All right, we can get started. Good morning, everyone. Welcome back to the Cantor Healthcare Conference. My name is Eric Schmidt, and my distinct pleasure to host our next session with Dyne Therapeutics. We've got John Cox, the company's Chief Executive Officer, and Erick Lucera, the company's Chief Financial Officer. We also have several members of the management team here in the office, sorry, in the audience. It's been a long couple of days. It's been a long week, too. We've had some news earlier in the week. Before we get into that, John, maybe you can just set the stage for those who are a little less familiar with the company. What is the state of affairs at Dyne today? The state of affairs are very good. It's a great time for Dyne. Really an exciting time, actually. Over the last probably year and a half, two years, we've spent time kind of building out a management team, leadership team, to prepare the company for the transition we're going through, which is to be prepared to launch two major drugs in two areas where there's very serious unmet need. Our first one is right around the corner with DMD. It is a phenomenal opportunity, with a drug called z-rostudirsen, and we have a PDUFA date in January. We're transitioning to a commercial company. We're executing well. Clinical execution has been very, very good. Regulatory execution, strong. We've got the team now to kind of commercialize a couple of products, and for a young company, it doesn't get any better than that. I think it all kind of builds off of the platform that we have as a company, and you know about the platform, Eric, and that platform is very much based upon a delivery technology we call FORCE that gives us the ability to deliver oligonucleotides broadly and deeply to tissue, and I think in a way that exceeds what anybody has seen before, including to the CNS. That same platform is what we've used with two different types of oligonucleotides treating two different diseases. We're in a really unique position now, overcoming that kind of technical hurdle in the field, and I think it just hearkens to a bright future for nucleic acid medicines, and we're kind of in a leadership position there. Great. Normally, I'd begin this talk with a discussion of z-rostudirsen. That's obviously your most advanced asset. It's an asset that we think is going to be a billion-dollar opportunity for you in DMD. Given the news earlier this week from Novartis and their drug del-desiran in the DM1 field, I think we should start with, if you don't mind- Sure. z-basivarsen, and make sure we address head-on the competitive event that's out there, that drug having failed in its pivotal study, similar to zevacavarsin. Novartis, of course, had an oligo antibody conjugate, and it didn't meet its phase III endpoint. What was your initial impression and read from that event? Well, I think we were surprised by that, just like most. I think that they had used a particular endpoint that they didn't meet as a phase III primary endpoint called vHOT, or video hand opening time for myotonia, and that's a very easy endpoint to move in that field. So we had expected them to meet that endpoint. We are using, as you know, vHOT as an intermediate clinical endpoint for an accelerated approval, very different kind of pathway, and only at six months. We can talk about some of the differences in approach with that. I don't have insights into what happened statistically for them. I would come back to, and I think it's important to come back to, there are very significant differences between our molecule and the molecule you referenced, and it gets down to the fundamental science, and people are now starting to go back to that as you know. Our payload is a very different payload from the Avidity or Novartis molecule. They used an siRNA. We are using an ASO, and we intentionally used an ASO, an antisense oligonucleotide, to get to the nucleus, and this disease is ultimately a nuclear spliceopathy. So it very much is about getting sufficient drug to the target. When we did our early work on our M ulti Ascending Dose study to pick the right dose to get to the nucleus and affect the disease broadly, including vHOT, we did a dose escalation study, and we saw that we had vHOT improvement at a very low dose. In other words, you need very little splicing correction to get there. We continued to evaluate splicing correction as we dose escalated and went all the way up to 6.8 mg, so a much higher dose than what we've seen with the competition, because we can. The Fab allows us to do that within a reasonable safety profile. One of the questions has been, in their early study in MARINA, at 2 mg/kg, they did not see much with vHOT. They went to 4 mg/kg, but dosing every six weeks. They saw vHOT improvement. I think now people are asking, well, when they went to the phase III HARBOR study, they extended the dosing frequency to Q8. I think we do wonder whether or not they had enough payload really to get to the target, or were they on the edge? We don't believe we're anywhere near the edge when it comes to vHOT. We are far beyond where we need to be for vHOT, and in fact, we're at a dose that ultimately is allowing us to see potential CNS effect and other much more clinically meaningful measures associated with this disease. In addition to the oligonucleotide versus siRNA payload difference, you did refer to the fact you've got a Fab, they had a full-length antibody, and you've done some very rigorous analysis of splicing data. Can you remind us or share with us that splicing result that you think well documented across your doses? The fundamental premise that this company was built on was that there are companies who are using monoclonal antibodies to target the transferrin receptor. Virtually everyone, including the Avidity molecule, would run into an issue where with monoclonal antibodies, you'd block that receptor for a month or more just based on the half-life of an antibody. We used an antibody fragment, just hit a particular epitope, and have a half-life of maybe three hours, so that the transferrin receptor could transport iron as normal. In other words, so we would not be limited in dose by anemia. That was the case, and we have continued. In fact, we weren't even limited at the 6.8 mg. At the 1.8 mg/ kg when we first started dosing in the mAb, we had some splicing correction, a little noisy, lower. As we moved up to 5.4 mg, we were getting in the 20% splicing correction range. Our belief was if you got to that kind of splicing correction, and without getting into too much of the molecular aspects, it would free up what was known as the MBNL protein that is bound up in the nucleus because of the disease, and that would allow for normal transcription, and you might start seeing all kinds of positive effects. The effects that we saw early on, even at 1.8 mg, was vHOT improvement. That was easy. You need very little splicing correction to get that improvement. But we said, "That's not enough. We want to see improvement in five-times sit to stand, quantitative muscle testing. We even want to see on MDHI, do we see CNS subscales because that's an important disease feature." One of the things about our fab compared to the other molecule you talked about is that the fab crosses the blood-brain barrier, and we are able to get our product to the brain, then CNS is a big issue in DM1. Ultimately, what we saw is that we got to a splicing level of roughly 20% at 5.4 mg and 6.8 mg, selected our dose, and that's what we moved forward with the registrational expansion cohort. Okay. One possible interpretation of the Novartis data this week is that the vHOT endpoint, the video hand opening endpoint, is just noisy. It's erratic. Sure. It's got a lot of variability in it. How would you respond to that potential criticism, which as you mentioned, is the same primary endpoint in your accelerated approval strategy? Right. Are you changing anything about your design or approach based on that? Well, it does raise questions about variability, but the variability is something that's been known. If you look at natural history with vHOT, there are patients who have zero myotonic issue with their hand, and there are patients that it can take them 50, 60 seconds to open their hand. So there is naturally variability with it. I'll just say that we studied that in our MAD. We analyzed the variability. We used that kind of analysis to determine with our registrational expansion cohort, the N that we would need, and also the inclusion exclusion criteria that we would try to match with the multi-ascended dose in terms of the patient characteristics. We have analyzed our stats extensively. I would love to see the Novartis data and to understand what was missed or what went wrong and could we learn something from that. That would be helpful. But we've also gone back to our stats and said, "We've got 71 patients in the study, 3: 1 on drug." We have accounted for, we believe, variability, and think we are reasonably or well powered under a number of different kind of ranges and considerations. So we will have that as part of an intermediate clinical endpoint. Again, I don't see that as a 12-month endpoint for a phase III. We used it for that. Then we've come on top of that, as you know, with the overall clinical development plan is I think we're the only company out there at this point with a phase III program, with a primary endpoint, with what we think is a field defining clinically meaningful endpoint in five-times sit to stand, and that program is moving forward. So we've got both paths, near term accelerated approval with vHOT, supported by splicing correction, which we're powered for in that study, then we come in with our phase III, which is ongoing. That's an interesting comment. The implications of your ongoing phase III with the clinical endpoint is that you almost have a second shot on goal. If vHOT for some reason isn't the right endpoint or isn't measurable, hopefully that's not the case. That's right. But you're the only game in town with a clinical trial in late stages that addresses other endpoints that are non-vHOT. Well, that seems to be a fair statement based upon what we heard out of Novartis on Tuesday. Okay. Just timing of the achieve results using the accelerated approval strategy and next steps if the trial is to be successful. We anticipate a readout from the registrational expansion cohort in Q1 of next year. That is not far off. We are also going to provide some data at both AANEM here towards the end of the month and at World Muscle, which will be some longer-term data from a group of 24 patients at 12 months on drug that had gone into the long-term extension portion post MAD. That data will be data in which we show vHOT. It will also be data in which we will also be providing some baseline data from our rec on vHOT. We are going to provide a series of functional measures at the 12-month time point. We had picked that, Eric, because we had actually anticipated that the data from Novartis would be okay, and we would be talking about function, because vHOT is not that clinically meaningful. The other functional measures were what we wanted to share. We will be sharing that data soon, but the actual readout from the rec is in Q1. Okay, the other implication from Novartis is there is no other commercial player. Can you size up this market for us? This is a really meaningful market. I think when Novartis bought Avidity, in many ways, what it did was validate the importance of and significance of that market. We've estimated that there's roughly 30,000 patients that would be addressable in the United States. It's probably, as is often the case in rare diseases, much higher. Once there's a drug, and once people realize that there's a treatment, more and more patients get identified. This disease, I hope people look at it closely, but there is nothing for the patients. There is really no standard of care. It is a devastating disease, and it is a disease that does not get diagnosed typically for seven years. It's misdiagnosed for seven years. People might have GI problems, so they get diagnosed with UC. People have CNS issues, and they get diagnosed with sleep apnea and other things. It can go on for. In fact, we'll have patients that a person will have their newborn have congenital DM1, and that's when the mother gets diagnosed, and some relatives. I think this is probably a much larger market, but even at the numbers I gave you, it is a very significant market. Okay. Probably best to transition to z-rostudirsen then. Sure. The opportunity in Exon 51 amenable skipping DMD. Just first level set us on this program. What have you shown to date? Where are you in terms of the regulatory process? DMD is, and you know this well, I think people know, there are a number of drugs out there. There is nothing that is resulting in clear functional improvement for these patients. There is a desperate need. The community needs something that gives them some functional improvement. Now, we had provided data from the registrational expansion cohort in which we measured dystrophin, which everybody measures as a biomarker. z-rostudirsen is for a subpopulation of DMD that are amenable to Exon 51 skipping. That's the most significant population. It's also arguably the toughest exon to skip. We took on one very challenging. The drug that's out there today, eteplirsen, had shown maybe they could get to 0.7%, 0.9% dystrophin, something like that. Very low. We're roughly 10X. That's what our data has shown at six months. We've even shown longer-term data at MDA that roughly tripled from that number in a small set of patients. The dystrophin bar, in terms of a biomarker, we have real significance there. We feel confident from an accelerated approval pathway that that's what's needed, and we'll meet that. The real question is what dystrophin level will ever result in people being able to get up from the floor faster, increase their 10 m walk run, et cetera, extend the strength of their heart and their lung activity after they've been in a wheelchair. We measured all six kind of major functional measures, time to rise from floor velocity, et cetera. What we saw at six months and out to roughly 24 months, on every single one of those measures, we saw improvement from placebo or baseline. Not slowing of disease, but actual improvement. I don't think anybody's seen anything quite like that, and so we're really excited to get this in front of patients, and there's a lot of enthusiasm for it. Where are you in the process? You filed, you've been accepted for priority review. You've got a PDUFA date. Well- Go ahead. -you just covered the regulatory piece perfectly. The regulatory piece has gone quite well. The FDA came back, as you said, they accepted it. We got priority review. They indicated they did not expect an advisory board meeting. All of that has been positive, and we're continuing through that process. We wouldn't comment too much on details right now, but we're moving right through it. January 21st is the PDUFA date. As a company, I would say at the beginning, it's quite a transformative time. We're doing everything that you do to build a great biotech company. We have a commercial organization. Our team, Johanna's here, who's leading that. We have brought in just absolute pros into commercial and medical and market access, patient services, all the pieces you need in neuromuscular rare diseases. All that's coming together. We've got a CMC supply team that is working hard to make the product and build inventory. We're very much out there talking to payers and clinicians and patient advocacy organizations, and we're preparing for a very meaningful and successful launch. Okay. I know you earned your stripes in the operation CMC part of the world. Anything with this new class of molecules, first-in-class antibody conjugate that's coming to the market that we need to be concerned about or aware of? Well, listen, as you said, I spent much of my life in supply chain and tech ops and launching products at Biogen. I'm always neurotic about it. You have to stay all over every step of it. It's not like you just build inventory and put it in a freezer two years in advance. You're building the supply chain components along the way, and you are scaling as you're getting ready to launch. All of those activities are in process. We are all over it. Our inventory build is as we planned, and it is kind of matching up with what we're planning from a commercial launch. So we feel very good about it. With this, again, novel class of molecules from a cost of goods benchmarking standpoint, anything you'd say about relative cost of goods? I think I'll give the CFO a chance to- Oh, thank you. -to talk a little bit. Thank you. I think with respect to cost of goods, remember, we have three components. You've got the antibody or you got the fab, you got the linker, you got the oligochemistry. So it is a complex molecule to make. We feel very confident about our ability to do that. And when you think about where cost of goods are, obviously where we are today, the first products that are sold have already been made and expensed as R&D. So the initial cost of goods will be zero. At some point, we'll burn through that inventory, and then we will transition towards a cost of goods that you're more accustomed to seeing in antibody land. So we'll. Antibody cost of goods. Yeah. Very good margin. Yeah. We'll see. Okay. Let's talk about the opportunity commercially then, and the size of this market. How many patients have DMD Exon 51 skippable mutations? In the United States, where we'll first launch, we're estimating about 1,600 patients. Of those patients, there's 400- 500 we believe that are on EXONDYS, the eteplirsen drug from Sarepta. Obviously, we would anticipate those to switch, and fairly rapidly. It really depends, in part, on the process with payers and so on. There is anticipation there, particularly since with that drug, set aside challenge in terms of efficacy with the drug, they have to dose and get it infused every week, and we're a monthly dose. Beyond that, there's probably an equal number, 400- 500, that had been on EXONDYS who had quit. Then you've got another 500 or 600 that have maybe steroids, but have never quite believed that there was something for them. There's a handful on gene therapy, but the excitement over gene therapy has waned for a number of reasons, but particularly safety. The question is, how do you get to these additional patients? I think the switches will be those with the experience should be fairly straightforward, but we are putting a lot of effort into making sure that there is awareness out there for the other 1,000 or so patients. That doesn't sound like a huge number of patients, but man, is it meaningful for those that have it. Beyond that, the current pricing paradigm, which you'll probably get to next, with the Sarepta drug, is roughly estimated about $1 million a patient. So that in itself becomes a fairly meaningful market for us. But I will tell you the bigger, and I know you and I, we've talked about this before. You were excited about us focused on DMD. It goes so far beyond Exon 51. Our CSO here, Ron Batra, is here, and he has been working on the additional exons preclinically. For us to just simply change the nucleotide sequence and have the same link or the same fab and really move these other through, hopefully in a basket type trial, now you are talking about tripling or more the market we just talked about. I very much. Hold that thought. You bet. You got me going. Two more questions quickly on Exon 51. First, you talked about a relatively rapid transition or switching period for those on EXONDYS to z-rostudirsen. What would be the likely rate-limiting step in that process? In these rare diseases, and particularly high-priced rare diseases, the natural friction is the process of moving through coverage with payers. You think it is just that? Yeah. I think that will be the biggest piece. The awareness in the community of what we are doing, how our drug has been working, the clinicians that treat in this way with exon skippers and those that have seen our results, I think there is a lot of enthusiasm for it. I do think much of that is just going to be kind of the normal friction during the first year. Okay. The opportunity ex-U.S., where are we with regard to plans to try and bring this more broadly? We need to get this type of medicine to Europe. We need to get it into Japan. These boys need it as well. Our base case right now is that we will be required to complete our phase III, and that phase III we've initiated. That will be further out. We're not anticipating an accelerated approval in Europe. Maybe that changes, but we don't think so. We see that as the base case, and we're planning for that. A big part of the phase III is a confirmatory trial obligation as part of the accelerated approval pathway with the FDA. The bigger part is this will enable us to launch ex-U.S. Okay. Now we can get to the other exon-skippers. You got 44, 45, 53, 55, four others. I know you're keen to talk about them. So timelines for getting them into the clinic and how does this kind of platform technology designation? We haven't given a timeline simply because I think it does come down to discussions that we will need to have after we have this first approval with the FDA. Things like platform designation, absolutely, but you have to have a product approved before you can get platform designation. So we need to get that approval done in January. The work that we're doing now is we've taken the drug candidates off the shelf, moving through the preclinical work, including tox work, and doing the things that we need to do. Then we can sit down with the FDA with that data, with the data that they've seen from z-rostudirsen, and make a case, I hope. I'm very confident we can make a case, and we'll have that discussion about a basket type trial, and that's kind of where the rubber meets the road. We need to design that. Going through every one of these exons with the same type of development path we just went through would not make sense. Hopefully, the FDA will be cooperative with that and work with us, and then I think we can come up with a timeline. We're moving as fast as we can. We've just got a couple minutes left, so I want to touch on your most recent IND candidate, DYNE-302 for FSHD. You got that cleared earlier this summer. Tell us about how the profile of this drug is different from the benchmark drug, del-brax, also from Novartis. Yeah. Listen, I think again, we're using really the same Fab, same platform. We're using an siRNA, which I think is the right payload. The drug that you just mentioned, the competitive drug, is also using that siRNA, so I think it's the right payload. Now, we may have some slight modifications in terms of how we target. But in that disease, it's really about knocking down this DUX4 expression, which is intermittent. And one of the nice features of our FORCE, again, is the ability to dose higher. Now, whether we would need to dose higher than the competition, we'll see, but it allows us to do that. And I think the dosing piece and the distribution, having a Fab that is smaller, it distributes, we think, more diffusely across the tissue, is going to be absolutely key in a disease like FSHD. And maybe the dose and getting that dose optimized to deal with that intermittent nature of that expression could prove to be differentiating in terms of functional improvement for that disease. We just got our IND approved. We'll start evaluating. We'll have a blood biomarker. We'll take our biopsies. We'll look for drug in the tissue, and we'll evaluate that, and then we'll come to an optimal kind of dose, and then we can see if we differentiate it. Whatever the case, that's also a very big market, and if there's two or three of us out there, that's fine. You think we'll get data next year? I don't think it'll be next year. I think we'll be moving through our dosing work at that time, but that would probably be a little early. Okay. Erick, we'll close with the prototypical CFO question on cash balance, runway, milestones. Anything else you want to tell us? Yeah, I would just say in terms of cash and capital and how we think about it, obviously, we think we're doing something really unique and special. The FORCE platform has given us an opportunity to develop multiple products, and we've identified seven or so right now where we can leverage CMC and commercial organization to give us a strong growth profile and strong profitability well into the next decade. Specifically, we have $1.3 billion of cash pro forma adjusted for the raise we did in July, and that gets us into the second quarter of 2028. So we feel we're in a great capital position to allow us to execute on a very unique strategy that we think will deliver great results for patients and investors. John, Erick, thanks for a very timely- Thank you. -and very informative session. Really appreciate it. Love to. Thanks, guys.