Okay, welcome everyone. It's Josh, and we're from the Cantor Fitzgerald Biotech team, and continuing with the muscular dystrophy symposium, it's my pleasure to welcome the wonderful team from Avidity, a company that's developing muscle-targeted oligos for very important unmet medical needs in the muscle disease space. The focus for today's session is really going to be trying to connect the dots of the myotonic dystrophy program, the underlying disease genetics, biomarkers, and ultimately clinical outcome and development path, hopefully in a way that everyone can really benefit from, those who are newer to the story and those who are a little bit more familiar with Avidity. Why don't we start right in and focus on the myotonic dystrophy program. Sarah, maybe some quick intro comments and then a quick snapshot of myotonic dystrophy, the disease, the phenotype, and genotype. Yeah, yeah, thanks so much, Josh, and thank you for inviting us today. I'm really looking forward to this chat, and we love to get into science, and we also like to pull back and remember what it is we're trying to do, which is to be able to make a profound impact on people's lives. So maybe a little bit on myotonic dystrophy. So myotonic dystrophy is a rare genetic disease. There are no approved treatments for people living with myotonic dystrophy. And up until our announcement, I think a month ago, yeah, it was, it was in March. We're in April now, up until our announcement in March, no one had even ever done a phase III. We are incredibly excited to be initiating the HARVEST study, which is our phase III study in this quarter, and really pleased with the design of the study, which is a very simple, straightforward study, which we view as being very much de-risked from the data that we've seen in the MARINA Open-Label Extension study. Our goal is to recruit that study within a year, so we are moving very expeditiously. The reason why of that is because of the high level of unmet medical need. People living with myotonic dystrophy, as I said, it's a genetic disease. You also see the tragedy in genetic diseases where you see family members impacted as well. It doesn't just impact one individual, but a whole family. The hallmark of the disease is in the name, in the myotonic, which is myotonia, the inability to, or the slowing of, the ability to release a contracted muscle. So I'm contracting my fist, and you see that I can do this very easily. People with myotonic dystrophy cannot. If people haven't seen it on our website, I would urge you to go to our corporate update where you'll see a video, and that very simply will show you what del-desiran can do in a very visual, simple way and why this drug is so important. It's caused by a mutation in the DMPK gene, which leads to a set of CUG repeats. Ultimately, what happens is a really important splicing factor called muscleblind, gets stuck, and that impacts a whole range of thousands of genes, actually, and a whole range of downstream issues that leads to a disease that is multisymptomatic and incredibly debilitating. So that's sort of the overall disease at a high level. With del-desiran, we designed a drug. It's an siRNA, which we deliver to muscle cells that directly targets the underlying causes of disease. We see the release of muscleblind, and actually, in our latest data set, reversal of disease progression across a broad range of functional measures, which is why we know that we have an incredibly important program and a great responsibility to be able to initiate the HARBOR study and get it recruited as quickly as possible to get this drug to people. All right, super. If we focus on the CUG repeats, I guess what's happening is you have these long mRNA trinucleotide repeats that are taking on a quaternary folding structure that's sequestering the muscleblind. As you describe, the sequestration of that muscleblind leads to all these downstream splicing aberrancies that ultimately lead to the disease. How do we think about the dose effect? In theory, the more of these repeats that a patient has, the more muscleblind sequestration and the worse the disease phenotype. Do we see that in databases? Yeah, I'll take that. It's a great question, and really, we're learning so much about this disease. I mean, we know quite a bit. We've done RNA sequencing. We have terabytes of data, and we're really learning. And I mean, it's been exciting as a scientist to just get into the space, be able to have a therapy that really interacts with the underlying cause of disease. So we know a lot. We're learning a lot, and there's still a lot to know. So thinking about the CUG repeats and kind of the relationship between CUG repeats, actually, it's a pretty poor correlation between the number of CUG repeats and the disease severity. And you kind of go like, "Why is that?" It seems like it should be such a straightforward kind of connect the dots, like you said. It's really, I think, what we need to think about and maybe introduce a new term is kind of CUG load. So what is CUG load? What does that mean exactly? It's really kind of the CUGs that sequester muscleblind. It's different than just having repeats because not every repeat will bind muscleblind and sequester it. I think that's why you don't see a really tight correlation between the number of CUG repeats and disease. So I think we need to think about it as a load. How much muscleblind-like protein do these CUG repeats carry? How much do they carry? I think that's the way to start thinking about the disease. You talked about the role of muscleblind-like protein in splicing. Is it unique to splicing in muscle cells, or does it play a role in non-muscle cells as well? Yeah, it has a role generally. I mean, but what happens is that, for whatever reason, and it's still unclear as to why it manifests itself mostly in muscle. So it does have this kind of effect in muscle, although the heart, and there's some cognitive issues also around DMPK. But I think the majority of the patients really see the effect in the muscle. And so it has this underlying cause in muscle. But again, it's really unclear exactly why that is. There isn't a smoking gun where you can point to a specific event because it affects thousands of different proteins. Got it. And how do you hone in when thousands of proteins are affected? Which might be the ones that are actually important for, I guess, the two components? Because there are two components of this disease, at least as it pertains to muscle. One is that myotonia, which feels a little bit more like an ion channel kind of consideration. Then one's the muscle weakness itself, which may be driven by other splicing abnormalities. Yeah, I think it's a great question, kind of trying to uncover what is the smoking gun, really trying to hone in on that. And we continue to learn more and more about the disease. I think the best example, like you pointed out, and kind of what Sarah alluded to initially, is the myotonia. What causes myotonia? I think the best example, or what's most cited in the literature, is the chloride channel. And the chloride channel, what happens is that because of the sequestration of muscleblind, it actually affects the exons that are spliced in or spliced out. And then what happens? You get a stop codon. And what a stop codon is, is that it prematurely terminates that protein, so you don't have a functional protein. And if you don't have a functional protein for chloride channel, then it's hard to flux ions across the membrane, and that provides that inability or slowing of relaxation of your muscle. So that's probably the best example and the most proximal event that people can point to. But when you start looking at the data, it's not quite that biology is never that clean. It's always complex. So there's a number of other, probably the calcium channel, the ryanodine receptor, there's a number of different parts that play into that role. And that's probably why you see different patients having different effects, because every person's slightly different. But I think the chloride channel gives you kind of a sense of that myotonia. And when you release Muscleblind, you get improved and more normalized splicing of that chloride channel, which then leads to that functional ability. So I think going back to connecting the dots, del-desiran, when we can deliver to muscle, it knocks down DMPK, the target that it's directed towards. That knocking down a DMPK releases that CUG load, or the CUGs get degraded that then allow muscleblind to be released, or newly synthesized DMPK doesn't suck up muscleblind. That muscleblind then is able to do its normal job, which is to splice normally all these different genes. And that's where people start feeling—we heard anecdotes from people where they start feeling better, right? They can start going back to the gym. They're doing things that they hadn't been able to do. I mean, really reversing disease for a number of these events that people experience day in and day out, which is super exciting. So as Sarah described, the program for myotonic dystrophy is an antibody to the transferrin receptor to target the muscle, conjugated with an RNAi against DMPK to knock down the DMPK to ultimately lead to less sequestration of muscleblind, free up the splicing machinery. So one thing that we've heard about, at least in theory, is that RNAi is good for targeting cytoplasmic mRNA, whereas antisense is better in the nucleus. This seems like it's a nucleus disease. I think we've probably seen that theory about RNAi versus antisense debunked in other settings. But why choose RNAi, and what is your confidence that RNAi can really get to the nuclear mRNA to knock down DMPK? Yeah, it's pretty simple, right? siRNAs are super potent. They're highly durable. They're catalytically active, and they work both in the nucleus and cytoplasm. And we can deliver them to the muscle. And we've had this kind of conversation over the years about cytoplasm and nucleus. I think our data in humans demonstrates that we can target siRNAs or target siRNAs to the nucleus, and that siRNAs can knock down nuclear transcripts. So I think, without a doubt, we've demonstrated that because you're seeing functional benefit in patients. And I think everyone can agree that mutant DMPK is in the nucleus. And the only way you're going to see functional benefits is if you knock down that target in the nucleus. So I think, first, we've demonstrated in humans, and then we could go back to preclinical where we've demonstrated in preclinical models. But really, the proof is in humans, and I think we've demonstrated that. All right. Yeah, sorry. I mean, I was just going to add to that, and maybe to put it more, yeah, to emphasize that point from a simple perspective, it does. siRNAs are active in the nucleus. del-desiran, yes, it's literally that simple. And you see it through all of our data. Agreed, yeah. Let's talk about measuring stuff when it comes to myotonic dystrophy. Let's start with first serum biomarkers. Are there any that can guide clinical development, CK, or otherwise? Yeah, we would love to have a circulating biomarker. CK is not that biomarker. It's kind of variable in myotonic dystrophy patients. Unlike DMD, you can measure CK, I think. But for people living with myotonic dystrophy, CK is not a good biomarker. So we've looked for other biomarkers and have been unable to find a circulating biomarker for DM1 patients. We'd love it, but we don't have one. Yeah. All right. So. Yeah. I'm sorry. I think we would love it because muscle biopsies are really hard, hard to do to get that consistency. You're doing it with a fine needle. But ultimately, for patients, nobody wants a needle stuck in the muscle, in particular when you have a muscular dystrophy. And that's also why, for the HARBOR study, there's no muscle biopsies because we don't need them. But yeah, a circulating biomarker would be fantastic, and we have not found one. Sarah, you point to some of the challenges of muscle biopsies. Maybe we can elaborate a little bit on that and talk about the noise that may come from muscle biopsies in this condition, whether it's heterogeneity of what's actually in the biopsy, whether it's heterogeneity of the disease from muscle tissue to muscle tissue. Yeah, maybe I can start, Sarah, and just kind of just thinking about—so let's just go back to the patient, right, and think about the patient. So they come in. They've been on del-desiran. They're coming in for—they've had a baseline biopsy. They're coming in for their second biopsy. When you do these biopsies, it's a fine needle biopsy done in the muscle in the front of the shin. And you've done a baseline on one muscle on the shin, and you're doing the follow-up biopsy on the other leg on the shin muscle. And then when you do these fine needle biopsies, you're doing multiple passes, which people don't like that. But to be able to get that tissue, you need to do multiple passes. When you do that, you get not only muscle tissue, although sometimes the muscle tissue can be atrophied, and people, because they have disease, their muscle is weakened and atrophied. What you also get is you get blood cells, of course. You get fat that's infiltrated that muscle because of the weakness. You get fibrotic tissue. Then you're grinding it up and then looking for a signal, right? We deliver only to muscle cells. So these other cells have DMPK in them that, to some extent, contaminate your biopsy. Now, we do everything possible to really eliminate that contamination, but there's always going to be some. That's why, when we did some of our earlier analysis in MARINA, we looked at muscle-specific transcripts. And there, we saw 30 (I think it was 38%) splicing changes in those muscle-specific transcripts. So that's kind of how we've started to try to hone down on that. And then, of course, we've also done RNA sequencing on those samples, where then we can look at muscle-specific transcripts as well as a number of other transcripts during that kind of timeframe. So that's how we've tried to look at it. In addition, what we've done, and this gets back to the CUG load, is that we've looked at using our RNA-seq data to really look at inferred MBNL concentrations, which is the most proximal signal that you're, this is really what you're trying to do, right, is that you're trying to release MBNL. So we've been able to use our RNA-seq data to infer what MBNL concentrations. We see a nice dose dependence and increase in muscle blind, which then relates to that improved splicing that gives you that chloride channel, that provides you that improvement in myotonia that we can measure by vHOT that results into the muscle strengthening that we can see. Steve could talk more about that. Maybe before we get there, just on the, there's heterogeneity in the CUG repeat burden just based on the instability of the CUG repeats from cell to cell. Now, muscle cells can be multinucleated. Does that mean you can also see different CUG repeat loads within the same muscle fiber? I think if you take a biopsy, you're going to get a number of different cells. And like you indicated, different cells or nuclei have different levels of CUG repeats or CUG load. So when you're taking a biopsy, you're taking a general population of cells and then trying to link it to then linking it back to the CUG repeats. That's why there is a poor correlation between those CUG repeats because of this hypermutation. So that's why I think thinking about it as MBNL-like or CUG load makes more sense to us. As we think about what you can measure in a muscle biopsy, the DMPK levels themselves, you've shown very good knockdown there. You talked about trying to indirectly measure MBNL sequestration. You've shown muscle splicing measures. What do you think are the most or least noisy signals to really get a read in terms of, is the drug affecting the biology? Right. Yeah, for us, after looking at the data, being kind of the first ones pioneering the space, what we found is that the best correlation is to muscle blind. And I think we showed that recently in a poster that we presented at the Myotonic Dystrophy Foundation. We showed that. And we've seen that across a number of different kind of muscle strengths correlating to how people, myotonia and things like that, and also DMPK levels. So I think, really, we're focused on muscle blind. And it's not surprising, right, because muscle blind is really the most proximal signal that you're trying to measure. And the way that we've measured it in the past is by looking at this 22-gene transcript or signature, right, or splicing panel. What we've done now with RNA sequencing is be able to look at a broader panel that really helps us infer what muscleblind concentrations are. What we found is, actually, looking at muscleblind is the best correlation to disease. That correlates to the function. Yeah, we like muscleblind. I think also, sorry, Josh, but I think also, when you have a little bit of noise in the system, it's also helpful to just look for multiple indicators and consistency of data because that makes the data more believable. If it was just one thing that was changing, maybe you could say, "Well, maybe yes, maybe no." But when you have very consistent data through DMPK knockdown, increases in muscle blind, and particularly changes in multiple different clinical measures, and we've done what's called vector plots where we plot the vHOT versus all of the other clinical measures that we're looking at, and we see very good concordance with individual patients, so not only improvement in the vHOT but improvements in the muscle strength, improvements in the DM1-Activ as well. All of that gives us a huge amount of confidence that we are definitely affecting the biology because that's playing out in clinical measures and actually reversing the course of the disease versus the natural history dataset that we recently showed. Now, as we think again about the biology and the treatment effects, you're knocking down DM1. And from there, the natural subsequent effects are you're reducing the MBNL sequestration, you're improving the splicing metrics, and ultimately, you're improving the disease phenotype. But it all starts at that first domino, DMPK knockdown. The more you can knock it down, right, the more you can release MBNL, etc., right? So as we focus on DMPK knockdown specifically, and I think you've done a good job essentially proving, right, DMPK will correlate to MBNL, splicing, and ultimately the clinical outcomes, talk to us about the ability to knock down DMPK because it looks like there's a ceiling effect. And this is really important to understand. It took me a while, as someone who's been following the company for a while, it took me some time to really appreciate and understand, "Why isn't it more? Why don't you dose higher and just get more DMPK knockdown until you've knocked it down completely and ameliorated the entire disease? Yeah. We kind of thought, going into it, we thought the same thing. We were in the same line with you, Josh. But then when you start looking at the data and really kind of understanding what we're seeing and trying to understand what we see in the clinic, what we and others have seen preclinically, I think it really goes, so let me back up. So preclinically, you can dose a lot of siRNAs or antisense to animals. And we and others have shown that you get about 50% knockdown, even in an animal that each animal is kind of the same, unlike people. And that translates into changes in splicing. So you kind of go like, "Oh, how come we don't get more?" And then when we went into people, we saw the same thing. And in fact, our lowest dose showed about 50% knockdown. So we saw kind of this effect. As we dosed more, we saw the same kind of 50% knockdown. You kind of have to start thinking about what the data are telling you despite your biases. I think what it's telling us and what we think, although we don't have, it's still a hypothesis, is that there's a separate set of DMPK that's sequestered in these foci. Those foci, so DMPK is bound up with a number of proteins. One of the, we're trying to measure muscleblind, but that's not the only protein that's bound up in these condensates. Those condensates, what we hypothesize is that they're not available for our siRNA to hit. So think of it as a clogged sink. You get a little bit of water going through the sink, but you have this clog that is really hard to unclog. That's always going to be in a background signature or background when you do biopsies. So you always have this kind of DMPK that's sequestered, unable to be knocked down. But what you're doing with our siRNA is that we're knocking down newly synthesized DMPK. So if you think about, "Okay, the clog's there. I get it." But now what I'm doing is I'm allowing the free-flowing water because I'm knocking down newly synthesized DMPK each time. So at the same time, I'm making new MBNL. So the MBNL now is free to do its normal job because there's no CUG repeats to bind it. And that's what we think is going on, is that you have this background clog, but at the same time, you're still able to flow water through because you're not adding to the clog anymore because you've knocked down DMPK. Is there any way to quantify the load of those condensates? Yeah, it's a great question, and trying to understand how that occurs. We're working on it, but we haven't come up with a really good way of trying to understand it more deeply. I mean, we continue to work on it, and it's something that we're learning more about. But at the same time, yeah, it's challenging biology. That's been a consistent theme throughout these two days, is learning as we go. It's an amazing field of muscle biology, and so much we don't know, and even more we don't. I think you. you. Who are you, Josh? We're here talking about really deep, cutting-edge science. Then at the same time, we're talking about a clogged sink. Exactly. All right. So Mike, you did note that you were hitting that maximal knockdown just at 1 mg per kg, your lowest dose. So why push higher? What's the benefit of going higher when you're already knocking down DMPK as much as possible? Yeah, I can start, and then Steve can follow up. I think for us, first, we wanted to—we had a dose-dependent—we were doing a multiple ascending dose. So we wanted to go higher to see what we saw. And then what we found is that as you dose higher, what you see is a better durability. So that means that you're knocking down DMPK for a longer period of time between your doses. And if you knock down DMPK during that whole dose interval, then you're continuously freeing up MBNL. That then allows you to have that splicing improvement. And that's exactly what we see. When we look at muscleblind-like protein, what we see is that at our highest dose, because it's continuously knocking down DMPK between the dose intervals, that we see a nice increase in MBNL. I think that then leads to (and going back to your connecting the dots) that leads to that improved functional benefit that we see with myotonia really early, that then leads to that improved muscle strength. Higher doses allow you to knock down DMPK during the full dose time. Right. And implicit in that is the ability then to extend the treatment interval between doses by going higher. You're getting that same knockdown, but it's more persistent. And if that's the case, why stop at 4 mg/kg? Why not go to 8 and try to get even longer dosing intervals for patients? Steve. Yeah, I'll try that one. So at 4 mg per kg, we've seen reversing the course of disease. We're doing that with an every 13-week dose interval as we go out through MARINA into the MARINA open-label extension study. And really, a highly effective dose is 4 mg per kg that can be given at a very convenient dose interval for patients. And our goal now is to get into patients in a phase III study as quickly as possible. We've got alignment with the regulators, multiple different regulators globally, around that 4 mg per kg dose. So it really doesn't make sense at this point when we've got a highly effective dose already and also a very convenient dose interval. And in phase III, we've tweaked the dose interval to bring it up a little bit to every eight weeks. If there is any more efficacy to be had, then we believe that we could get that with the slightly more frequent dosing that we've got. We're very confident that 4 mg/kg is the optimal dose from the doses that we've tested. Got it. A good segue into the phase III HARBOR design then, the patients you're going to be evaluating, the endpoints and timelines. So yeah, so the HARBOR study is a phase III study. As you would expect for a phase III study, double-blind, randomized, placebo-controlled. We have a 50/50, so one-to-one randomization between placebo and active. So we'll have around 75 active, around 75 placebo patients. We're stratifying on various baseline characteristics to make sure that the placebo and the active treatment arms are well balanced for important things that we think could affect efficacy and/or safety. We haven't given guidance on what those baseline stratifications are at this point in time, but they're in there. 4 mg per kg is the dose, as I just mentioned. The first dose in the study is given at 2 mg per kg and then 4 mg per kg for every subsequent dose. The dose interval is every eight weeks during the study. Endpoints, we have vHOT as the primary endpoint as a measure of myotonia. So it's the video hand opening time where patients are asked to make a fist. And those people that have seen our video, there's a prerecorded instruction to the patient that says, "Squeeze, squeeze, squeeze, and open," and the patient opens their hand, and it's timed how quickly they can open their hand. But myotonia is actually a very important multi-system issue for the patients. It doesn't just affect the muscles of the forearm and hand opening. It affects every muscle in the body. So it can have really profound effects on the patient's ability to go about their daily lives. And in association with myotonia and muscle weakness, patients get a lot of pain as well. So that's our primary endpoint. And then we have three key secondary endpoints that will be tested statistically as well. We've got hand grip strength. So hand grip strength together with the video hand opening time gives us a good assessment of overall hand function. Then we have a composite of muscle strength in upper limb and lower limb muscle groups that gives us an assessment really of global improvement in muscle strength. And then we have a patient-reported outcome, the DM1-Activ, that tells us really patients are reporting in their own words how they're better able to go about their activities of daily living. And you'll see from the data that we presented recently, we saw all of those measures improve very nicely in the MARINA study as compared to placebo. And then those improvements were sustained as we went out through the open-label extension and actually continued to improve even further. We also showed those and done a comparison of those key endpoints versus natural history and shown that we actually reversed the course of disease as compared with the natural history study. That was the END-DM1 study, which is a contemporary dataset that's ongoing as we speak. The endpoints for the clinical study have been very well validated, we think. Given the improvements that we're seeing, we think that we'd really de-risk the study from the endpoint perspective. Because we're showing improvement, we're able to measure the primary endpoint at week 30. We don't have to wait for the placebos to get worse. We'll see improvements in the active treated patients that will allow us to see separation very early. The placebo-controlled period of the study will continue out through to week 54. The regulators like to have about a year of placebo-controlled safety data for comparison. Our goal would be to file based upon the week 30 data and file while the study's ongoing, and then to provide the additional safety data during the review period. So that brings up our filing by about six months as compared to waiting for the end of the study and allows us to get the drug to the broader patient population as quickly as possible. A couple of other things about 40 or so sites needed actively recruiting to recruit the study in the time that we've stated, which is around about a year to get the study completely enrolled. The MARINA study enrolled only adults, so 18 and up. The HARBOR study will go down into pediatric age range, specifically the late adolescent group. It's patients from 16 and up in that clinical trial. Excellent. There should be a case report on how you've leveraged the biomarkers of myotonic dystrophy to optimize dosing, ultimately to design your phase III to the point that you no longer need the biomarkers, right, to kind of show that clinical benefit. I mean, we don't spend much time talking about that in particular, but just textbook example. I think you've noted over 40,000 patients in the United States with type 1 myotonic dystrophy. Where are you in terms of the outreach, identifying them? And ultimately, we're not too far away from preparing for commercial launch. Yeah, maybe if I take that one, and Steve, if you want to add as well. So yeah, as the estimation is, about 40,000 people are living with myotonic dystrophy in the U.S. It's about the same in Europe. This is a large rare disease. It's based on cystic fibrosis. It's an example. The patient and the clinical community is really well organized. There's the natural history study that's been enrolling for some time now. There's over 300 people enrolled in that. We are deep in all systems go, so to speak, with regards to getting the HARBOR study up and running as quickly as possible. We have a lot of engagement with the patient community. We actually, a couple of weeks ago, presented the data from the open-label extension studies to that community, where there were many, many people on the line, and also were very engaged, as you would expect, with the key centers around the world. Look, if we wanted to, we could recruit this study entirely in the U.S. This is a global study because we're looking towards global commercialization. Obviously, it's really important to have centers from around the world. We assessed over 200 centers in our selection process for those sites and came down to that around 40. The MARINA study recruited extremely well, and we're anticipating the same. I think our goal is to, again, write the textbook on how this can be done and how this can be done for a rare disease very quickly, efficiently, and done well, and to be able to get del-desiran to people who need this drug as quickly as possible. There's huge enthusiasm in the patient community. As you'd expect, Josh. I mean, gosh, if it was me and it was a member of my family, I know what I'd be doing. We take that responsibility very seriously. We really do see it as it is our deep responsibility to do this well because people are relying on us to do that. Yeah. We've really made a very early start on identifying the touchpoints for patients. A couple of years ago, we mapped out the patient journey. We've done that for all of the diseases that we're in. We've recently hired a global head of medical affairs that's got loads of experience in rare diseases. We're bringing in MSLs. We've got a number of MSLs now. We've got boots on the ground to be able to actually go out and have all of the engagements beyond the first tier of experts that we've been already working with and really out into the communities to start identifying where patients first make contact with the healthcare system so that we can really push educational programs that really resonate with the first touchpoints and where it counts. Yeah. I think actually very recently, we had one of our board members, Eric Mosbrooker, who is a real expert commercial leader, deep experience in rare diseases, and actually directly in myotonic dystrophy as well through a former role. So we're thrilled to have him on board with the team as well. Thanks a lot. This is between many of us, this is in our sweet spot. We have a lot of experience in developing and getting rare disease drugs approved and getting them to people who need them. Excellent. We're almost out of time. We're going to come back. We're going to do another webinar to preview the FSHD programs. Looking forward to that. But I'm going to close out with just a very quick snapshot because this is just the beginning of Avidity. So what else do you have cooking? Yeah. I mean, it really is, Josh. I mean, if you think we're looking forward to our FSHD data in the second quarter, another rare disease that is cystic fibrosis, no approved treatments, we directly hit the underlying cause of the disease, which is the aberrant expression of DUX4. So we're really looking forward to that data. We have data from the first patient data from our DMD program in the second half of this year. But I also think there's an element that there's the parts that you don't see yet that we're also really excited about, which is we have on our pipeline another muscle program that we have sort of noted. We have not disclosed the target. And then one of the other areas for people that's really interesting is precision cardiology. We signed a collaboration with Bristol Myers at the end of last year. They are currently leading the precision cardiology field. That's a 5-target collaboration. We also have our own precision cardiology targets as well, which are more sort of the more rare and ultra-rare targets, whereas BMS is directed to the larger targets. And that's game-changing for what happens in a cardiologist's office. This is actually being able to sequence people and give them a very targeted treatment. So that's kind of our next, if you look at this, is we have our skeletal muscle franchises. We've moved to heart and have a pretty large program now between ourselves and BMS. And then in terms of where we'll look to move next, we are an RNA delivery company, and we're looking to make a profound impact in people's lives. That is our goal. This is the start. This is very much what you're seeing is the beginning of that journey and what we can do. Excellent. Well, thank you so much for joining. I also want to acknowledge the very patient-centric approach that Avidity has been taking. It's something we hear from the community is very much appreciated. So thanks, everyone, for listening, and please stay tuned for the announcement for another FSHD webinar as well.