionally, with the monthly versus weekly dosing, would this encourage some patients who are not on drug to potentially look at being prescribed?

Yes. Catherine, I -- we estimate that there's roughly about 400 patients on a weekly standard of care today out of about 1,500 patients. Whether they're on the standard of care or they're not on any care at all other than maybe steroids, what the field has been looking for, I think what families have been looking for is not just a dystrophin number, but actual functional improvement. And this is the data we've been waiting for. I think it's the data they've been waiting for. So today, people are being dosed on a weekly basis, evidence of functional improvement is hard to find. So I think this is something that is in a really good position to create some value for patients and rapidly.

Our next question comes from Gavin Clark-Gartner with Evercore.

We just had one question on the 2 new safety events. Just wondering what was the time course of onset and then the resolution for the events post infusion?

Yes. So we reported those 2 new serious-related TEAEs in the open portion of the study. Those occurred essentially 2 to 6 days after the drug administration. Out of caution, patients were admitted to the hospital. They were evaluated, they recovered, they were discharged. They did not miss a dose. They continue in the study without dose interruption at 20 milligrams per kilogram Q4.

Our next question comes from François Brisebois with LifeSci Capital.

Congratulations on the data, especially on the functional side here. Can you maybe help us understand kind of 2 questions here. The FORCE platform, you touched on it, but what do you think might be the secret here to getting this kind of dystrophin function, especially in DMD? And then on the commercial side, maybe just help us understand a little bit more the expertise of the team. It seems like the team has been brought in on the commercial side for a while now. How ready are you guys to take this on here?

Frank, so maybe I can start -- I'll start with the commercial side and Doug can jump in on kind of the special distribution that we see with this -- with the platform. We brought in approximately a year ago, a commercial leader, Johanna Friedl-Naderer, who had -- one of the drugs she had launched globally was SPINRAZA. And so she has been building out a team. We've also been adding medical leadership, medical affairs and MSLs. We've been building a team regionally at the kind of management and upper management level. We're doing it in a staged approach. We're trying to be, I think, kind of capital efficient here and responsible about it.

But in rare diseases, the beautiful thing about being in rare diseases is that you don't need a massive commercial workforce. You need a workforce that is experienced in neuromuscular rare diseases and have the right type of relationships. And I think we're partially built. We're continuing to build it, and it's all right on track. So we feel good about that. And then I would just add to that, that -- the other piece that I know our CFO likes is that, that infrastructure will be leveraged for DM1 approximately 1 year later. So we can do this in a very capital-efficient way. As far as the platform and its distribution, Doug, do you want to take that?

Yes, it's a great question. And I mean, I think the way I would answer it is we've said and we are on a mission to increase the functionality to result in functional improvement of these boys. It turns out it's not just the dystrophin number. It is really delivery and dystrophin. And that's key to the success of the FORCE platform in DMD. So the FORCE platform was designed to deliver the genetic payload, which in this case is a PMO to all of the tissues that matter in DMD. And even within the tissues in a diffuse way that really allows the muscles to function.

And then when the payload gets to the muscle, it increases dystrophin really 10x better than existing standard of care, and this is near full length, highly functional dystrophin. And then the last aspect maybe is time on drug matters. And we are seeing a sustained benefit out to 18 and 24 months in which DMD patients despite having a progressive disease, which would cause decline in function are not. They are actually functionally better at those long time points than they were at baseline on drug. So we think all of those aspects are really keys to the secret sauce of what we're doing here and why this is so transformational for functional improvement in DMD.

Great. And thanks for including all that new long-term data, too. I appreciate it.

Thanks, Frank.

Our next question comes from Brian Skorney with Baird.

Congrats on the data. I think you had previously talked about dystrophin-positive fibers and generally, we sort of see a correlation between expression and positive fibers. But I'm just wondering if you've analyzed the IHC from these patients yet and what it looks like both in terms of dystrophin positive fibers as well as any standing for restoration of the dystrophin sarcoglycan complex to show localization?

Yes. We don't have those data at this point. We were really laser-focused on top line readout, the data that we would need to support accelerated approval. Obviously, we've got those biopsies. We'll look at them, but we haven't looked at them at all at this point.

Our next question comes from Keay Nakae with Chardan Capital Markets.

What is your understanding of what the EMA is going to require in terms of functional improvement measurement of the ones that you're assessing?

Keay. The -- we know that the EMA likes stride velocity 95th centile. You've seen the improvement that we've shown from baseline. They have a clear MCID that they call to as well. So we would anticipate that the EMA would be looking at stride velocity, but this -- the other data that we've shown across these measures will be important too. So stay tuned on kind of the Phase III confirmatory trial designs and what endpoints we'll have for Europe as well as for the United States.

Yes. I appreciate that. I guess just in thinking of the multiple goals of the confirmatory Phase III, will it be driven more by seeking to expand into the EMA or more checking the box of the U.S. requirement of the confirmatory to back up the accelerated approval and whatever measurement they want to see.

We're going to address both. I don't know if you want to add anything to that, Doug?

Absolutely. We think we can do both with a single really good, really robust field-defining study.

Our next question comes from Tess Romero with JPMorgan.

First one is, do you intend to have a pre-BLA meeting ahead of your planned BLA submission in the second quarter? And if so, has this meeting been scheduled? Or when do you expect it would take place? And then the second question is, to be clear, you did not see any thrombocytopenia at the 20-milligram kilogram dose. Can you just clarify exactly what you saw?

Yes. Let me start with the regulatory piece. And we haven't been providing kind of the play by play, but you can expect a pre-BLA. We've had breakthrough designation. So we'll be following the normal course that you would do with that, which includes a pre-BLA but we haven't been giving kind of timing. You can anticipate, though, that we're going to be filing in Q2 of next year. So it's not too far off into the future. And then as far as the thrombocytopenia, Doug, do you want to touch on that?

Yes. I mean we've seen no persistent related thrombocytopenia in the trial. And the reason we include the word persistent here is because in the context of a clinical trial with lots of phlebotomy, you see fluctuations just randomly of laboratory measures. What really matters is if you have a sustained drop in any of these hematologic parameters, the FORCE platform, remember, was designed not to interfere with the things that would do that. What we're saying here is, indeed, that is the case. We're not seeing persistent related drops in hematologic parameters due to drug.

Okay. And how do you define persistent?

Persistent really is essentially 3 months, right? If you have something that comes and goes, random fluctuations of a laboratory measure, that's one thing. If it persists, that's something that could be clinically meaningful. We're not seeing that.

Our final question comes from William Pickering.

Congratulations on the data. I was wondering if you could describe the imputation approach you used in the REC, how much of the data was imputed and any related sensitivity analysis you may have run? And it looks like you used imputation for all endpoints except FVC. So could you describe the rationale for that?

Yes. Okay. So the data, obviously, as per ICH guidelines, if you're submitting a data package to regulators, you must account for missing or out-of-range data. That is why the imputation. This was prespecified in the SAP. It was done before data was unblinded. And it's a fairly standard methodology in that if there's missing or out-of-range data, then you are imputing things that increase the robustness of those data. So that's how we did it. We did specify that in the statistical analysis plan. Those are the data that we're going to use to regulators. Those are the data that we showed you today.

FVC was not imputed. You saw that on the data. This is a tough measure. It's very tough for young patients to actually complete the task. And so especially for younger children, it's an onerous task for these patients to do. It requires putting on a mask, putting on a nose clip, forming a tight seal, inhaling completely and then exhaling through the tube without allowing any air to escape. So that's challenging. So in some cases, those data would fail QC. They actually couldn't do the task. Now there's no clear way for what you would do to impute in that. You just can't get the data. So we presented it as is for that.

This concludes today's call. I will now hand back to Dyne Therapeutics for closing remarks.

Well, thank you all. Obviously, we are really, really excited about where we are today. Moving forward with the accelerated approval package is top, top priority for us. Seeing 6 functional measures move the way they did, it certainly feels transformative for the field, and we're really excited for the patients and families, and we're going to do our best to get this drug out there as soon as we can. Thank you.

All right. Good morning, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here. It's my pleasure to introduce the team from Dyne Therapeutics, including John Cox to my immediate left, President and CEO; as well as Erick Lucera, CFO on the far left.

Just before we get started, I need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representatives.

And with that, maybe I can just hand it over to John to make a couple of sort of introductory comments for people that might not be familiar with the story.

Yes. Thank you, Mike, and we'll be making some forward-looking comments as well. Good to see you. So maybe I just mentioned about the company where we are today because it's really, it's an important moment in time for us as the company. We've been waiting to get to this moment, frankly, and a number of us joined the company because we wanted to build a pure-play neuromuscular company. And we're like right on the cusp of doing that. And I say on the cusp of doing that because we have 2 major programs right now, which I'm sure we'll talk about, DMD and DM1 that are in registrational cohorts, now the implication of that since they're an accelerated approval pathways, both of them is that we could be commercializing these products in 2027.

In fact, DMD, we're planning for early 2027 and the commercial efficiencies across both programs is meaningful. And that means we could be really generating revenue soon. The other thing that's come together here recently is that we have been building intentionally a management team that would be able to not only raise capital, which Erick Lucera recently did, but could manage that capital, allocate the capital and also a management team that could generate revenue in the near term. That takes a particular phenotype of a leadership team. And I feel like we have built that and put that into place.

And then the final point is that we've got this platform that is playing out exactly the way we had hoped it would play out. And I'd love to talk more about that, but it's led into not just 2 late-stage programs, but now we have programs in preclinical or first or IND-enabling studies that allow us to kind of build out a platform and a pipeline as we go forward. So now you've got this kind of full pure-play neuromuscular company that's completely integrated. So we're in a really, really good place. And we're kind of -- we're more than a little excited about the next 1.5 years.

So a lot to look forward to and maybe we could just start with the platform because that's sort of the base and what's driving all your discoveries here. So maybe talk a little bit about FORCE platform and why it's well set?

Yes, I'm happy to. So the FORCE platform is really the secret sauce of the company. And I would put it this way first that in this industry, there are these points in time where people overcome some major biotechnical hurdle. And then there's an explosion of therapeutics. Countless examples -- not countless, a few examples of that in our history. One of the big technical hurdles over the last 10 years has been how to deliver genetic medicines to tissue. People knew what the genetics were.

Many of us worked on ASOs years ago for things like DM1, you could not get enough genetic medicine to the tissue and particularly to the tissues that matter. So in this case, you've got to get to the billions of muscle cells that matter and you need to get to the CNS.

First-generation delivery technologies tended to focus on monoclonal antibodies targeting the transparent one receptor. And so mother nature, God has provided us with a perfect receptor for transferring payloads in that case, iron into cells. And scientists had figured out how to use a monoclonal to occupy that receptor and transfer a payload into a cell. Sometimes they design to the CNS, typically not getting to the CNS, but sometimes. The challenge has always been with that is that when you occupy that receptor, you block the iron transport and you see anemia, and that limits your ability to dose. What the scientists at Dyne had done was just really interesting. I mean what they had done is said, what if we designed a Fab, just an antibody fragment targeted a particular epitope of the transparent receptor.

Don't occupy for any period of time to avoid that issue of anemia and allow you to transfer payload into cells efficiently. Would you be able to dose at a high level? And would you not only get to muscle cells but would you be able to get to the CNS. And our data not only in animals, but now in humans is suggesting that we're getting to muscle cells, quite definitely but also potentially even to the CNS. So it's kind of a step change with a next-generation platform and it's playing out in our clinical work.

Maybe we can switch into sort of your -- one of your programs DNY 101 (sic) [ DYNE-101 ] for DM1. And maybe to start there, just talk a little bit about why target DM1, what sort of makes it an attractive market opportunity?

First of all, DM1 is a -- it's a horrible disease affecting about 40,000 patients in the United States, maybe another 55,000 in Europe. So it's large for a rare disease. There is nothing for these patients. It's remarkable in many ways because the way that the disease works, it's -- we can get into it, but it comes down to a core spliceopathy in the nucleus that results in mis-splicing across many different genes. So you can end up with all kinds of different effects for different patients.

Those effects can be something simple like expression of myotonia in the hand, not so clinically significant, but the ability to release your hand to things much more clinically meaningful, such as the ability -- such as your strength, the ability to walk, GI issues to CNS issues that affect a significant portion of those patients. So I characterize that because our platform, the fourth platform allows us to deliver a payload in ASO, which gets to the nucleus to address the core pathobiology of the splicing and at the same time, is using a Fab that allows you to get to the muscle and get to the CNS. So DM1 in some ways, our platform is just made for addressing the heterogeneity and the core biology of DM1.

Got you. That's a nice sort of segue into sort of what you're seeing in the clinic now from the ACHIEVE study. You've given us a couple of updates. So maybe just what are the key takeaways or what have you learned so far from that study?

Yes. So the ACHIEVE study has been a multi-ascending dose study in which we were really guided by taking biopsies and evaluating splicing correction to determine the dose. And ultimately, we determined that at 6.8 mg per kg, we started seeing the kind of broad effect that I just described on many features of the disease. And it was very exciting to see that. So some of those effects were a very simple measure called Video Hand Opening Time or vHOT, which is the ability to open your hand and middle finger to touch a table at a certain amount of time.

We saw a 40% improvement on that particular feature. It's an early indicator of clinical effect of those things that are more meaningful. And so the things that are more meaningful are, for example, quantitative muscle testing, where you're testing upper limb, lower limb according to a standard set of measures. And we saw remarkably a 10% improvement at 6 months on strength. At 12 months, we saw a 20% improvement. That is a really meaningful improvement in muscle strength. And then we also looked at time function tests. So now you're trying to look at kind of how the muscles are all working together, things like 5 times sit to stand, 10-meter walk run, those improved significantly as well.

And then the final feature that really got our attention was when you looked at patient-reported outcomes with a measure called MDHI, there are multiple scales. Six of the scales touch on CNS-related features. Those scales moved significantly. We saw roughly 40% improvement across multiple CNS-related scales. So that told us we're getting to muscle suggests that we may be getting to CNS and as I mentioned to you, the CNS effects in this disease affect a significant number of the patients and that becomes often the most debilitating aspect of life for them. So the data from the ACHIEVE multi-ascending dose trial really impressive set of data, and that's given us the confidence to kind of move forward into a registrational cohort 6.8 mg per kg.

Yes. Maybe talk about sort of the registrational cohort and you've made some fine-tuning on the strategy there. So maybe walk us through that a little bit.

Yes, we did. So when we started the registrational cohort, we started with using. Well, first of all, treating it as an accelerated approval pathway. And in that pathway, you can use either a molecular surrogate end point as a predictor or you can use what's called an intermediate clinical endpoint, which may not be clinically meaningful, but is an early indicator of some response. We chose splicing correction as our molecular surrogate endpoint and we started moving with that because it's the best indicator of getting to the core pathobiology and that you're addressing the heterogeneity of the disease. So we have moved forward with that.

When we talk to the FDA most recently in a Type C meeting, their reply to us on that was that using a splicing index was a novel new endpoint. It was going to take more time to validate. The alternative that we proposed was and I'm glad the team was able to take the data from the MAD study and say, well, let's look at an alternative. That alternative was using vHOT, which I just described as an intermediate clinical endpoint.

And so we switched to that intermediate clinical endpoint. We do not have to go back in time. It was amendment to our protocol. It was certainly a meaningful shift for us. It was a shift for our investors because we were all in on the splicing. So we recognize that. The positive is that we were able to pragmatically adjust and move to vHOT and that's what we're doing as we go forward. And so we have a registrational cohort now that has increased the number to 60 patients in that registrational cohort for the purpose of having stat sig on vHOT. We'll have stat sig on splicing correction. And with that number, we think we will have very good trends on a number of other clinically meaningful measures.

Makes sense. And you spoke to the FDA and then you filed the protocol amendment? Have you gotten feedback or acceptance from the FDA there? Are there any next steps around that at all? Or is that all done?

We filed the amendment -- or we filed the protocol with the FDA. There's no requirement for the FDA to respond on that type of protocol. So we don't have additional updates from kind of a regulatory play by play. I will tell you that it is all systems go. It is execution. That's what we're doing. And that registrational cohort remember is just one part of our overall regulatory plan because the second piece of that is moving into a confirmatory trial, which we have been telling people will be Q1 of next year, so very soon.

And maybe just back to the registrational cohort. You have data mid mid-next year and for approval? Is it just hitting the primary endpoint on vHOT? Or are these other endpoints important to you to sort of build the story or how do you think about that?

So for accelerated approval, stat sig on vHOT will be needed. We're confident about the stat sig also on splicing. And I think that will be certainly complementary and important to the FDA. And then beyond that for accelerated approval, what you need are reasonable trends that you can see. And so you've seen our multi-ascending dose data. We have trends that are -- you don't have to squint to see them. They're very strong trends. So we anticipate with 60 patients, we would see that. And I'll just throw in just one other piece that I have not mentioned is that after we met with the FDA in the Type C meeting, they gave us breakthrough designation.

Got you. And I guess one question we get sometimes from investors is your competitors using vHOT as a primary endpoint as well. They have more patients than you do in your sort of registrational cohort. And so is there any risk around that or not, I guess?

So listen, this market is, one, it's a new market. Nobody has had a drug approved. We're taking one approach to the regulatory pathway. Others are taking another approach. So we're taking our particular approach. I think it's tough to compare the 2, but I'll try a bit.

First of all, we have -- keep in mind, when we talk about numbers of patients, we have 60 patients in the registrational cohort. It's 3:1 drug to placebo, so it's a significant number of subjects on drug. It's not a 75 on drug, 75 on placebo. Then we have the multi-ascending dose portion of that study, which had 56 patients. Those patients had all been dose escalated or the vast, vast majority, up to the 6.8 million per kg, and they had been continuing in the trial. And that becomes an entire substantive set of data. So you put all of that together, 50-plus patients, the number of patients we have in the registration cohort. This isn't a small trial. This is a 100-patient rare disease trial for accelerated approval.

And I think it puts us in a position to put -- to provide data that is differentiated at that point. And it will be differentiated for sure on splicing because nobody's got the splicing data that we're going to be showing as well as all of the other pieces that I just described.

Maybe talk a little bit about how enrollment is going in the expansion cohort versus your expectations?

Yes. I just -- so I would point back to I believe it was end of Q2 was when we provided our last guidance or not very long ago. We're not providing kind of intra-quarter kind of progress updates or commentary. We are moving with it. And as I mentioned, Q1 is our chance to be moving into a Phase III as well. So all of this is moving forward.

You just mentioned the confirmatory study to start in the first quarter of next year. Maybe just talk a little bit about sort of your thoughts on the study design and kind of what that could look like in terms of endpoints, et cetera.

Well, we're excited about it for a number of reasons. I'll highlight one, and that is that. So as I mentioned with the accelerated approval trial, I think we're going to have a fairly robust set of data that's going to show that when you get splicing correction at the levels we were getting at 6.8 mg per kg that you start seeing not just myotonia improvement, you start seeing clinically meaningful improvement across the board. That will help us differentiate with the accelerated approval product, label, et cetera. That's what we believe.

The chance to further differentiate as a Phase III. And in the Phase III, we are not planning to make this a myotonia vHOT trial. We want it to be about what is really clinically meaningful and important to patients. So if you -- when you look at the data that we presented so far, I think our CMO, Doug Kerr and his team have multiple options. That can be 5x sit to stand like meaningful time function test. The FDA cares about those things. 10-meter walk run. These are the types of endpoints that we can evaluate and include in our phase III.

And then I think we have a chance to further evaluate things like MDHI and CNS subscales and to do even more exploratory work on the CNS side. So I think it's going to be a really defining kind of Phase III for the field.

In terms of timing of the endpoints, is 12 months a reasonable expectation? Or is it -- could it be 6 months?

We haven't stated that yet. We're still -- so with the breakthrough designation, we're having the conversations with regulators, U.S., global, but we will let people know when that time comes, what that trial design before we start the trial design, what that will look like.

Makes sense. And maybe a couple of questions just on the competitor front. Obviously, there's one competitor out there, they're in Phase III and points of differentiation. You've mentioned some already like splicing, anything else come in mind?

Yes. So I guess from a differentiation standpoint, I tried to put it into a couple of categories. I think splicing is certainly important feature. I also think that the CNS is incredibly important. And I don't believe others are getting to the CNS. In fact, I think they argue that they don't get to CNS. And if you talk to any clinician, the CNS piece is really massive and important.

And then the other piece is around safety. So our Fab is designed to allow us to get to doses that are important for payload delivery, high dose is 6.8 mg per kg without seeing the kind of persistent anemia that people see. And I'll just point out that for these patients, one of the CNS aspects and the physical aspects is fatigue. You add anemia on top of fatigue that's a problem. So I think in those kind of 3 areas and the splicing ultimately will result in, I believe, it will result in differential kind of functional benefit as well. So we have an opportunity to be really differentiated as the data develops.

Makes sense. And another question we get is just implications of having sort of an accelerated approval when a competitor may have sort of a full approval at the same time and how you think about that?

We have -- we brought in a commercial leader and team. They've been obviously talking to payers. We've talked to clinicians. Having an accelerated approval label is not a deficit. If you've got meaningful data associated with that, and I think I hope I've made the case that we ought to, then you can have a label that is describing that benefit, and we're going to be presenting that data and making that public. Clinicians aren't concerned about whether you call it what pathway you call it. They want to know what does it do and what the data is. And the same thing with payers that we present to the payers that we've got an approved drug, and we should be in -- we should not be in some sort of disadvantage.

Makes sense.

It comes down to the data.

I guess just for the last question on DM1 program as you progress to sort of starting the Phase III 1Q of next year and data 2Q? Or are there any other sort of updates we should be paying attention to from now until mid next year.

For DM1?

Yes.

Well, so what we've been describing, I'll describe this across maybe both programs. I mean we've got what we call kind of our 221 program, our approach and milestones. And we have 2 programs that we will have top line data. So top line data for DMD end of this year, and then we have top line data midyear next year for DM1. Beyond that, we're going to have 2 BLAs. And then by early '27, we should be launching DMD. So that's kind of the 221.

And we've been highlighting that because based upon the work of Erick, capital raised recently and really providing kind of the overall discipline around capital management, looking at our budgets and so on. We feel getting out to that time frame takes us out to -- well, actually, it takes us up to Q3 of [ 2027 ] from the cash runway. So now you're generating potentially revenue in early '27. So there's -- that's a pretty good set of updates for people.

You guys will be busy for sure.

Yes.

Maybe we can dig into just sort of the DMD program and 251 and maybe just start, let's talk about sort of unmet need and sort of market opportunity there.

Yes. So DMD, I'm glad you're raising on that one. I know DMD has been -- is in the news a lot lately, mostly over gene therapy and a lot over safety. I would just comment that even if you set that kind of stuff aside, efficacy is what's missing in this field. I mean for those that don't really watch the progression of this disease, it is devastating. I mean, by the time the boys are 8, 9 years old, they are declining rapidly. They've been kind of improving physically slowly, and then it is a steep decline to the point that they can't get off the floor. By the time, they're 11, 12 years old in a wheelchair and by the time of 24, 25 years old, they are dying. It's just inevitable and is terrible. And nothing on the market is significantly changing that, nothing.

So the unmet need is very, very meaningful. Now we're focused on the most prevalent version of that mutation, Exon 51, which represents about 13% of the population and roughly 1,600 boys in the United States. Now of those, to describe the market a little in more detail, that submarket is the only, I guess, you could call a standard of care is eteplirsen, which is a naked PMO. We're obviously targeting our PMO. And those patients drop off. There's maybe 400 or 500 on drug. There's probably several hundred more that quit and there's another 400 or 500 more that have at best, maybe they take some steroids. So they're underserved.

If they're taking etep, they're getting dosed every week with an IV ports, infections, all of that, very difficult. And we should talk about what's different about ours because if you see that early data at 20 mg per kg and 10 mg per kg. We recently showed that at 6 months, 12 months, even out to 18 months, you're seeing sustained improvement, not slowing of decline, sustained improvement off of baseline. Now it's a small number of patients and patient numbers, which is why we're conducting a registration cohort but I don't think anybody has presented data that is improvement of baseline. Everybody is showing data about how they slow the decline, a little better than somebody else. We're about functional improvement and it looks like our product is enabling us to do that, and we hope we can demonstrate that in the next number of months.

Yes. So maybe just talk a little bit about you expect to provide the sort of registrational cohort data by the end of this year and kind of what's the focus there? And what's your level of confidence?

So that is also a program where we're pursuing accelerated approval, and that's well trodden is precedent for it. So we feel quite confident about that path. The bar for accelerated approval is well established as improvement in dystrophin. That's the biomarker. That's what's been done. We're -- we feel -- we don't be overconfident, but we feel quite confident on that because what we saw in our data is that we got up to about 8.7% dystrophin adjusted for muscle content at just 6 months. Dystrophin has a 4-month half-life. So that should keep improving.

And keep in mind, Exon 51 is the toughest to skip. And these patients typically have at best 0.5% dystrophin naturally. So it's a really meaningful improvement. A small improvement should get it approved and where we are today feels well above the bar. Beyond that, we want to take it further, and we want to see some clinical effect. So we had seen 10-meter walk run time to rise stride velocity, 95th centile. All these different measures had actually improved, as I just described over time. So hopefully, we'll see very strong trends with that. And that would be incredibly meaningful for the community.

You mentioned sort of continued confidence in the accelerated path. Just curious if you've had any interactions with the FDA just given sort of the new leadership and just any issues there?

We do have confidence in the path. So I'll remind you that we also recently received breakthrough designation for DMD. So I think it's a good signal for sure from the FDA. We had talked to the FDA some time ago, and they were clear that the accelerated path was open to us with dystrophin as the biomarker. I did attend one of these sessions with Dr. Makary and Dr. Tidmarsh, where they were kind of CEO talking, listening conversations. I specifically raised the question about accelerated approval. And they were very, very clear that they were supportive of accelerated approval. Dr. Tidmarsh had actually sponsored an accelerated approval drug at one point in his career that he touted in a positive way.

But they were also clear that they wanted to see a surrogate endpoint that showed some improvement, and they also want to see some trends and function, and they want to know you're going to do a confirmatory trial. We're doing all those. We're going to -- we will check off all those boxes as we plan anyway.

Makes sense. Since you could be in a position to maybe launch this maybe end of next year, maybe talk a little bit about sort of plans there, where you're at and sort of preparing ahead of that?

So we hired a commercial leader, Johanna Friedl-Naderer, who had launched SPINRAZA globally, launched many drugs and rare disease drugs very, very successfully in preparation for this kind of moment. So we have been prepared.

I will say that -- I think people are starting to realize that commercial opportunity is real and could be relatively rapid switching over from the existing therapies of this therapy. This community is looking and clinicians are looking for a next-generation therapy. Gene therapy, the enthusiasm is clearly waned. And the time is really right for us, and we are the one company really positioned well in Exon 51 to capture some commercial opportunities.

Are there other Exon 51 skippers in development you are aware?

There may be 1 or 2. I am not seeing anything that has the kind of data that we presented or an approach or an MOA or a targeting mechanism that compares to where we are. So I think we're really uniquely positioned in this way.

And just given the platform and your -- the data you're seeing in Exon 51. How are you thinking about other potential Exon skippers and thoughts about moving those forward in time lines maybe?

Listen, building a franchise is one exciting. In fact, maybe there's an opportunity to give Erick a chance to pipe in here because he -- when he came into the company, this is what he started talking to me about.

Yes. Thanks, John. I would say, as I was doing my due diligence, I sort of looked at the investment thesis that was out there, and I really felt that the DMD part of the story was just not getting the attention that it deserved. When you think about the Exon 51 being only 13% of the total patients, there's another 4 Exons, which we already have the DCs for which are small changes, but everything else is basically the same, which can get us up to 40-odd percent of the total DMD market. So my thought as a former investor, is this is really a pipeline and a product or we can have multiple product launches. And with the basket trial type designation that the FDA is talking about, there really is an opportunity for us in the coming years to build these out.

Maybe just talk a little bit about just the commercial opportunity there, but also sort of leveraging that for DM1. Are there synergies there that could sort of be helpful?

Yes. I mean one of the reasons that I had come to the company was I feel that we have the potential for 2 or 3 if you include FSHD, 3 muscle products all targeting the same centers, doctors or maybe some differences here and there, but you can really have that prototypical specialty pharma, rare disease, capital-efficient sales force that I think gives us a differentiated opportunity to be a sustainable organization.

Makes sense. And we got 2 minutes left. So maybe just last question, just FSHD and just remind us where you are with that program and next steps.

So FSHD, we've been an IND-enabling efforts right now. As I've said before, we are -- I think in FSHD is just a perfect market for our technology similar in the size to DM1. We are using an siRNA in that case. I think it's appropriate. I will just say we haven't given some guidance on dates yet, but we will. We're very serious about it. We've been spending time really optimizing that molecule for the unique aspects of that disease. And one of the unique aspects of that disease is that DUX4 suppression is variable. It fluctuates. It's not a constant.

And so that lends itself to getting the dose right. And I think we have an opportunity to really optimize with our technology, the amount of payload and the time it is there and in the cell to keep that volatility addressed. So we're focused on that. We're focused on particular safety and off-target aspects that you could have with that. Our technology is just, I think, perfect for it. So we're pursuing it. We're very serious about it. And as Erick said, it fits right into our neuromuscular kind of commercial structure.

Okay. Great. We're just about out of time. So a lot to look forward to. Appreciate your time, John and Erick, and thanks so much.

Thank you, Mike.

Thank you, Mike, and thanks for the support.