Okay. Welcome, everyone. Thanks for joining us. I'm Joe Schwartz from the Leerink Partners Biotech Equity Research Team, and it's my pleasure to host Avidity Biosciences. Today we have Mike MacLean, CFO; Steve Hughes, CMO; and Mike Flanagan, CSO, with us for the update. Thanks so much for being with us. Thanks for having us here, Joe. We always enjoy coming to Miami in March. Yeah. Why don't we start with a high-level overview of the company's recent progress and the upcoming catalysts we can look forward to on each of your programs? Great. Look, 2025 is going to be a very busy year. We've got a lot going on at the company. Over the top, we're going to provide data readouts on all three of our late-stage clinical programs. We are executing on our regulatory pathway. Most notably, we're filing a BLA for our del-zota product around the end of the year. We plan on being commercial in 2026, which is really exciting for the company. Also, on the regulatory front, we have what we call the quarter of del-brax, which is the second quarter of the year, coming up here shortly. The reason is we have around four or five catalysts in the quarter that all have to do with the progression of del-brax and our data related to del-brax. On a regulatory front, that's going to provide clarity for what our global full approval strategy and clinical design will look like, and our progression with the FDA on the accelerated approval strategy. Lastly, as I said, we're going to plan the commercial execution for del-zota in 2026. We are well underway in terms of building the company to be a company that is commercial. We are research, development, and commercial now. That includes the infrastructure that's going to be necessary to get patients identified, diagnosed, and on treatment. It's also going to focus on having the clinical supply and now commercial supply ready for the market. Okay. Great. Thanks for that overview. Why don't we dive right into del-desiran, your most advanced program in DM1? How should we think about the timing of full study enrollment for the HARBOR study? Quite frankly, the simple answer is we're on track. We commenced enrollment in July of 2024. We said we had a one-year target to complete enrollment, and we expect to complete enrollment in mid-2025. The uptake has been vigorous, which is what we expected. We are really excited about this as our first phase three trial and how it's going. Okay. Good. I guess, what is the most important endpoint to look for when we get to that moment? How do we think about the hierarchy of endpoints, if there is one, in terms of importance for patients with DM1? Let me try to take that. We designed the study and the endpoints that we look at with the aim of describing the important elements of the disease. There is no single endpoint, given that this is a multi-system disease, that is going to capture every element of the disease. We have endpoints that look across the range of the different symptomatology. The primary endpoint, of course, is looking at the myotonia element of the disease with vHOT. We have key secondaries that will be examined in a statistical hierarchy, looking at hand grip strength. When you look at the grip strength together with the video hand opening time, that gives you an idea of gross motor function of the hand. We have QMT, which looks at upper limb and lower limb muscle strength. Really a holistic view of what's going on from a strength perspective across the body. Finally, how all of those things translate into the patient's ability to self-care, looking at the DM1-Activ PRO patient-reported outcome for activities of daily living. A range of different endpoints. In terms of how they're looked at by the agency, of course, we have to choose one. That is the primary endpoint. We've powered the study so that it's very well powered for all of the endpoints, including the key secondary endpoints that we're looking at. In truth, the regulators are going to be looking not just at the primary. They're going to look across the range of endpoints that you have when determining the strength of evidence for approval. The fact that we're extremely well powered across all of our endpoints, the fact that we've already seen that we see good separation from placebo and good separation from natural history over a one-year time frame at our chosen registrational dose gives us great confidence as we move forward that we'll have a positive outcome. How does it work, given there's a look at 30 weeks and 54 weeks? Why the two cuts of the data? Is one more important for some purposes, whereas the other is more important for other purposes? Yeah. I guess one cut of the data is the data cut that's going to be looking at the primary endpoint and the key secondary endpoints. Because we see very early movement on the efficacy endpoints, we saw very early movement in the MARINA study and sustained benefit out through the open label extension, that allows us to cut those endpoints early. That allows us, hopefully, to have an early filing. Our strategy is to file with the week 30 data and then provide the week 54 data, which is primarily a long-term safety follow-up during the review period at the day 128 date. Okay. Great. There were some changes. There were some differences in the protocol for HARBOR relative to MARINA, such as you're looking at patients over 16. You're looking at a different dosing schedule and different randomization. I think the rest is mostly the same. Can you talk about the rationale for any of this evolution? Yeah, sure. When you do your first- in-human study, then it's usual, unless it's a purely pediatric disease, to start in adults. The MARINA study was 18 and up. As we move forward into the HARBOR study, we brought in pediatric patients in the upper adolescent range. In that 16-18 range that we've gone into, they behave very similarly to the adults. We don't anticipate that we're going to be compromising on the generalizability of the data that we saw in the MARINA study. As you go down younger in age than that, you start pulling in childhood onset and congenital patients, which do really have a very different phenotype with much more of a cognitive impairment. On all of the other changes, we kept the dose the same at 4 mg per kg, but we moved it to a more frequent dose interval at every eight weeks instead of every 13 weeks. By going more frequently, if there's any more efficacy to be had out of the drug, we anticipate that we might be able to squeeze some more efficacy out of the dose at every eight weeks. In truth, the rationale for moving the dose interval to be slightly shorter was because some of the patients were noticing that their symptomatology was starting to wane at the end of the dose interval. By bringing it up to every eight weeks, that allows us to keep everybody at the same level of improvement throughout the entire dose interval. If anything, that could improve statistical power. Moving from a three to one randomization to a one to one randomization, as you go for asymmetrical randomization ratios, you take a hit on power because of the asymmetry, but also you can get an increased placebo effect with a three to one randomization, for example, because patients know that they have an increased chance of drug versus placebo, and that can factor into the clinical endpoints. By moving to a one to one randomization, one, we maximize statistical power, and also we minimize the potential for placebo effect as well. Net-net, all of the changes that we made, we believe are going to increase, if anything, the statistical power, or at worst, have a neutral effect. Yeah. Very helpful. Thanks for that perspective. You are clearly in the lead for DM1 with an exciting profile and put a lot of thought into your program. There are some competitors in the space. How are you thinking about the landscape overall and how del-desiran might be differentiated? Mike, do you want to take that? Yeah, yeah. I can take that. Like you said, we're leading the space. I think it just solidifies our first-in-class and best-in-class feeling for this drug. The reason I say that, first-in-class, we're clearly ahead. Like Mike said, we'll be enrolling the HARBOR trial by Q2 or early July kind of time frame. We're looking good at that. Best-in-class, you can see that we've demonstrated great muscle concentrations that have led to DMPK knockdown that's led to dose-dependent Muscleblind-like protein and on to function that Steve talked about. I think you can see that we've connected all those dots. The competition, I think, really validates our approach, whether it's DMPK knockdown or release of Muscleblind-like protein. It just validates what we've been talking about for the last year or 18 months. Okay. How are you thinking about full approval in the space? Would a competitor getting accelerated approval shake things up in any way? It seems like not everybody is following the same playbook. Yeah, that for sure is the case. First of all, when we were looking at our registrational pathway, we did look at the accelerated approval pathway, whether that was available. Honestly, our logic was, wow, we're seeing functional benefits so early. It really is a cleaner way to run a registrational trial and results in what we'll see as global full approval in our first instance. Relatively quickly, as Steve said, our cutoff is at 30 weeks in terms of the power of the trial. We're very excited about the pathway that we've chosen. As we look at what we're really trying to do here, our mission is to get therapies to patients. With full approval, what we're going to have is we're going to have a global full approval. We will be approved in the U.S. and outside of the U.S., specifically Europe and Japan. We will be going to payers with a package for reimbursement that includes the functional benefit. The way I look at it is that's the right thing to do for patients. Competitively, having operated in the commercial environment most of my career, that is the package you want in a competitive environment. We would be first in terms of formulary, likely with most of the payers, because they would see that our drug results in functional benefit. We would be well along in the European and Japanese markets, which are going to be really important to our franchise. We do talk about the registrational pathway, but really the more meaningful way to measure it is how will this drug be delivered to patients quickly and broadly as soon as possible. With the global full approval strategy, that is a clear pathway. Yep. Makes sense. Let's switch gears to del-brax and FSHD. You're clearly coming up on a very busy second quarter. Can you lay out for us what your goals are and what we should look forward to there? Yeah. Look, I mean, as I said, there are multiple. The only catalyst in Q2 are del-brax, and I think there's five of them. We are going to show data from the FORTITUDE trial. Remember, we have shown some of the data from both the two and four mg cohorts, but we haven't shown all of the top-line data. We expect to show that in Q2. We are looking to show the regulatory pathway again for a global full approval strategy. The way I think about it, and sometimes these conversations can be a little circular, but the simple way I think about it is that we're focused on a global full approval strategy for del-brax. That's what we're working on right now with the regulators in the U.S., EU, and Japan and other places. In Q2, we're going to unveil that clinical design, and we're going to initiate the global full approval strategy. We've also created a pathway for an accelerated approval strategy on a biomarker in the U.S. We actually started that cohort in late 2024. That is ongoing. We're enrolling. Once we have the global full approval trial design agreed, we will go to the regulators, or the FDA specifically, with the accelerated pathway. We will be completed enrollment in Q2. We expect to update on what that pathway is in Q2. I think I've previously referred to it as the quarter of del-brax. There's going to be a lot going on for the FSHD program and the FSHD community in the second quarter. Great. If I could just drill down on the FDA part of all of the events there. I understand that it's usually best practice. The FDA likes when there's a registrational study ongoing before a company will broach the discussion of accelerated approval. They'll already have that data. You're going to have that data ongoing as well. Is this kind of in keeping with that kind of a strategy? Because I heard that the phase three trial design agreement is expected to occur before the accelerated approval discussion happens. It seems like it's in reverse, but maybe I'm missing something. I'm not sure if it's in reverse, but what we want to do is, again, back to we are looking for a global full approval strategy. We did not want to slow down that discussion with the FDA and others as we had a discussion on accelerated approval. That's why the order is first to get agreement on a global full approval strategy with the global regulators and then have the conversation with accelerated so that we're already doing the work on the biomarker cohort. That wasn't getting slowed down in any way. It's a very good callout that you have with regard to the fact that there will be a confirmatory trial already initiated because I do think that the FDA will look at that favorably in terms of the accelerated approval discussion. Steve, do you want to add to that? Yeah. The reason for kind of separating the two different conversations is really feasibility of having all of the conversations in a one-hour meeting. There are FDA guidance notes around what you should do for your type C meetings and really 11 questions, although about is the max. When you go in and are asking about your pivotal program, you're not just asking about the phase three study design. You're asking about the biostats approach that you're going to be taking. You're asking about eligibility criteria. These all form separate questions. You're asking about some non-clinical things. You're asking about what your carc package is going to look like, asking about what your CMC. There is a whole bunch of questions that you throw in there. If you multiply that by two for both accelerated approval and full approval, you very quickly run out of kind of space. It just made a lot more sense to separate them into two discussions. We're not keeping one secret. We're not coming in with this and then say, and then at the next meeting, pulling something else out of our sleeve. We're being very transparent that there are two discussions in play here. Those have been received very favorably by the agency in terms of having those two discussions separately. Right. Okay. That's very helpful. Makes sense. What additional FORTITUDE data will we get in the second quarter? You've already reported a fair amount. This is the top-line data from the FORTITUDE study. If you're in the FORTITUDE first two cohorts, cohorts A and B, all of the cohorts in FORTITUDE are one year in duration. We are now coming up to the point where the top-dose cohort will have run through the whole one year of study. That is the data that we're seeing from the first two cohorts in the study through one full year. That will include biomarker data. It will also include functional data from those two cohorts as well. Cohort C will be ongoing at that time. There will not be any data from that cohort because that is registrational. We need to keep that blinded. Okay. Good. Can you remind us again why you're taking this biomarker cohort path other than time and expediency? I guess what gives you confidence that it could work in your favor? What evidence do you think the FDA might need to see in order to agree that this is the right way forward? You can start, Steve, and then I can. Okay. There's a lot of questions in that one question there. Maybe if I forget a piece, then please jump back in. Maybe starting with why accelerated approval. First of all, it doesn't slow down the full approval. The strategy is global registration, full approval. That study has to be negotiated before you start it. We have to have the conversation with the regulators, and then we can start. The earliest that we could really start that full approval cohort was where we're planning to start it in Q2 of this year. There was an opportunity to get an even faster registration potentially in the United States by going down the accelerated approval track. We felt that we could start an accelerated approval cohort straight away after we had the data readout from the two and the four, and we were able to select a dose. Essentially, we're opportunistically taking advantage of the accelerated approval pathway for the United States only, but not slowing down our full approval. In terms of the tractability of the accelerated approval, really, FSHD is a perfect disease for an accelerated approval. Very high unmet need, no available treatments. It hits people in the prime of their life, causes a lot of long-term morbidity. Patients end up in wheelchairs, can't work, for example. The underlying cause is well known. There's a single underlying cause. It's aberrant DUX4 expression. Aberrant DUX4 expression doesn't lead to five other diseases. It only leads to FSHD. You can measure DUX4 activation through well-described biomarkers that have been described by other sponsors, have been described by various academic panels. All of that is well accepted. The biology of the disease in terms of the underlying cause is well understood. We've got a circulating biomarker, so we can track DUX4 activation over time. We've shown that when you treat patients with del-brax, that that circulating biomarker goes down. We've shown that the falls in the circulating biomarker correlate very highly with changes in CK. They come down as well. We've also shown trends towards functional improvement across several different functional endpoints. We have really got a very compelling package, we believe, to have a discussion and get alignment with FDA around an accelerated approval. Okay. Great. That answered it all. Great. Nothing for you? I think maybe we can just add in when we did look at the circulating biomarker, if you look at healthy volunteers, they're low or unmeasurable for the circulating biomarker. What we've done is looked at FSHD patients, not only our FORTITUDE, but you see an elevation in that circulating biomarker that's clearly discernible and statistically different than the healthy volunteers. We have looked at our FORTITUDE trial. We have looked at healthy natural history patients, a couple of different populations of patients, and continued to see that kind of circulating biomarker difference. Just on the circulating biomarker itself is that obviously, we know what the protein is. It's secreted. You can look at it longitudinally. We know that it's DUX4 regulated because there's DUX4 binding sites in front of it. Just to realize DUX4 is a transcription factor, so it turns on this gene. Perhaps most importantly, when you treat with del-brax, the circulating biomarker goes down in conjunction with the CK. We continue to put work into that circulating biomarker. Excellent. We'll stay tuned there. It's super interesting. Let's switch gears to DMD. How should we think about the readout any day now versus the fourth quarter when we saw the OLE data? What we've seen so far is kind of unprecedented. How are you going to top that? First of all, let's recognize we're probably talking about Avidity's first marketed product for del-brax. Exactly. Right. Exactly. Right. We're excited about showing the new data. I think that the way to think about it is we're going to be showing all of the data that is going to be meaningful to these patients and the dose selection for the BLA. Anything to add to that, Steve? I guess we've shown 5 mg/kg data already. You've mentioned that the data was remarkable. It was really unprecedented in terms of the dystrophin levels. So 32% dystrophin. I mean, that dwarfs anything that's been shown by any other treatments that are available for this disease. Good clean safety data as well. All of this was at the 5 mg/kg. The data that we'll be showing, I guess, in just a little around a week is for the 10 mg/kg cohort as well. A win there would be, again, showing unprecedented levels of dystrophin production that we're seeing, very high levels of exon skipping, very high levels of delivery to the muscle, and a very clean safety data package. There won't be any surprises in the data. We've already looked at the patients, and we've got in our corporate deck a slide of the patients that were on placebo from the 5 mg per kg cohort in the EXPLORE44 study. When they switched over to active drug, their creatine kinase levels came down very, very quickly to close to the upper limit of normal. They followed the same trajectory as the patients that started on 5 mg per kg. Very good consistency in the data that we've seen in terms of improvements in muscle health. We fully anticipate that the 10 mg per kg data is going to recapitulate those changes. Cool. I guess, how are you thinking about what the FDA wants to see here? We obviously have some treatments that were approved with some flexibility. Are you thinking that that regulatory pathway is still available? Yeah. So we've met with FDA. We've had a type C meeting with FDA specifically around the data. They saw all of the 5 mg per kg data. They saw data for 10 mg per kg for about a little over half of the cohort, which is what we had available at the time. It was very clear that the accelerated approval pathway was open. We had a broad group of reviewers in the meeting, and they were all very excited about the high levels of dystrophin that we're seeing. Also the CK as well was extremely exciting for them. We got very clear guidance. Pathway's open. We've got all of the dystrophin data that we need. We don't need any more biopsy data. That's fine. It's now just about safety follow-up. We have added additional patients to the open label extension to enlarge the overall number of exposures to around about 40, which is within the range of other drugs that have been approved in this disease. We just need a little bit longer follow-up on those patients before we're able to file. The goal is, well, we're on track for filing in Q4 of this year, so BLA next year. Great. Mike, you mentioned that this is going to be your first commercial product. Can you give us your view into how the company is going to evolve from here as you build out and support this launch and ultimately some others? Yeah, absolutely. As I mentioned at the beginning of this talk, we've already started building out our commercial function, and we're well along. The beauty of our three late-stage clinical trials, the potential products that are going to come out of them, is that they are all in the same space, and they all reach out to the same call point. It's a significant DM1 and FSHD, it's a 100% overlap between the prescribers, doctors who treat these patients. There's a significant overlap for DMD. Some docs only treat children, so they wouldn't overlap with the others, but it's still quite remarkable. As we think about building everything that we need to build for a rare disease population for DMD, that translates over to FSHD and DM1 too. That is patient access, that is patient services, and the things that surround that in terms of being able to provide this medical treatment to these patients. We will be building an infrastructure commercially that will leverage three products or three potential products. There is going to be tremendous efficiency. We literally have a perfect scenario where we get to build the infrastructure and test it with our smallest patient population, at least in the US, and maybe in Europe as well. We will see what the timing is among all of these. We are really excited about it, and we think that this is such a privilege to treat the rare disease population. To be able to have one infrastructure that can service all of these patients is very efficient and is going to be meaningful relationships that we're going to build with the doctors and the patient populations. Yeah. Right. It's nice when the whole model comes together. Lastly, maybe we can just touch on the two precision cardiology programs that you introduced last year. When will we hear some more about how they're advancing? Yeah, yeah. We have two programs in precision cardiology, phospholamban and PRKG2, so two kind of distinct spaces, one in hypertrophic cardiomyopathies, the other one in dilated cardiomyopathies, both precision targets that are gain of function targets. They are perfect for an siRNA approach where we are delivering to the heart. Both of those, they are moving quickly through our research. We are expecting in 2026 and 2027 for INDs and be bringing those towards the clinic. At the same time, in November, we also indicated that we are starting to introduce some of our new technology into our precision cardiology programs where we are able to demonstrate better delivery to the heart. You are kind of seeing the next wave of things that we are looking at. We have selected precision cardiology because we know we can deliver there. We know we can deliver high amounts of silencing RNA. It's a wide open space with a lot of gain of function targets, so it's perfect for silencing RNA. We expect to, just like we're in neuromuscular, we expect to be in that space for a decade or longer, right? There's enough targets to be there for a long time, so we can build another franchise. Very interesting. We will stay tuned. Thanks so much for the update. Thanks. Thanks. Great being here.