I was gonna do a little karaoke here. All right, good afternoon, everyone. Thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here at Morgan Stanley. It's my pleasure to introduce the team from Dyne Therapeutics, including John Cox, CEO, Doug Kerr, CMO, and also Wildon Farwell, CMO as well. So we're fortunate to have two CMOs today, so we'll get a lot of our technical questions answered. But before we get started, I just need to read a quick disclaimer. "For important disclosures, please see your Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales rep." And just a quick reminder, the format for today is a fireside chat, so if anyone in the audience has a question, please raise your hand, and we will try to address it in our discussion. And with that, you know, John and team, thanks for joining us, and I'll just hand it over to you, John, to make some introductions. Great, thank you. Thanks, Mike. Well, as usual, we're gonna be making some forward-looking statements. But before we do that, I actually wanna talk not about forward, but maybe about the last week, and get in front of a few of the questions and be transparent about it. You know, earlier in the week, we had presented in advance of this conference, information about executive changes, and we had also announced information about our DMD program. And frankly, we timed it so that we could have more conversations here. Really, to be very transparent, I think we overloaded people with information, and the effect of that was that, in my view, some of the lead messages and stories got buried. I was quite really in some ways surprised and a bit disappointed that the stock had taken a hit. I know it's been recovering, and that seems appropriate. But I do wanna get to a couple of the messages and be really clear about it. One of the headlines was that several executives had resigned and that I think the expression was they had left the building or some phrase like that. I'm looking to my left at Wildon, and I think that was one of the people that they said left the building. I don't think I've left his side or vice versa, and he's here through the end of the year. And I will say there are a couple of people who'd come to us as just, to me, normal transition of a company going from an early-stage company, people who spent five years getting it to a certain point, proof of biology in humans, incredible accomplishment. We've been celebrating what they've done, and a couple of people on the team said, "You know, it's time for me to think about doing something different," and they happened to come to me recently. So rather than just kind of drag that out, we decided we'd get in front of it. But they haven't left the building, and they're still working with us, and they'll be advising us and so on. Beyond that, I thought the lead story for us and the lead message was that we were bringing in people for the next phase of this company. One of those people sitting next to me is Doug Kerr, and Doug is a renowned neurologist, neuroscientist, and clinician, and he's treated the kinds of patients that we are trying to go forward with drugs and present. He's worked with Wildon and myself at Biogen on things like Spinraza, and I want you to meet him today. I could go on and on, but I can't think of anybody better to take us across the finish line, and I think Wildon is. He can speak to the fact that this is the kind of person you'd like to hand these things off to. The other big news around people was that we did not have anyone for commercial. People talk about accelerated approval, and that's what I know people are excited about with our company. Two programs, potential of accelerated approval. It's not just getting it approved. That means you've got to launch it. And that means in rare diseases, you have to start preparing the market. Man, I'll tell you, when I was joining this company, the first person I wanted to bring in to lead commercial was Johanna Friedl-Nader. She is world-class. You need to get to know her. She was starting in September, and so we announced it, and I think that is a really big addition to the team. You may also notice that the company is a small company, did not have a Chief HR Officer. I need one. Lucia Celona has built companies with me in the past, and she's fantastic. I think with you know the folks leaving, for me as a CEO, seemed like kind of a natural thing for us to be dealing with. We have a lot of the great people that are still part of the leadership, our Chief Scientific Officer, our Chief Regulatory Officer, and so on. Unfortunately for the new people, that story of the capability build was missed. Hopefully, we can take care of that, and you guys can get to know the team a little bit. The second part is maybe even more important, and that is you know we had data on safety for DMD and DM1. We did have two SAEs at a high dose, which we'll talk about. But we also had efficacy, functional, and dystrophin data at our 20 mg/ kg dose. And that data was data that when we looked at it internally, we said, "My God, we've got functional data that tells us not just that we are maybe not slowing the disease, or the disease isn't progressing as fast, or we're slowing the decline." We actually saw a change from baseline, improvement, and that's in six months. And now everybody, we've dosed up, and we've taken some people who are at forty, and just to be cautious, we said, "Let's move them down to the twenty." And now we've got this fifty-plus person study with 20 mg/ kg, with the highest dystrophin level people have seen. And most importantly, I don't think anybody has seen functional benefit like that in the community. I think the regulators, and certainly anybody we talked to, has been excited about it from that standpoint. And that story, to us, was the story. We actually thought people were gonna be really feeling good about that 'cause we were celebrating internally about that piece. And then the final piece that we will talk about a little bit more is the question has been: How are you getting functional benefit, both in DM1 and in DMD, in such a short period of time? I mean, you use biomarkers for accelerated approval. You use those because you don't expect to get improvement that quickly, functional improvement. And when I joined this company, I know you may be asking, Well, why did I get here? You know, what brought me to the company, what I like about it. You know, when I talk to our Chief Scientific Officer, Oxana, her thesis has always been that with this Fab-targeting construct, we will get not just the skeletal muscle, we'll get the cardiac, we'll get the diaphragm, and in fact, we get to the brain, and we get broadly and deeply to these tissues that matter in these diseases, and if you do that, get that kind of distribution, then you will see or could see functional benefit much sooner than anybody would expect. That's translating from preclinical to today, so that's my preamble. Yep. And we are gonna be moving forward, I'll tell you, in terms of trying to get these things registered. And I'll stop there. Yep. No, that was a good introduction and clarified a couple things. Maybe a few follow-ups, maybe just one on the leadership changes. Yeah. Are there any plans to make future changes, or are we kind of, you know, in the right spot for now? Listen, I. Let me, let me answer, but first say I really like the leadership team we have. There isn't even the people who are leaving, nobody was asked to leave. Nobody was fired, nobody was asked to leave. I think we've got a great group. And that hasn't changed. Do I think as the company grows, are we gonna have to add some capabilities? I mean, I think if you look at our website, we don't have a Chief Financial Officer. We have some great finance people. I think a Chief Financial Officer is gonna make sense. Yep. So I think there'll be some additions like that, but. And And will there ever be more turnover? I'm not. I haven't come into this company that's being run so well and executing so well to say I need to shake it up. Yep. I don't. It's a great group. Yep. Maybe we can just switch to the DMD data, and you brought it up, just the two patients that experienced the safety. Can you maybe just give us a little bit more details on that, you know, and why that, you know, is or isn't concerning? Yeah. I mean, we've been all over it, and I think instead of me playing MD, I got two here that know what they're talking about. Wildon and I can both do that. Yeah. I mean, we had three SAEs in two patients in a single country, in Europe, in the summer. We think those SAEs are confounded by a likely infectious etiology, and actually are more likely to be related to that infection rather than related to drug. You know, the first one was an HUS, hemolytic uremic syndrome, in a country in which this was quite prevalent at the time, and HUS is largely attributed to infectious etiologies. This is what we think- Mm ... caused that. The HUS symptoms include hemolytic anemia, renal dysfunction, and thrombocytopenia, occurred four to five days after a dose at 40 milligrams per kilogram. There was treatment in an inpatient setting, and then the event resolved, and the patient was discharged and has recovered. The patient also had a Hemoccult positive stool, right? And that's very- Yep consistent with the hemolytic uremic syndrome also. Yep. Lots of very consistent pattern for hemolytic. We talked with multiple consultants, both world experts as well as experts in the country, who were very familiar with the epidemiology, very familiar with the ongoing presentations. All felt very consistent that the most likely etiology was due to an infection. We might have even had a culture positive, except the patient was put on antibiotics empirically. So there's lots of reason to think that this was not related to drug. However, we could not definitively declare an alternative diagnosis, an infectious etiology, so we should and have considered that it is possible that this is related to drug. The second event was a couple weeks later in the same country, heightened index of suspicion because the investigators knew about the first event and was actually pretty benign. It was a low-grade fever and tonsillitis, no big deal, but because of this index of suspicion, the patient was admitted and was found to have mild to modest drop in hemoglobin, platelets, and white blood cells. The tonsillitis resolved, the hematologic parameters resolved, no treatment was given. The patient was discharged, completely recovered. So those are the two events. You know, we feel very comfortable about the safety, but we elected, because we cannot rule out a relationship to the drug, patients down to 20 milligrams per kilogram. That is the dose at which all patients in DELI VER are now at 20 milligrams per kilogram. So we're gathering a huge data set. As it turns out, this is a profoundly important level of dystrophin and functional improvement at that dose, so we're tremendously excited about that. We will go forward. We're initiating a registration cohort at 20 milligrams per kilogram right now. And just to kind of preempt something that is on other people's minds, does that read through from a platform perspective over to myotonic dystrophy and achieve? We believe the answer is no. The most compelling reason for that is we've got data of over 675 doses in ACHIEVE, in myotonic dystrophy, over 50 patient years of exposure on drug, and we've seen nothing. Nothing in terms of hematologic parameters, certainly no renal insufficiency, nothing like that. And so we're very comfortable with the data package in myotonic dystrophy. And we should also note that the exposures to cargo, nucleic acid cargo, in DELIVER and the Fab dose in DELIVER at 40 mg per kg, both of those are higher than any and all exposures within ACHIEVE in myotonic dystrophy. So they are lower doses for many reasons, one of which is that the cargo in myotonic dystrophy utilizes a RNase H mechanism. It's enzymatic. You don't need to get as high doses. So we feel very comfortable about the safety profile because of what we've seen in ACHIEVE and because the exposures are lower, even if the SAEs that we saw were related to drug, and we don't think they are, but even if they are. And just to build on this, so we shared all of this data with the regulators. We shared this data with the FDA. They were very comfortable with our approach. They're very comfortable with how we're conducting the studies. They felt very good about how we have been moving forward. There has been no read-through. None of the regulators have been concerned about what was seen in DELIVER and been concerned about ACHIEVE. There's been no read-through on that. Everything that we saw in DELIVER, we've not seen anything on ACHIEVE. Again, we're very comfortable with the safety profile in both programs. Maybe just a quick follow-up, just given that it's, you know, considered most likely unrelated, you've obviously dropped the dose, but there are other things you can do to maybe mitigate this potential risk in the future, or any thoughts around that? Yeah, I mean, we'll look into it, right? So we haven't identified anything in particular that could preempt a particular patient. We plan to gather all of these data over the fall. Look at those patient characteristics. You know, the second patient had a preceding history of hemolytic anemia. Maybe that's relevant, maybe it's not. Maybe it's PK. Maybe there's kind of an exposure that was related to this. So we'll look at patient characteristics in those patients, other patients, PK, PD, and make some decisions as we go forward. Yeah. And could you decide to go up on the dose in the future? And what might be some of the considerations that, you know, lead you to do that? We certainly can. You know, we're really very. We have deep conviction that 20 mg per kilogram Q4 weeks is a transformative drug with really important functional benefits for DMD. That will be a registration, but we can and may explore higher doses, alternative dose regimens. What would you say to that, Wildon? Yeah, absolutely. Again, what we see is a very good safety profile at 20 mg per kg. We've clearly seen data that shows best-in-class dystrophin. We're seeing functional data that's never been seen before with an exon skipping, especially for exon 51. Again, this is a very severe phenotype, and to be able to see this degree of improvement in exon skipping, to see this degree of improvement in dystrophin, to now see functional benefit across multiple different efficacy measures, such as NSAA, such as Timed Up, such as SV95C, this is remarkable. This is what the field has been asking for for years and years. Now we're seeing that at 6 months across multiple cohorts. So we feel very good about the 20 mg per kg dose level, and we'll see whether we want to continue the dose escalate. Yep. Can you maybe talk about just next steps from the program from here and, and when we might get another update? Well, I think, in terms of updates, what we've been saying, and I think we'll stick to it, is that, by year-end, we're gonna provide clarity in both programs from a regulatory standpoint. You know, focusing on DMD, because I think that was where your question was, so I just add a bit more color. You know, we wanted to go up to 40 mg in hopes that we could quickly see some functional benefit. That was a pretty significant jump. We didn't have the 20 mg. If we had the 20 mg before we saw this 40 mg, I think everybody would be saying, "Man, this is really something," and how quickly can you move it? Now we've got, instead of just a small cohort of people on twenty, we've got a significant number of patients on 20. So when I think about next steps just internally, operationally, we need to move the registrational cohorts forward. We need to get with the FDA with this data. You know, I may be an optimist around it, but I think the FDA has spent a lot of time looking at data, trying to analyze dystrophin in hopes that they can... If you squint enough, you might see some- Mm-hmm ... functional benefit someday, some promise of it, and I get it. This is a different dialogue- Yep ... and a different data set, so I feel an obligation to get in front of the FDA because I think we have a and in front of the EMA. Yeah. There's nothing there for in Europe, and so we've got an obligation, in my mind. It's hard for me to imagine. I mean, if we talk to patient advocates, and at World Muscle, we're going to be showing this to KOLs people. I mean, the investor view is really important, but the clinicians are the ones that are dosing these patients and make the decision on the medicine. I think there's gonna be an expectation that we get this to patients as quickly as we can, and the 20 mg is a great outcome for us. Makes sense. And how do you think about, you know, expanding beyond exon 51 into sort of other exon? Oh, we're working on it. You know, I, I. We'd already, our scientists had already been basically applying the same platform, move right down the list of exons. We've got a number of exons in the works pre-clinically. We'll move hopefully, we can get those into IND enabling. I think the fact that the FDA has started talking about platform regulations, so ideal place for that. Dying to move those along now that we've seen the kind of functional data that we've seen. And then in exon 51, I think most people would agree, is probably the toughest exon to skip, and we're seeing this kind of impact. Imagine if we start moving out to exons that are easier to skip with our technology. and that expands the market in a big way. And with this proof of biology and maybe proof of concept we're seeing so far. Yeah ... that's another area we feel an obligation to move. You want to jump in there? Just to build a little bit upon that, John, because you talked about exon 51 being a severe phenotype, and that is very true. In fact, if you look at our 20 mg per kg cohort, one of the reasons we were so excited by that, the baseline NSAA in that cohort was 15, okay? That is a low score. That is a severe phenotype. So what did we see? What did we see on treatment? By 6 months, we saw a 2-point improvement in NSAA compared to baseline, let alone compared to placebo, compared to baseline, 2 points. What did gene therapy see? They saw, like, 0.6 compared to placebo, and that's after a year of treatment. So cross-trial comparisons, very difficult, different populations, but within the liver, what we see at six months, even on NSAA, is remarkable. Now, then you take it out of further to SV95C. SV95C, this is an objective endpoint. This is where kids are walking at home, and what's the stride velocity? How far, how fast are they able to perform? We know that this is an approvable endpoint in Europe. Europe has published that with SV95C, with a point one meter per second change, that is a bar that they would accept. What do we see in the trial? At six months, in 10 mg per kg, we already saw point one. That was replicated then at 12 months at 10 mg per kg. Then in this more severe cohort, with more severe phenotype, 20 mg per kg, we also see 0.1. That's all compared to baseline, let alone placebo, where we know this is a functional endpoint that can be approved in Europe. It makes us very confident in what we are seeing in DELIVER, and that John's point allows us to be confident in bringing forward these other exon skipping. Doug, do you want to add anything? Yeah, I mean, the only other comment is back to the basket of other exon approach. This is the perfect example of this. The FAB is the same, the linker is the same, the chemistry of the ASO is the same. And there is every opportunity, we believe, to expedite the approval of those, rather than completely independent clinical development programs. Then finally, you know, what gets us really excited in Duchenne, four states now are screening at birth for DMD, before the onset of fibrosis, inflammation, and adipose replacement of muscle tissue. That is an amazing question that has never been answered, is what if you give these boys normal dystrophin or near normal dystrophin at birth? Will they ever get Duchenne muscular dystrophy? Wildon and I did this together for Spinraza in SMA, and the answer to that question was no, they never got SMA. We want to do that same thing in DMD, and that possibility is now before the RUSP for newborn screening for DMD right now. It's an exciting time. Doug, Doug? ...The field of neuromuscular disease has always known that the greatest benefit occurs in patients, if you're able to get in early before the disease has the opportunity to set in. In DMD, before fibrosis, before you have a loss of function. So, what we would anticipate is getting in earlier, we would be able to see even greater benefit. What's remarkable in DELIVER is it's a broad patient population. You see just from our baseline characteristics, you see patients that have milder disease and patients that have more severe. In total, we're seeing benefit across the entire population, and so that is very encouraging, and it's replicating what we saw in DM1. Again, what we presented in May and with ACHIEVE is broad improvement across multiple functional domains across the entire population. So again, this is showing the power of FORCE with targeted delivery to deliver therapies where it's needed most, and we believe that's going to translate into function. Yep. And John, you talked about rapidly sort of advancing the program. Maybe just talk, you know, commercially. I know we're a little bit away from that, but just the impact of gene therapy and how exon skippers can kind of fit into that paradigm. You know, Look, I would love for gene therapy to work and be a cure. But what we know right now is it's a single dose with questionable durability and potentially some functional benefit. So I hope it works, and I hope it's additive to something like we have. But when I look at our data, to me, that's a first-line drug. That is a drug that you can dose repeatedly and not excessively, like, weekly or whatever. I mean, you can dose it once a month, so relatively convenient. Doctors can kind of will be able to determine what kind of outcome they have and keep dosing. So, and beyond that, you know, as Doug you know alluded to, you're talking about near normal dystrophin. We're not. It's not micro dystrophin. Mm-hmm. which people are still trying to learn whether micro- dystrophin, what effect does it really have? So I, I'm not trying to pooh-pooh it because there's certainly a world like these gentlemen know SMA so well, and there's the SMA world. People use gene therapy and, you know, oligos, so... But I, I do see this as a product. I, I just can't imagine in the current world, with patients being treated, you know, every one of these boys has an advocate, and it's a mom. Mm-hmm. They know what they're getting from the current naked oligos. They have questions about what's happening with gene therapy, and if we can provide some clarity on function. I think that's a market that's ripe for innovation. Yep. And I think they'll see it. Makes sense, and maybe we can shift gears a little bit just to DM1, and I think you're going to present an update later this year so maybe just kind of remind us, you know, what you've shown so far and what we should expect. Yeah, I'll listen. I will. I'll just kick it off- Sure. But I'm going to let the clinical guys really take us through it, because what I'll say about DM1 is, you know, I'm fairly new to DM1. Fortunately, when I joined the company, there was an event that the Myotonic Dystrophy Foundation was having a patient event in Boston. And I went, and you met the patients. And what struck me was that what the patients struggled with, we asked them: "What do you need?" Virtually, every one of them was having trouble with CNS-related manifestations, meaning they don't get to sleep, but they're sleeping essentially all day. They can't keep their eyes open, fatigue. It's awful. I mean, you see it when you're sitting with them, and they're struggling to function. They're not telling you, "Please fix my myotonia." I mean, that's nice, but there's drugs for myotonia. They're also telling you that, "I got cardiac issues, I got massive strength issues in different parts of my body, GI issues." The heterogeneity of that disease is absolutely profound, and it gets worse by generation, and hits them at different ages. So, what I love about our drug is that we know preclinically, and so far, what we've seen at various doses is that we're getting to, preclinically, we get to the heart. We get to smooth muscle. We know we get broadly and deeply into the brain. So the tissues that matter, just like in DMD, we hit those. Our studies and the way Wildon lined up those studies gives us a chance to see: Are we getting functional benefit in each of those areas? Everybody's excited about vHOT because it's a quick, easy, probably the first thing that you can see. We're happy to... We love the vHOT data, but we're going broader than that. Guys, take it. I mean, we know, you know, and Wildon go next. We know this is a spliceopathy. We know you have to get the drug to the nucleus. We know we get a lot of drug to the nucleus. We know we modulate splicing across tissues. This is a famously multisystem, multi-organ disease that you have to get everywhere. It's one of the powers of FORCE in the TFR1-mediated uptake, is you get this diffuse uptake. All of that functional benefit in DMD is, we think, going to roll over to DM1 because you're getting to a broad set of skeletal, cardiac, and smooth muscle tissues into the nucleus, modulating splicing. ...and we think including the CNS, and all of these manifestations can be corrected by that correction of that spliceopathy. And so myotonia is the low bar, but going beyond that and saying, when you fix the missplicing of other MBNL genes, what else will you do? You will affect muscle strength, ambulation, excessive daytime sleepiness, cardiac failure, cardiac arrhythmias, CNS, etc. So we're, we're really excited to see these higher dose cohorts and longer dose cohorts as we go later, through this year. Yeah, that's exactly what we always believed with ACHIEVE. When we set out, first and foremost, obviously, safety tolerability, we continue to see a very favorable safety profile. We knew the foundational biology was splicing. We've been able to see dose-dependent improvement in splicing. Our goal was 20%-25% improvement in splicing. We began to see that with the 3.4 mg per kg data, where we saw 19% improvement in splicing at three months. Now, with the 5.4 mg per kg three-month data, we saw a 27% improvement in splicing, so we're right in the range where we wanted to be. Then we said the first thing that has a high likelihood of change is improvement in myotonia. We evaluated vHOT. We continue to see that. We first saw that with 1.8. We continue to see that with 3.4. We continue to see that with 5.4. We're very confident in the improvement in vHOT, but we know the patients want more than that. That's what John described. We know that they are looking for a therapy that treats the totality of their disease. And so that's where we get excited when we see the benefit among the timed function tests, when we see the benefit across strength, when we see the benefit in these PROs, the activities of daily living, the MD HI, that has broad description of the comorbidities that these patients are suffering from. We continue to see benefit across all of this. So when we're thinking about going forward, we want to see the longer-term data on the 5.4. We haven't seen any of the data yet on the 6.8 mg per kg. We have the opportunity to see that data later this year, and so we'll look at that data and decide the next steps. Yep. And maybe just quickly, last minute, just the current thinking on the regulatory path forward. I know you're going to give us specifics, but just what are kind of the options at this point? I can start it and I'll be kind of brief about it, but you know, obviously we've got data we talked about in DMD that we're excited about. That's data that we have said we're initiating our registration cohorts. We'll do that, execute on it. And as we get data, we're going to get in front of the FDA and before the end of the year, we'll give you more clarity around that. Yeah. DM1 is a slightly different story in that, you know, DM1, we started those trials outside the United States, and in the United States, the key event for us right now is to get the IND approved, and that's all in the works. Mm-hmm. It's an IND, importantly, and it's not just a preclinical package. It's exactly what the company had planned long before I got here, and that is to collect data at higher doses outside the United States, and then come into the FDA with a comprehensive package that includes human clinical data. We had one meeting with the FDA, and it was on the splicing, and then we've talked about it. It was a, in my view, an exceptional meeting. The outcome of that meeting was: it was a pre-IND. They gave us a good full hour, and they said, "Guys, get your IND in, so we can have more conversations. Yeah. We're going to do that. Okay, great. So we're out of time, unfortunately, but yeah- Oh, shoot. Thanks so much, John, Doug, and Wildon. Really appreciate your time. Thank you. Thank you.