Brian Skorney, one of Baird's Senior Biotech Analysts. I am really excited to have Dyne Therapeutics with us in a fireside chat. I think this is a really exciting company. They got a number of awesome programs going on in the muscular disease space. Maybe to start, John, would you mind providing just a little bit of background on Dyne as a company, the broader approach and technology that underplays your efforts in rare muscle diseases? Yeah, happy to, Brian. Good to be here. Thanks for hosting us. Listen, I think Dyne was really built on the notion that the delivery of genetic medicines, antisense oligonucleotides, in neuromuscular diseases needed to be done in a way that would broadly and fully distribute the oligonucleotides to tissue and across the blood-brain barrier, and to do so in a way that would be considered a safe way to do that. The intentional design of our platform, and it was very intentional, was that we would use the targeting of the transferrin receptor 1, which others have used, which naturally transports iron into cells. And we would target that particular receptor, not with a monoclonal antibody like most, but with a monovalent Fab. The idea behind that was that what people had seen with mAbs is that you tended to block that transferrin receptor, and you would be limited by anemia. And we always had a concern that we wanted to avoid any cross-linking of multiple transferrin receptors, particularly around the blood-brain barrier. And so we intentionally designed a Fab that would allow us to deliver to the CNS, broadly to tissue, a much smaller molecule than you, about a third of the size of a mAb, so that we could dose escalate in a way without seeing anemia and deliver high quantities of genetic medicines. Everybody knew the genetic basis for things like DMD and DM1. The challenge was being able to deliver enough of the payload. The scientists at Dyne, this is before I came, but this is the reason I came, is we started to actually see pharmacology and ability to dose higher, that you started to see functional improvement. And last year, in 2025, we had actually, I think, validated this platform in two really tough diseases, DMD and DM1. In both of those diseases, across multiple functional measures, we didn't just show slowing of decline, which is what most people would hope to see at best. We actually saw functional improvement from baseline and from placebo, both in DMD and in DM1. So this year has been all about execution, and we are hoping to launch our first product next year. Great. We have a hot topic here, specifically in DM1. Novartis had a really bad Labor Day weekend. The company they acquired last year, Avidity, the two of you have sort of been in a competitive horse race over the last couple of years, specifically in DM1, beyond DM1, but in TfR1. Maybe walk through what you see as the differences between z-basivarsen's role in treating DM1 and what the Avidity Novartis drug is able to do, and how to compare and contrast some of the biomarker data. Yeah, I am happy to do that. Listen, when we saw the announcement recently that they had failed to hit on their primary endpoint, the video hand opening time for hand myotonia, we were surprised because that is a particular endpoint in DM1 that is, it moves early, it moves easily, and it moves with very little biological activity, meaning drug activity. So we had anticipated that they would hit on that. We have gone back and really taken a look at it, and I think what we should first start with is the fundamental biology. Foundationally, just foundationally, we have a very different molecule, and really, I think in two ways. One is the payload, and one is the distribution. If I start with the payload, that is really important because I think you know, Brian, with this disease, with DM1, the target has to be the nucleus. The target, more specifically, is the mutant DMPK that is causing the mis-splicing that cannot get out of the nucleus. Our payload is an antisense oligonucleotide because that payload gets to the nucleus. The other drug that you are referring to with Novartis is an siRNA. siRNA acts in the cytoplasm. So getting the first principle of making sure you are getting enough drug to the target to get sufficient splicing is key. That is one point, and we can talk a little bit about the trial differences in a second. The second point is that it is not just getting to the target, but it is about enough payload to the target to drive enough of what we call splicing correction, and there is a way to measure that. It is called a CASI analytic. We measure that in every single patient. When we did our dosing at a very low dose, the first dose in the multi-centering dose study, 1.8 mg per kg, we saw vHOT moving. It moves with very little splicing correction. But we did not stop. We kept dosing higher. We went all the way up to 6.8 mg per kg. vHOT was taken care of. But then we started seeing potentially CNS effects. We started seeing broad functional improvement across multiple measures, and that is where we selected our dose. So that distribution and what I described before with the Fab, us being able to go to a higher dose without the safety limitations that are referred to, allowed us, we believe, to get a very different level of targeting and amount of material to the nucleus, unlike the other product. Now, when we go back and just look at some of the early work, I really would like to, I hope Novartis releases some of this data so we can all learn. Maybe there were just some outliers, things we can learn about vHOT. But if you go back to their MARINA study, at their low dose, their first dose, 2 mg per kg, they did not see much in terms of vHOT. They went to 4 mg, and that is when they saw a good vHOT response. But that was dosed every six weeks. Then they went into the phase III, spreading out the dose to every eight weeks. If you were sort of on the cusp of having enough, and their splicing numbers were never very high, unlike what we had seen. Fundamentally, you have got to get splicing. That is where the truth lies. If they were borderline on that, which would make sense if they are not getting in the nucleus, you would expect with an endpoint like vHOT, which has variability, that you have got to be definitive about getting enough material there. Great. Yeah, I was always bullish on your program over Avidity because of the CASI-22, could never understand how, if you cannot have an impact on the biomarker there. I remember you making that point before. I agree with you. Why don't you talk to us a little bit about the ACHIEVE data that you've shown so far, and as we're looking at potentially pivotal cohort data that's coming out early next year. What data are you going to share, and what do you anticipate both across DMPK knockdown, CASI-22, and vHOT measurements sort of put you in a good position to file an accelerated approval with the FDA? Yeah. In terms of the data, I'll go back a bit to, again, sort of the fundamental foundational biology here. We had presented some time ago, and I think it was actually at a JP Morgan conference the first time about a year and a half ago. We presented data from our MAD study, which showed at the 6.8 mg per kg a registrational dose. We showed DMPK knockdown, then we showed splicing correction, all at 3 months. We saw about 25% splicing correction. That's a very significant, we think, biologically meaningful number. And then what we saw at 6 months was across five or six different functional measures, broad functional improvement. Strength, Five Times Sit-to-Stand, 10 m walk/run, even on patient-reported outcomes related to CNS. So that is basically all the biology adding up, right? That was the data we had presented. Now, that was for that cohort of 6.8, that was six patients. So that brings me to what we're going to be presenting going forward. Actually, Brian, we had anticipated that Novartis at this time would be saying they hit on vHOT, and we were looking forward to comparing our secondaries and functionals. And so we actually did a data cut on the long-term extension data from that group that was part of the ACHIEVE MAD. And we did that at 12 months, 25 total patients. We'll be presenting data from that. Yeah. You'll see the various functional measures. You'll see if they stand up compared to what we saw with the original N of six. You'll see MDHI data, and particularly you'll also will show the CNS subscales, all of which will be, in this disease, CNS is also a very important part of the disease and debilitating. And then the other piece, and it'll be compared with propensity matching to natural history. So I think it'll be really a fulsome opportunity to look at that, but you'll also see vHOT, and you can look at vHOT at 6 months, and I remind you, we're applying for accelerated approval. So what we want to be able to say is vHOT is a reasonable predictor of functional benefit downstream. Right. So you'll have the six-month vHOT data, you'll see how that changes, and then you'll see the various functional measures and whether we have the kinds of trends. That gives people an idea, are we meeting the expectation for an accelerated approval package? Right. The final piece of data that I think people are interested in is around vHOT. People want to understand, are the baseline characteristics of our patients in the registrational expansion cohort, that's what we're going to file on for the AA. Does it match up with what we saw in the MAD? So we'll show a vHOT baseline, compare that to the MAD, and people can come to their own conclusions about how they feel about the probability of success and the powering and so on. Great. You're also planning to start the confirmatory study as well. You have a different take in terms of primary endpoint. How do you think about the endpoint that you're utilizing versus the primary vHOT endpoint that Avidity and Novartis use and how that translates into utilization and- Yeah Predictive functional benefit? You've heard me say this before, all of us at Dyne have said this. We always felt that vHOT made sense as an intermediate clinical endpoint, not a great endpoint in terms of clinical meaningfulness for a phase III. We always said we will not use it for a phase III, and that was in part based on conversations we had along the way with the FDA. Appropriate as an intermediate clinical endpoint for AA. For the phase III, we said we are going to have a clinically meaningful primary endpoint we liked, and after talking to the FDA, a timed function test. Five times sit to stand. After talking to KOLs and looking at all of our data from the MAD study, we came to the conclusion, and with the FDA and for our phase III, that this would be the primary endpoint. It's clinically meaningful in multiple ways. It involves core strength, truncal strength. It involves quad strength. It involves the ability just from fatigue and so on, to be able to follow instruction and get up and down. People know that 5x sit to stand in other diseases relates to fall risk which is really important for morbidity. We think it's the definitive endpoint for the future in this field, and that's what we have in that study. The only other point I'd make, it's amazing how when we've talked over the last couple of years, Brian, I think we've all assumed we were going to be second to market. Man, did that change in the last week. Yeah. Things have been so dynamic. Now I think we're the only company with an actual phase III that is enrolling, it's actively enrolling, around a primary endpoint that we think is the right endpoint. Yeah. On one hand it's given some caution around vHOT readings, but yeah, certainly a good point that the stock would be up 20%, 30% on positive vHOT data. Right if Avidity was filed with positive data. Yeah. Now it's like 150% up on positive data, right? Moving on to the next leg, DMD. This is also a very interesting story. There's obviously a number of comparable drugs that have already been approved on much lower levels of dystrophin. Walk us through what you've been able to achieve here in terms of targeted muscle dystrophin production Yeah And your current standing with the FDA. Yeah. I am glad we are talking about that. We are a company that is getting ready to launch our first drug in an area of massive unmet need, where the reimbursement pathways have been established, where the patients are known. It is a wonderful market for us to step into. Speaking of unmet need, nobody has really been able to show a functional improvement, maybe a slowing of decline on current treatments, which brings me to the kind of data that we have had. Look, I think people have always wondered what dystrophin level, everybody focused on dystrophin because that is clearly the protein that is missing. What dystrophin level do you need to see an impact functionally that would result in efficacy? I really felt like we might be the company that can actually answer that question for the first time, because nobody has gotten to the dystrophin numbers that would matter sufficiently. They certainly were not distributing enough dystrophin deeply, broadly to the tissue to have an impact. I think with our Fab we are getting that kind of distribution. So we saw that with these patients, exon 51, they have very low natural skipping, meaning very low natural dystrophin, less than half a percent. We, at 6 months, were over 5%. That is at 6 months. Now, it is adjusted for muscle content because they have fat and so on. Over 5% at 6 months. Even at that level, at 6 months, we saw that we had improvement from baseline on things like stride velocity, ambulatory tests like NSAA, and time rise from floor velocity. These are really incredibly important. They are all the standard measures. We even saw improvement on upper limb strength. Then we took data that went out even further, and we saw further improvement. We saw cardiac improvement, pulmonary improvement, or at least stabilization. That is what you want as these boys go into. When they go into a wheelchair, you really need to stabilize around the diaphragm and the cardiac. So the data was just remarkable data. We even had taken a few biopsies that we presented at MDA. They were just four optional biopsies. You only want to take so many biopsies from the boys. So you take them to 6 months. We know that is not the peak dystrophin level. Sure. We thought, based upon our modeling, that the dystrophin level would double. So you get to double digits, low double digits over about, I do not know, 12, 15 months. We took four biopsies from boys the age 12 to 24 months after their dose of dosing. The number had roughly tripled. Roughly tripled. So people were 18, 19%. It is just a remarkable dystrophin number, and we are seeing functional improvement across virtually every measure at 6 months, 18 months, 24 months. I really believe we have a chance to become the foundational therapy in this field. We need to get everyone with exon 51, I hope they will get exposed to this drug, and we are preparing to launch it in early next year. Yeah. On that front, you have January 21st PDUFA Date. I would assume at this point you are well past the mid-cycle review, maybe knocking on a late cycle review. Normally, I would not ask the recent sort of change in leadership at FDA with the permanent appointment to CDER, if it matters, but I do not think there has ever been a drug approved for DMD where there was not a center director intervention. I guess, does Michael's permanent appointment as CDER director, does that impact you guys? It would seem like that would be a positive given his neuro background, but I think people had some concerns previously with some of the leadership about AA. We have not seen that kind of concern in our interactions with the FDA. Okay. I will tell you, our design of this trial was such that we should not have to get an exception. We should not have somebody intervene. We are hitting on dystrophin, where the change in dystrophin is statistically significant. Really statistically significant. You have to have trends on function. You do not need spectacles to see the trends that we are showing. In fact, we have nominal P values on two of those measures. Then we have got a placebo control group. You have got 32 patients in the REC, we had 50-plus patients in the MAD, all of that data in totality. This is how you should present an AA package. We feel very good about it, and our interactions with the agency have been highly professional. Great. When we think about commercial launch here, EXONDYS 51 is obviously on the market. There is a number of, I do not know if I would say liabilities, but certainly things that you can counter detail on, whether it be from the dystrophin production, the frequency of dosing. How do you think about the addressable commercial opportunity in terms of patients who never took EXONDYS 51, patients who dropped off of EXONDYS 51 for one reason or another, versus patients who are converting patients on EXONDYS 51? Where is the low-hanging fruit at launch for you guys? Well, let me start by saying we started organizing with some confidence for a commercial launch over a year ago. The investments, and I'll tell you one of the reasons Erick Lucera is sitting here with me, joined the company as a CFO, is because he saw the opportunity so near-term with DMD. Even a broader franchise, which we can talk about. The commercial team, we have built that with neuromuscular experts, people working on market access, and we have been studying that market deeply. To get to your question then, we see the market as having roughly 1,600 exon 51 amenable patients in the U.S. There's only about 400 to 500 that are on the current, if you want to call it a standard of care, I guess, EXONDYS 51. They have to get dosed every week. A significant portion of patients dropped off of that drug. They quit. You just don't see the results. They get discouraged. Weekly dosing. So there's probably, of the 400 to 500, another 300 or so that are quitters. All of those are, I think, people that are astute to it, they're aware, and they're willing. If they could dose once a month, like with our drug, and when you see the kind of functional data, I would expect them to switch, and I would hope they do for their sake. Now, the other part of this, I think you said low-hanging fruit or whatever, but I think the group that will be very responsive are the clinicians. The clinicians who are the top clinicians around the country that have dosed patients with our drug. I think they see it as a foundational therapy. You get them on the drug. Maybe you use gene therapy on top of it, maybe you use some of the other anti-inflammatories. You obviously can use steroids. But those are people that really understand the drug. Then I think it's incumbent upon us and our commercial team to make sure that this entire community is aware of it, because there are so many people out there that I just left another 800 that are essentially maybe a few tried gene therapy. Most have just used steroids. They just have not believed that anything is moving the needle. We need to make sure everybody's aware of what we have. Right. When we look at CMC and commercial supply, no one surpassed the launch of EXONDYS 51. Naked PMO had a much different cost of manufacture. There were supply limitations. Any of that here, do you feel adequate that you could meet any demand that comes out? How do you compare and contrast COGS of naked PMO versus TfR1 conjugated? Well, the COGS have to be higher than just a naked PMO, right? Obviously, we're making a Fab and a linker, and we're conjugating. It's a very different molecule than a naked PMO and has very different results, obviously. I will tell you, I spent a lot of my life in CMC and tech ops, formerly at Biogen. I brought in some really great people. We have a Chief Technology Officer, Raj Manchanda, who has worked with me in the past and in other places. We have been working on supply chain now for a couple of years, preparing for this moment, and all of that is on track. That includes scale-up, that includes redundancy in certain nodes of the supply chain. That includes building inventory relative to the commercial forecast analysis with some potential upside. I know we feel pretty good about where we are with inventory build. Got it. Last question on DMD. Obviously, there's a number of other exon-amenable subgroups that are targeted with commercial therapy right now. What are the plans upon successful approval and launch here in terms of expanding to other exons? Yeah. Erick, you want to roll with that? Yeah, I can roll with that. Obviously, the response we got from the patient community on the other exon, or DMD 51, was tremendous. But following on that, a lot of people are like, "Well, what about my boy? They have a different exon." I think we feel a tremendous desire and need, a burden, to get the other exons out as quickly as possible. To that end, we were able to find some money in the budget this year. We accelerated IND-enabling tox studies. We accelerated some of the CMC. That way, we could get to the point where after we get approval for 51, knock on wood, we can have the conversation with the FDA about a development plan. Currently, if Doug were here, he would say he'd like to do a basket trial. I think that makes sense from an incidence and prevalence standpoint, and we'll get into that at the appropriate point. This is a very high priority for us. We're moving it as fast as we can, and we look forward to getting those discussions going with the FDA post-approval of 51. Great. You recently put in a program into the clinic in FSHD. I've been eagerly anticipating this for a while now, Novartis. To give them some credit, they're not just trying to pivot to FSHD now with Avidity, but they were very enthusiastic about it on acquisition. Can you walk through the compare and contrast in terms of your goals with the FSHD program? Listen, I think what is similar is we are both using an siRNA in this case. It is a cytoplasmic target, and so I think they have the right target. And what they did show was roughly 50% knockdown in the DUX4 transcriptome. And that is a good indicator that there is activity. Now, we are going to use a Fab. That is our difference. I think back to what I was saying at the beginning, we have an opportunity to dose higher. DUX4 has this intermittent expression, and so I think this distribution, broad coverage, and potentially being able to dose to a higher level to reduce that DUX4 even more could be an advantage for us. There are some other design features in how we have designed our siRNA, which we have not discussed yet, but that ability with our Fab to dose in a different way may give us some advantages. Whatever the case, this is a big market too. Sure is. Maybe last question for Erick. Cash was just about $900 million in June. Funding operations to the second quarter of 2028. Does that runway assume revenue from z-rostudirsen? How does that Yeah, we have the full commercial build and commercial P&L in there. Okay. But the runway is not including revenue from z-rostudirsen. Oh, yeah. That was the question. If that was your question. Yeah. Yeah. So it is only on the spend side of Just the spend, yeah. That could be a big offset there. Yeah. I guess just last question would be what are the key three or four catalysts to look for over the next year? Oh, man. It seems like there's a lot. There's some good ones. Maybe more than three or four. Yeah, there's some good ones. Listen, I think the first is approval of z-rostudirsen. You know the PDUFA date, January 21st. For a company like us, in a market like that, and the opportunity to become the leading company in DMD, that's a meaningful catalyst for us, I'll tell you. We're geared up for it internally. I think the other big catalyst is we've also told people in Q1, we will have the readout of that registrational expansion cohort. People are going to talk about vHOT a lot between now and then. Fortunately, all that gets settled in Q1, and we present the functional trends around that. That's a really important catalyst for the company, and we're excited about it. We also, as you mentioned, we initiated the FSHD. We need to get our first patient in and move forward with that program. Then I think this conversation that we just had about meeting with the FDA and start designing a basket trial. If we can make that, and I don't have dates for you, Rhonda, but we can do that really gives us an opportunity to essentially triple the market size fairly rapidly. Then we've talked about getting into later next year in terms of having our BLA for z-basivarsen. Man, those are that ought to move the needle for a company like us. Yeah. It's going to be a different conversation. You bet. Here next year. You bet. Looking forward to it. Yep. All right. Thank you. John and Erick, thanks so much for the time today. Appreciate it. Thank you.