Tomorrow, it's going to have side effects. It's going to have sound effects. Anyway, thank you, everyone, for joining us for the Avidity Biosciences Fireside Chat today at the 45th Annual TD Cowen Healthcare Conference. I'm covering analyst Ritu Baral, and joining us from Avidity today, we have Sarah Boyce, CEO to my right, Mike Flanagan... PhD, our CSO and Steve Hughes, CMO in the middle. Thank you, guys, for joining us today. So you've got a lot of catalysts this year. So we're just going to start running through the three phase II/III programs, one by one in order of data. And then we'll touch on the pipeline and some of the corporate strategy going forward. But first up, what is going to be your first commercial program is del-zota in Exon 44 DMD. In early January, after a December meeting, you announced FDA confirmed the accelerated approval path is open for del-zota with biomarker expression data for BLA filing. What should investors expect as we approach this high-dose 10 mg/kg EXPLORE44 data, which will be at the MDA conference coming up? What's good data going to look like given the 5 mg data was already strong? Do you need 10 to be stronger? And if it is stronger, will it translate to even better clinical benefit? Yeah. So I would say, in terms of what does good data look like, you've already seen it. Actually, you've already seen what great data looks like with the 5 mg data. The agency has seen the 5 mg and the 10 mg data. And from. Did they see it at once in January? Yes. So they have seen the data. And from a dystrophin expression, we have more than exceeded what we need to show from a dystrophin expression with regards to for a filing. And the great news also coming out of that meeting was for the additional boys and young men that we were enrolling into the open- label extension study, which that enrollment has now completed, they didn't need to have muscle biopsies. So from a dystrophin expression perspective, we have already met what is needed. What I would say from the 10 mg data, while it's double the dose, it's given at a longer frequency duration. So it's not that much more drug. So data that you've already seen is great. And I would expect a lot of consistency as you look across the two dose groups. It's going to be representative. We shouldn't expect some incremental. Insofar as they have agreed for filing, they have seen all the data. They have essentially signed off on the reviewability of the data, understanding their discretion to do whatever it is they always do. Sometimes makes more sense than others. That's OK. We're on their side these days. Do you have any functional data? Has any correlative analysis been done between functional and expression to either support the accelerated filing or for eventual confirmatory? Yeah. So I would say for the acceleration filing, it will be on the basis of the dystrophin data. The data that we're looking forward to showing at the MDA meeting is from the EXPLORE 44 study. That's only a four-month, in the case of the 5 mg participants, and a five-month study for the 10 mg participants. So it's a little too early. It's too early. A little too early to look at functional. Maybe, Steve, if you want to talk about that a bit more from an aspect of when we're looking forward to showing that, and then also any other additional color. Yeah. So as Sarah said, it's not very long in terms of follow-up in the EXPLORE study. We have seen encouraging signs. The data is just not mature enough yet for sharing. We're giving guidance, or given guidance that we're going to share functional data in Q4. And that will be from the patients as they've gone out through the open-label extension study. So they'll have a longer duration of follow-up. Have you come to an agreement with FDA already on what confirmatory trials will look like? No. Typically, you would get agreement around the design of your confirmatory study at around about the time that you do your BLA submission so that that study can be well underway in terms of preparation at the time of getting a BLA. Got it. So BLA filing is guided for year-end at the same time. Yeah. And we've already done a lot of work on what the phase III study will look like. It's just that, as always, we don't really speculate until we've got. Are you waiting to generate more data before the BLA filing if they've already seen the 10 mg? No, so the data that we have to generate now is the safety follow-up. OK. That's the gating item. So we need a certain number of patients through one year, a certain number of patients through six months, and an overall size of database. So we've involved the additional 16 participants in the OLE. That's now complete. And it's just a matter of following them up. And then we'll cut the data and file by year-end. Oh, and going back to the correlative analysis, is there some sort of correlative analysis that needs to be done between expression and dystrophin? There isn't a requirement to show a correlation between the biomarker and the functional endpoints. Those are kind of things that are often done. But there is no requirement for it. Because it's essentially revertant fibers that are generated, correct? It is, so oftentimes, you'll see sponsors are looking at where the dystrophin is expressed, the percent positive fibers, the membrane-associated protein complex where the dystrophin is associated with that kind of thing. We will submit functional data as part of the package, but this study isn't designed for statistical significance on the functional endpoints. That will be the confirmatory study. Got it. Well, then the next question is the promotional plans for this. What sort of sales effort, commercial effort, is going to drive the launch? Obviously, the data looks very good. I think there's low--I'm sorry, very high probability of approval, low probability that anything's going to be wrong. That means you need to gear up for a 2026 launch. Probably you have like a year and three months or so for that. Yeah. We are in pre-launch planning. One of the real advantages around, we have three programs that are all in the rare disease space, all in the skeletal muscle space. It's actually a great deal of synergy from one drug to another. So what that means is what we build for del-zota, we can then just layer on del-des and then del-brax. So we are putting a lot of time at the moment in building out our patient services model on our market access and reimbursement preparations. And for del-zota and DMD, the field force will probably be pretty small. There's 500 neuromuscular specialists in the U.S. There's about 100 who are dedicated to pediatric. So that's a pretty small population. And I'm getting some feedback from my microphone. I don't know if you can help me at the back. I think I am too, actually. Yeah. But thank you. Let's see if that, actually, that is a bit better. That's a better thing. So it's a pretty small target physician-patient population. So the sales team will be pretty lean. Actually, most of the work is in building the patient services, the market access, the MSL team, patient mapping. That's going to be a fixed overhead cost for all of the three programs. Correct. So you're going to make that investment upfront for Exon 44, understanding that it's a smaller addressable market than FSHD and DM1. And then you just build on top of it. It's really--we've used. Those 100 pediatric reps will do DMD. They won't necessarily. I'm sorry, not reps. 100 pediatric neuromuscular specialists will do DMD. However, you do need to hit a larger number for FSHD and DM1, which is adult. Yeah. So this 500 neuromuscular specialists, so for those, we would actually anticipate the sales force calling on all of those for DMD. But it's about 100 that are just pediatric. For FSHD and myotonic dystrophy, it's the neuromuscular specialists. But remember, these two patient population sizes are each on their own the same size as cystic fibrosis. So the next layer of prescribers is actually the neurologists. Oh, OK. And that's where we're actually also now doing our work on the next layer of prescribers. Beyond the neurologists? Which is the neurologists. What's that number? It's about 3,000- 4,000 neurologists. OK, and that's community neurologists or specialists? It's specialists and some community. OK. Got it. OK. Got it. So you'll see us kind of expand out. OK. But initially, for del-zota, for DMD. The 500 call points. Narrow call points. Yep. Building what we believe and our goal is to build the best patient services team in the industry, the same for market access, and then we'll just layer on the same team. That sort of patient hub will encompass insurance support? Yeah. Like the usual? Yeah. What sort of patient services could you bring to DMD, DM1, FSHD that would be useful to these patients? Oftentimes, they can be very tailored. We absolutely would envisage something that's very tailored. Our head of patient services, we recently hired out of Horizon. She built what is one of the best patient services teams in the industry there. A big part of it is working with payers. But it's also about, often in the neuromuscular space, is the people living with disabilities, helping them figure out how they can get to and from clinics, making sure the setup is there for the infusion centers, that the infusion centers are ready to receive these patients, as well as also around disease education, education around the drug, family support. So it becomes pretty all-encompassing. And often, look, and I'm someone who spent a significant portion of my career as a marketer and in sales and marketing. But really, in rare diseases, a big part of it all sits in your patient services and your market access. Yeah. The easier you can make these patients--the patients' lives are hard enough. They have enough. The easier you make them, the more you become a partner in their lives, versus a marketer for a product or service. It's a real sort of white glove type service approach. As you're building any organization, often when you're launching a drug, you're doing the two things at the same time. You're building all your infrastructure. You're building all your ability to handle patient-level data, insurance data. You're building all of that while launching the drug. We're going to do that for del-zota. Then for del-des and del-brax, we already will have had it built. It gives us a big advantage. Is there somebody who does it really well that could serve as an example? We really liked the way Horizon did it, which is why we hired them. OK. Fair enough. Fair enough. Let's move to del-des and DM1 now. In early January, you noted Harbor, the phase III study, is on track to finish enrollment in mid-2025, which was your answer to the question when I first answered it, when you told me about the Harbor design. So that's consistent. And then U.S.-EU regulatory submissions in 2026, as promised. Any updates on when we should expect that 30-week top-line efficacy data? And I want to ask you around disclosure given the longer duration of that study, including the longer blinded duration of the study for efficacy. What should we expect? Yeah. So maybe just taking it in order. The study will be completely enrolled by mid-year, so around July time frame, plus 30 weeks for that last patient to complete. I'm glad you say that because some people consider September mid-year, and it's not. Then 30 weeks, and then some time to clean all the database. First half of next year isn't a bad time point for that. As you said, the study is still ongoing at the time we file. Although we're analyzing statistically all of the endpoints at week 30, the regulators are still going to be very interested in those endpoints at week 54 as well to make sure that they're maintained. We have to be very careful not to create any perception of bias. What other sponsors have done in the same position is to disclose whether the study met its primary and key secondary endpoints, and then what the p-values were, and then to disclose the actual data from the study at a subsequent scientific meeting. Are you going to Alnylam us? You are, aren't you, which is going to get a p-value? We've looked very closely at what other sponsors have done in this position. So maintaining the integrity of the study is incredibly important. Of course. Of course. And then the full data, will you be allowed to disclose that after last patient, last visit? Yeah, so once last patient, last visits happened, and then we've cleaned, we've locked the study, then there's no obvious concerns about the data. So then everything will be released at once, the week 30 analysis as well as the week 52 analysis. Yeah. There's a lot of data points that we're looking at in the study. So obviously, some of it will come out at scientific congresses. But the fulsome data set of everything is likely to be a manuscript. Oh, everything would be a manuscript at that point. Yeah. So we'll obviously disclose the primary, the key secondaries, how big the change from in the placebo and the active group. On the press release. And the other data points as well. It's not just those four endpoints that we're measuring. There's a number of other endpoints that we haven't disclosed publicly. And those will be coming out by way of a manuscript at a later point in time. Safety and tolerability, will that be released with the 30-week p-value? The safety and tolerability in the terms of the tables, no, because that would involve disclosing unblinded data. Qualitatively? Qualitatively, yeah. OK. What factors could gate the filing in 2026? What do you need to wait for outside of efficacy data? Nothing, really. So it's just a matter of executing on the pivotal trial, getting the patients enrolled within that mid-year time frame, and then. No additional data to be generated in any capacity. OK. And I would say from a BLA submission preparation, this is where we'll start to see some of our efficiencies from one program to another. Because the CMC section, for example, with the antibody, it's the same. So that's also going to help us. Could you do a rolling where you put the CMC in first? We haven't gone into that level of detail. OK. OK. That's fair. Recently, you guided to additional phase I/II MARINA data in Q1 and open-label extension data in Q4. What are we getting in Q1? So we're very pleased to be able to say that we're well along the way now of getting that data accepted in a top-tier journal. OK, so that's a journal. So that will be a journal publication where we're able to disclose more of the data than we have been able to do in platform presentations and posters so far. Will this include the 2 mg- 4 mg dose titration patients? This will include the manuscript is focused on the 2 mg and 4 mg cohorts from the MARINA study. It's the totality of data from the MARINA study, much more detail on the safety profile that we saw, more detail on the individual clinical endpoints and breakdown of those. Are these clinical endpoints that you've already disclosed, or are there other functions? If you remember, some of the endpoints, such as 10-meter walk run test we disclosed very early on, as we switched to the data that we were going to use as the primary and the key secondaries, at the one-year time point, we didn't disclose the subsequent 10-meter walk run data. So that will be part of the manuscript. And there's some other clinical endpoint data as well that will provide updated cuts. And then for things like quantitative muscle testing, where you're testing multiple different muscle groups, we've shared the aggregate data. And we'll be breaking that out by individual muscle group as well. Oh, got it. And then the longer-term data we're getting from the OLE in Q4, same thing? The longer-term data from the OLE will focus on the 4 mg/kg patients again, because that's our registrational dose. That data through, if you remember, the last cut of the data we did was at a one-year time point. Now we'll be looking at a two-year time point and again comparing with natural history. So for del-des, I think that the conservative viewpoint is that you will have competition eventually, and not too far away, as your competitor continues to talk about the potential for accelerated approval on splicing. As you think about their shorter time path to approval, how do you think about the commercial positioning of del-des versus competition? Yeah, so I would say for the HARBOR study with del-des, we designed it both from two aspects. One, for global regulatory approval, and then also for reimbursement and for commercialization, so it was designed from a commercial strategy perspective. Both from the payers and the clinicians? Correct. OK. Payers, clinicians, regulators. So it gives a complete package. And in terms of form, we do this in FSHD as well, we do that payer research as part of the study design process to make sure that we can build a package that's going to be acceptable to payers and also one from a prescriber's that, in terms of, is the most robust data package for them also. So what is that? I'm usually, as I am, familiar with rare neuromuscular diseases. There's one player. The payers pay or they don't pay. They don't really have a choice. What do they value in these rare neuromuscular diseases? What do they see as worth paying for here and not there? I think it's in terms of one of the elements as you look as to how we design the study. It gives a holistic look of the disease from an aspect of myotonia, which we measure through the video hand opening time, quantitative muscle strength that gives you strength throughout the measures of strength throughout the body, hand grip strength, and then the DM1-Activ. If there's an eventuality where, let's say, there's another drug that has accelerated approval, and it's approval on biomarker data, and you have a drug, you have del-des, then from a payer perspective, one's going to get preference over the other. And it is the drug that has the functional data. Then on top of that, also the fact that we're doing it around the world is really important as well. U.S. is the biggest market. Japan is the second biggest market in the world. And then you have each of the European markets in importance as well. So we've really gone after a global study for global leadership for both first-in-class and best-in-class. OK. We've got 10 minutes left. Yes. Absolutely need to hit rapid fire. Early January, you indicated the phase II/III Exon 44 trial cohort C, the biomarker cohort. Enrollment should complete in Q2. When are we going to get that cohort C biomarker data? And what are you going to tell us what this biomarker is? Yeah. So, Q2 is kind of like the quarter of FSHD, and there's really two aspects. There's an FSHD meeting correct in Q2. There is, yes. There is coincidence. OK. So, Steve, do you want to talk about sort of, and I would say there's two pieces of work. One is the FORTITUDE data. And then also there's our global phase III study designed for full approval in the U.S. and obviously approval in Japan and Europe. And then also, really importantly, the accelerated approval path in the U.S. But maybe Steve, if you want to get into it a bit more. Tell us what this biomarker is? Good. Trying to. You have to keep trying. FSHD really is a perfect disease for an accelerated approval. It ticks all of the boxes for further regulatory guidelines, very high unmet need. It hits people in the prime of their life, in their teens and early 20s. Causes a lot of disability. A substantial number of patients end up wheelchair dependent, high socioeconomic burden, high health burden, no approved treatments at all. A biomarker that's very tractable with clear line of sight through to the mechanism of the disease. A highly plausible biomarker, which is DUX4, single cause of the disease, DUX4. DUX4 doesn't cause other diseases. FSHD isn't caused by other causative factors. We can measure the downstream gene signature of DUX4 at single points in time using a muscle biopsy. And we've seen that data for the 2 mg/kg cohort, where we looked at the biomarker in multiple different ways, showed very consistent greater than 50% reduction. And we also have the circulating biomarker, which is the protein that reads off of one of the DUX4 regulated transcripts. So we know that the circulating biomarker is DUX4 regulated. The novel piece is that nobody knew that it existed in the plasma before. And we're able to track that over time. It correlates very nicely with creatine kinase, which is a measure of muscle damage. And we've already shown in the 2 mg/kg cohort that we shared last year that we're seeing directional improvements in multiple different functional endpoints. So we've really joined all of the dots from the biomarker all the way through to clinical improvement. The goal in Cohort C is to basically replicate that data set in a larger cohort at the registrational dose of measurement, which is 2 mg/kg every six weeks. How fast is this biomarker expressed? So the biomarker is actually there in very low levels. So what we've done is we've looked in plasma samples from healthy volunteers. And we've looked at two different healthy volunteer cohorts. And we've looked at two different natural history data sets. And we've looked at the FORTITUDE data set. And patients are up here. Yeah. Healthy volunteers are down here, very, very low level of expression, and there's good statistical separation between the two. OK. And so. I guess the right question is, how fast does the biomarker fall? OK. So that's what I was coming on to. So we see the biomarker comes down very, very quickly. So we saw the biomarker was reduced at the first time point that we measured it as compared to the placebo cohort. Which was which time point? I think that was around six weeks. OK. So it was very, very, very early that we saw the biomarker come down. And when it comes down, it stays down. So the biomarker comes down quickly. The 2 and the 4 mg/kg cohorts basically are superimposable so that we don't see any further reduction in the circulating biomarker by going from 2 to 4, which is the reason why we selected 2 as our go forward registrational dose. Creatine kinase also comes down very quickly. It mirrors the changes in the biomarker that we saw. And there's a very high degree of correlation between the two. And then you have data from FORTITUDE coming out in Q2 as well, correct? Is it this Cohort C data, or is this other data? No. It's data from cohort, so confusing with the different cohorts, so it's data from Cohort A and B. A and B. OK. The original cohort. Cohort C is the cohort we started for accelerated approval, which we're tracking to have enrollment completion of in Q2 also. Got it. And you said it was the first time point is six weeks. So it can't possibly be this Cohort C data. That Cohort C data was. And Cohort C, we're looking for that study for accelerated approval. So that study will stay blinded. OK. On your point on the circulating biomarker, look, it's a huge breakthrough for the field. We do plan to disclose it. We've said we have made that commitment. That will be something that will be coming up as well. I'm assuming that there will be IP wrapped around this. Yes. OK, and do you need that final Cohort C data to have confirmative, confirmative, is that a word? Confirmative FDA buy-in to the accelerated pathway? Or can you get that buy-in before the final data? We're looking to get that buy-in, and we're looking to provide an update on that and sort of get that accelerated approval path sort of agreed to in Q2. Obviously, that will then be subject to data, of course. Of course. But you can hopefully lay down. Get alignment. Before the final effect size. Correct. OK. Got it. And then you also indicated you were going to get FDA alignment on the global confirmatory phase III. That's the Cohort D. What are your current thoughts, oh, three minutes. What are your current thoughts on functional endpoints for the accelerated approval? I mean, we've talked to KOLs who are big fans of your program, but crap all over the reachable workspace for practical reasons. One of them even said something like, yeah, you have to go to RadioShack to get the point, to get the equipment. There's no RadioShack anymore. So that seems impossible. So it has to be. It leaves me thinking it has to be some composite of like 10-meter walk, strength measures, or something, potentially in conjunction with the biomarker. But what functional measures are in play? Yeah. So all of that is coming soon. We talked to the same key opinion leaders in Sweden. If not, probably more often. We'll send you to RadioShack. We also have spent a lot of time speaking to payers as well around, from a payer perspective, what's going to be the most meaningful. The great thing is that we have choices. We have choices of a broad range of different measures. We have our preferred design. We know what we're looking to get alignment around. And that work's ongoing. Is there alignment between different global regulatory agencies or reasonable alignment that you can get? We were able to do that with the HARBOR study, and we're looking to do the same thing here. Got it. We provide the equipment. We don't go to RadioShack. We give it to them. Thank goodness. OK. Sarah, in 90 seconds, please talk to us about the preclinical pipeline. You know, we have 90. Come on, 90 seconds. Let's see. Preclinical pipeline. You know what I think you should know about the pipeline, so everyone knows about the first three programs. Yeah. But what people don't realize is that we have a robust pipeline that follows that. For neuromuscular as well as cardio, you saw precision cardiology. Yes. So we laid out our first two programs. We have multiple programs behind that, as well as also neuromuscular programs. This is 1086 and 1072. These are the cardio pipeline. Yeah. So PLN and PRKA G2, as well as a neuromuscular pipeline. We haven't disclosed that target. And a DMD pipeline. So we've talked about DMD 45 as our next exon that's going to enter the clinic. And we're in IND-enabling studies right now. What is the population for 45 versus 44? 45 is actually bigger than 44. It's about 1,100, whereas 44 is around 900. Meaningful. You saw the 44 data. That's awesome. Yeah. What you should take away: love the first three programs. As the CSO, you should also love the pipeline. How are the partnerships going? You have a Lilly partnership on immuno-oncology. You have a Bristol partnership on cardiovascular. Yeah. So the BMS collaboration's going great. If you remember, they have five targets and we have five targets. So we're working on their targets also, moving really quickly towards the clinic. So we're super happy working with BMS. As you know, they're kind of a premier cardiovascular space with mavacamten. So the precision cardiology fits really nicely with that. Lilly is awesome. They're doing great. We have both an immunology as well as an undisclosed target with Lilly and those continue to move forward. So we're looking forward to those entering the clinic. Great. With that, we are out of time. Thank you, guys, for joining us. This was very helpful. Thank you. There's a lot of data to keep track of. Yes. What's this one? What's this one? What's this one?