Good morning, and thank you for joining Guggenheim's 2025 Healthcare Innovations Conference. I am Debjit, one of the therapeutic analysts. Our next presenting company is Dyne Therapeutics, and joining us on stage from Dyne are President and CEO John Cox and CFO Erick Lucera. Good morning, and thank you guys for joining. Good morning. You've had a very interesting couple of weeks with a pretty big-sized acquisition in the space. How are you thinking about what do you think are the implications for you and your platform when you think about what just transpired? Yeah, thanks for hosting us, Debjit, and we'll make some forward-looking statements. Listen, I think it was really positive for the space and positive for us in a couple of different, comfortable different points, I think. One, it's highly validating for the therapeutic areas. I mean, the commercial opportunities we've always thought were in the unmet need was really significant: DMD, DM1, and FSHD. Those are all places where we're participating. Novartis has obviously clearly made a statement that those are meaningful opportunities. That's positive for the space. I think it's also positive for the TfR1 receptor approach. Avidity has been using a monoclonal antibody approach. We've come along a little bit after them with what we think would be a next-generation Fab type of approach to the TfR1. All of that is quite validating, I think, in terms of delivering genetic medicines to tissue. Novartis obviously is smart and did their homework. From both standpoints, that's good. I would see us as kind of a pure-play neuromuscular company in the space. These are all areas: FSHD, DM1, DMD, and more. These are the spaces where we're participating. I think it's a real positive. Got it. We are a month or so away from the DMD data. How are you guys internally thinking about the output on the other side, especially given the challenges one of your competitors has had with their pivotal readout? Yeah, as you said, it's been a, I mean, the last week or so has been really active in the space. Sarepta had reported a lack of functional benefit with an exon skipper, but this was first-generation naked. I don't think anybody's surprised by that. I don't think you are. None of us are surprised that if you have really low levels of dystrophin, 1% or less, that you might not see functional benefit. That's the reason we came out with a next-generation targeted TfR1-directed type of molecule with DYNE‑251. Then you've seen the data that we have. We are something like 10x beyond where Eteplirsen has been in terms of dystrophin. You've seen really interesting and exciting kind of functional improvement across multiple measures with the data that we've presented so far. Now, I think we're all waiting, and people are waiting. We're excited to see the DMD data from the registrational expansion cohort. We had recently announced that that top-line data would become available in December. Stay tuned. Does the FDA require trends on the secondary endpoint, or do you think clear differentiation on dystrophin expression will support an accelerated approval? You know, for AA and DMD, there's been a precedent well-established. Dystrophin is, you know, statistical benefit in dystrophin would be reasonable for accelerated approval, supported by a safety profile. I think we feel very, very good about that, and particularly because our dystrophin levels have been far beyond what anybody has ever seen before, particularly for exon 51, which is a very difficult exon to skip. Yet we've seen 3.7%, 3.8% non-muscle-adjusted dystrophin and 8.7% or so with the muscle-adjusted in these earlier cohorts. You take on top of that, would the FDA want to see some trends? I think we've accomplished what we need to for AAA. Do you have a reason to believe from trends? Sure, you see that from the data, and hopefully we'll see some good trends in the data coming up. You brought up the safety. Is Dyne monitoring safety on a real-time basis in the study? We do. Have there been no changes on the safety side from what's been disclosed publicly? We disclosed back in March, I believe was the last time we disclosed. We've been monitoring since. We'll have another update in December. If there were some material change from where we had been, we'd be reporting that as we've done in the past. The update will be here very shortly. Got it. How closely will the baseline characteristics in the expansion cohort, or actually in the pivotal cohort, reflect the expansion cohort population? You know, the inclusion-exclusion criteria, that has been consistent. It's also been basically the same sites that we've been using. So we don't have that baseline data to report yet, but we would anticipate something similar to what we've seen through the multi-ascending dose portion of the study. Now, granted, you had pretty remarkable for exon 51, 3.5%-ish raw dystrophin expression. Is there a concern that if you get patients who are older, more fibrotic, you won't be able to replicate that number? You know, we've had patients from 4 to 16 across this study. We don't have a patient-by-patient data, but you've seen the cohorts have varied, you know, by age and baseline. We've seen improvement on dystrophin. You know, certainly as a patient gets older in DMD, you have more fibrosis, more fat content, but the ability to penetrate muscle remains through the TfR1 receptor. We would expect to see reasonable dystrophin across the board. Of the secondary functional endpoints, which one do you think moves first, right? Because SV95C, at least from our perspective and maybe even from EMA, seems to be the most non-fungible data, right, that needs measured. Yeah. I think there are publications that talk about SV95C tends to move early and be a good indicator of other functional improvement that you see later, including NSAA. That has been well published and shown, I believe, in Europe. The European authorities have been very positive about it. We like the SV95C because of all the reasons, particularly because of the kind of non-subjective nature of it, the accelerometer on the ankle of a boy over a period of time. Our data and that, and Doug Kerr, our CMO, has talked about it extensively. Our data, it actually shown that we were at six months, just six months, well above the MCID as established by the Europeans in the 20-mg per kid cohort. That is early and not just early, but clinically meaningful in a small data set. Hopefully we will definitely be looking at that in this next top-line readout. There are other functional endpoints that we are excited about. Our NSAA had improved. Time to rise from floor is incredibly meaningful for this patient group. We had seen improvement, even improvement, not just slowing from decline, but improvement relative to baseline in multiple measures, which I do not think people have shown before. Got it. Now, let's talk a little bit on the commercial side of the equation here to give a couple of advantages outside of the efficacy. It's administered once every four weeks. What% of the market do you think is currently taking an exon 51 skipper, and how quickly can you convert that market? Within exon 51, it is the most prevalent. In the U.S., we believe there's roughly 1,600 patients. If you break that down, our commercial team has been obviously preparing and studying the market and preparing for the market. We estimate roughly 400-500 patients are on Eteplirsen. That's the naked exon skipper that's out there today. There are likely a few hundred patients who had quit taking the drug, whether it's because of a lack of efficacy and/or, as you mentioned, the weekly dosing is extremely inconvenient. You have three or four hundred that you could put into the quitter category. Beyond that, you have another 500-600 plus that at best have used steroids. You have a handful that have used gene therapy. There is an entire market of people that just have not believed in any of these medicines and have not pursued them. It will be really interesting to see what happens with that group over time, because that is an opportunity to build the market significantly. We also see of the 400-500 that are on Eteplirsen, there is an opportunity for a rapid switching, and that seems very practical based upon what we hear from clinicians today. Got it. Given that you're monitoring safety on a real-time basis, you seem to be confident on expression. What could derail the study? You know, this is biotech. Anything can happen in a clinical study. However, as you look at the data we have shown, we have a real high confidence right now. It's not as if we just dosed, you know, a dozen patients. This multi-ascending dose study moved up to it through a total N of 56 roughly patients. Those patients that were on placebo have also been dose escalated. Now we've added another 32 patients to that group. It's a meaningful set of data that we will have as part of the accelerated approval trial. If you, I'll tell you, if you look at the data at the 20 mg per kg cohort, that is the cohort that for me, I know for Doug, it really got our attention because exon 51 has very low natural levels of dystrophin. The progression of the disease is quite aggressive within DMD. At about eight years old, these boys decline rapidly. Up until that, there is some improvement, but at eight years old, they decline rapidly to a wheelchair. In that 20-mg per kg group, six boys on drug, they actually improved relative to baseline on function. Again, I'm not talking about slowing of decline. They had improved. I, you know, we don't want to get overconfident about it, but people have not seen, we haven't seen data like that. We are anxious to see what this data looks like in the next few weeks. Got it. All right. Good luck on the DMD side. Let's switch gears to DM1. Just had a push out on the program from enrollment in the fourth quarter to the second quarter of next year. Just walk us through the challenges that you had in Europe. Is the second quarter guidance right now a beatable number? Listen, we obviously feel good about the guidance that we're giving at this point. We're not happy about, in fact, we're disappointed in the fact that we had a delay. It is not fatal, but it is a delay. It is something that myself and our management team is all over. We're not happy about it. With that said, we have moved really well with the DMD trial operationally. With DM1, we had some delays here as we expanded to a registrational cohort. I'll put it, Debjit, in probably two categories. You'd mentioned Europe or ex-U.S. That trial has been a trial outside the United States historically. We had nine sites ex-U.S. That's how we enrolled the 56 patients, and that moved well. We had assumed that we would be able to take those same nine XUS sites and just, even though they were caring for existing patients, the 50-plus patients, that they would be able to add more patients in a fairly expedited way. We also said that we would start to get to the end of 60. We had said earlier that we would add some sites in the United States as well to expand capacity. I would say we missed two things. One is some of the sites XUS did not have the capacity to add additional patients. In other words, they got to five or six patients, and they were really at capacity from the standpoint of their formulation and pharmacy group, staffing, and other in space. There were things that we could do and we've been doing to help each of those sites. What we have done since is add two more sites in Europe to expand the capacity, new patients, new sites that are very excited to work with us. I wish we had made that happen earlier, but we actually had thought in the summer that the summer months, things were just moving a little slow with enrollment and it would pick up. It was a capacity issue. In the United States, what we found was that it was just operationally taking us a bit longer to get these sites up. We thought we would have two sites up a little earlier. We have two sites up now and enrolling, and we are adding two more sites to that. The corrective action has been expand the capacity, deal with some of the operational issues. We sat down as a management team and said, with our whole clean ops and with our CRO, how will the enrollment lay out over the next few months? I think the guidance of early Q2 we feel very good about gives us some shift, but I think we still have a competitive timeline out there. Got it. The way I understood it, the study is at this point about 50% enrolled? Close. How many patients from the U.S. will you land up actually enrolling in the study? I don't know. For the accelerated approval trial with Achieve, we've never said that you had to have U.S. patients. We'll have U.S. patients, but it wasn't a matter of number or ratios. It was strictly a matter of capacity. It'll be a function of whatever sites are enrolling fastest, we'll see how many patients shake out. We'll have them from globally, but we'll have them from the U.S., but not a particular number that we have to hit. Given the focus for the registration cohort is going to be VHOT, is there any fundamental differences between Europe versus U.S. with baseline VHOTs? I believe you want to keep it very close to the eight to ten seconds at baseline. Baseline is important with VHOT, but that's also why we've been pretty disciplined about our inclusion and exclusion criteria. Those inclusion criteria for Europe, U.S., actually all the sites, is equivalent. You'll recall that with those, essentially those same inclusion and exclusion criteria with the Achieve trial, the multi-ascending dose trial up to 56 patients, that got us to roughly a baseline of about 9.2 seconds. That was a good place to be. Now we've expanded the number to having 60 in the registration expansion cohort with similar or identical inclusion and exclusion criteria. We would anticipate similar kind of baseline. Got it. The VHOT is sensitive to splicing changes. Any there has been some rumblings from some docs and your competitors' program that the patients can get functionally unblind given how fast the VHOT moves? Is that a good thing or a bad thing for the program? You know, we have not been seeing that as a risk with the program. You'd have to, a physician would have to kind of know baseline at each time point. VHOT varies at baseline by patient. I don't think we're, you know, that's something longitudinally that we have been seeing or concerned about. MDHI seems to be something very unique for you guys. How reproducible do you think that is? And can that get on the label? I do think it's a bit premature to determine what will be on the label. We'll have to, obviously that'll be a matter of review with the FDA. The nice thing about accelerated approval is that you don't have to have statistical significance on these various measures to have them be on the label. Now, I think raising the MDHI, we really like this patient-reported outcome. I mean, it's comprehensive. The total MDHI scores that we had improved significantly in the 6.8 mg per kg cohort. What was also very interesting is that there's a subscale of CNS-related patient outcomes, six subscales. What we saw at the 6.8 is that those improved roughly 40%. That was a really big change. What will we expect going forward? Some of that is a function of how many patients come in with a CNS issue. We'll see how that shakes out. In the future, we'll look at that. In phase three, we'll really dive into the CNS aspects of it. The kind of signal that we saw of potential CNS benefit is really important for the field because many of these patients, that is the biggest issue for those patients. I'll remind you that our Fab is a technology that gets to the CNS. We have all kinds of animal data that shows profound penetration throughout the brain. If that data holds up, that will be really important to the clinicians and to the patient community. You mentioned the FDA. Dyne is also in the process of initiating a phase three study. How are those discussions? What do you think is going to be the primary endpoint there? A reminder, we have breakthrough designation, both programs, and got those fairly recently. We have had the opportunity, and we do through breakthrough have the opportunity to have conversations with the FDA. The opportunity for us to take a phase three and make it what we call a field-defining phase three, I think is a really big deal. Pick an endpoint that is actually very clinically meaningful that across or represents the heterogeneity of the disease. We have liked using the accelerated approval portion as a way to move fairly quickly, create a robust set of data early, but then use VHOT as an intermediate clinical endpoint, but then move to a phase three and really start evaluating CNS and many other features that are clinically meaningful. We do not intend to use hand myotonia as a phase three primary endpoint. Our CMO, Doug Kerr, is working through based upon the data that he has seen so far, what is a meaningful clinical endpoint. I think where we'll end up is something more like a time function test. These are the types of things that the FDA likes and correlate those with kind of lifespan, quality of life, and other features that are really, really important to patients. This is our chance to define for the field what an endpoint should be and what a phase three should really look like in DM1. Given that the harvest study data may not be available till maybe third quarter at this point next year, does that generate some operational challenges or strategic challenges for Dyne? Because their data is not available? Yeah, I mean, it would have been a de-risking event for your DM1 study, right, if that VHOT data looked really good. I don't see any, for example, first of all, Avidity is not enrolling at this point that I know of. They're done. We will be setting up a phase three operation and clinical sites in the U.S., but also globally. The number of patients that are out there in this field is really significant. There should be plenty of demand for clinical operations with us. I don't think we're dependent on any or any VHOT data is going to affect us. It's just, frankly, other than a nice, simple early regulatory endpoint, what matters to these patients are these other features, like CNS, like being able to get out of a chair, you know, like being able to function daily in a more normal physical way. Hand myotonia is not going to be what defines that. The current guidance is, I'm sorry, your registration data in early 2027. If you can enroll faster, do you think that timeline can be moved into 2026 at this point, or this is still to be seen? Let's stick with our guidance to Q1, but I will tell you we're working as hard and fast as we can. Eric, since you're on stage. Yes. One thing we keep grappling with is this conversation about cost structures. I know we talked about this in terms of from a number of patient perspective, you guys have exactly the same number of patients as Avidity. Does that adequately explain the delta in the expenses? It's part of it. I think there's a number of things. From 30,000 feet, if you just think about kind of what we're trying to do right now, we're getting prepared to launch two drugs and we're getting prepared to launch two phase three trials. If you think about that in an abstract manner, that would be four products. If you then take a step back and say, how are you doing this? We're doing it under accelerated approval. Oftentimes, our numbers are compared to another competitor. If you look at, for example, DMD, we're enrolling more patients, we're having more visits, and we're doing more tests. That inherently is going to drive up the CRO costs. When you look at DM1, that's again another accelerated approval program. When you compare the number of patients that we have dosed with drug to one of our competitors, they're almost the same. Some of our competitors are older than us, so we're compressing those costs into a shorter time period with the same number of patients, with more visits and more data points. By math, you end up with a cost structure that looks high, but I'd say some of the recent capital raises that some folks have done, I think, lean more towards the run rate of burn that we've had as well. All right. Unfortunately, we're on the clock. I wish I could ask a couple of more, but we'll keep it for another day. You know what? Thanks so much.