Hi, everyone. Thanks for joining us today for the Avidity Biosciences Chat at the TD Cowen Genetic Medicine Summit. I'm covering analyst Ritu Baral. With us today from Avidity, we have President and CEO Sarah Boyce and CMO Steve Hughes. Thank you guys so much for joining us. With the Fireside Chat, I want to go through your DM1 program, your FSHD data. I do want to touch on next data readout for DMD. Sarah, I'm going to put you on the spot and give us just a little more detail on the Precision Cardiology program that you tease with the FSHD. But for a very high level, going back to some marketing conversations I've had in the last couple of days, as you see FSHD together with DM1 data that your platform has generated, what do you think that means for your platform, your technology platform, and your pipeline? And if you could just review for us some of the topics of conversations that I've had with potentially newly interested investors, which is the components that set you apart, your decision-making behind the payload, your linker, and then the antibody itself. Yeah. So what I start off sort of at a high level in terms of, obviously, last week was a really big week. Actually, for us as a company, but most importantly for people living with FSHD, I'm wearing orange today because orange is World FSHD Awareness Day. And I think one of the most striking elements with the data that we shared, and this is speaking to the platform, given the data that we've also seen from delpacibart braxlosiran and our healthy volunteer data with AOC 1044, is the reproducibility and consistency that we're now seeing. We can deliver siRNAs to muscle cells really, really well. And from a PMO perspective, we can deliver more PMO to muscle cells than anyone's been able to achieve before. So it's an aspect of that delivery. And then what we're seeing now is kind of a reproducibility of a data set where you engage a target. We then go really, really deep on our scientific work around understanding the downstream genetic implications of engaging that target. And you saw that last week, as well as also with the work that we have done in myotonic dystrophy. And then when you engage a target, when you impact the actual genetic signatures that result of that, what you then see is, in the case of delpacibart braxlosiran, where we saw early signs of functional improvement across a broad range of measures. And obviously, with del-desiran and myotonic dystrophy, we now have much more longer-term data where we're actually seeing reversal of disease progression. So really, it's an aspect of, we know we can deliver. We know what our safety profile looks like. We're seeing reproducibility and consistency in that. We know how to do the muscle biopsies. We go really deep in how we understand diseases. And then in terms of how then, with what we're able to do from a delivery perspective, the impact that we can make on diseases. That's why last week we talked a lot about how now is the time for us to lean in and look at how we can both accelerate individual programs, but also across the platform. And we're really in a situation where we kind of pretty much know what our dose range is going to be before we even start the study. We know what the safety is going to look like. We know what our tissue concentrations are going to look like. So how can we then turn on the gas, so to speak, in engaging other targets? Does that mean you would broaden precision cardiology, or should we be thinking additional other neuromuscular indications or maybe less small neuromuscular indications? It's kind of both. So it's looking for the neuromuscular indication. We have an undisclosed target in our pipeline around how can we accelerate that. And then also looking for precision cardiology, how can we accelerate our work there as well as expanding our work there. In precision cardio, we have our collaboration with BMS. That's a five-target genetic collaboration. And then we have the genetic targets that we're working on ourselves, which we wholly own. So it's both in terms of accelerating in skeletal muscle and then setting up a whole other therapeutic area, which is around precision cardiology. Got it. So let's start with DM1. Can you outline for us the market opportunity, patient numbers, addressable patient numbers that you see in DM1 in the U.S. and Europe? Yeah, we'll start there before going to the DM1. Yeah. So DM1 is one of the most common muscular dystrophies. It's estimated there's about 40,000 people living with DM1 in the U.S. and about the same in Europe. What I would say, as with any rare disease, whether or not approved treatments, the epidemiology is often not as well understood. And from that aspect, we'll look to learn a lot more. From people who are diagnosed, that's always a harder number to get a fix on. I think it's a higher number than what you'd typically expect in rare diseases. We're leading the field. There are no approved therapies. We initiated the HARBOR study last week as well. So that's our global Phase III study. And in terms of, if you think of it from a market opportunity size, it's probably not that different from cystic fibrosis. So a pretty big orphan rare disease. You would think that there would be in the U.S. probably around 20,000 or 30,000 diagnosed patients currently? Is that fair? It's probably less than that. Less than that. Okay. Claims data would suggest. More like 10. Exactly. More like 10. Okay. Is this the sort of population like we've seen with Fabry, Pompe, even now with epidermolysis bullosa to a degree where once there's an approved therapy, you start seeing high single-digit annual diagnostic growth? Is a genotyping program, something that you guys would look at to establish the market now that you're barreling towards Phase III data? Yeah, absolutely. So I think in terms of there's a natural history study that's already in place. We are now building out, as you would expect, our medical affairs team, our market access team, our commercial teams. A big part of that will be understanding the diagnostic journey. Typically, it's kind of like you're talking about a seven-year journey to diagnosis. So building an understanding of where are the points along the way that people are misdiagnosed and then working you actually really support a diagnosis through an education strategy. It's also an element as well that for myotonic dystrophy, typically when you diagnose one person in a family, you diagnose one person. You get sufficient. Yeah. It's often the case where it's upon the birth of a child who is more severely affected. And we've had many cases where grandchild, mother, and grandmother all diagnosed on the same day. Yeah. I remember, I think the literature for Fabry is something like a three or four-factor index patient. As far as these patients themselves, what is, and we'll get to the Phase II data points and the Phase III design, what is the main deficiencies in their activities of daily living? What is the real unmet need in their lives? Yeah. Steve, do you want to talk to that? Yeah, sure. So myotonic dystrophy is really a progressive muscular dystrophy that, in addition to muscle weakness over time, also has myotonia associated with it. So the patients get progressive weakness over time, but they also have associated with it difficulty in relaxing muscles once contracted. So on the skeletal muscle side, you can imagine that has a very large impact on their activities of daily living. You'll have seen the videos on our website where we show hand myotonia when we do the video hand opening time assessment. And for some of those patients, it's taking many, many seconds to open their hands. And that can really be an impediment in just going about just about any activity of self-care that you can think of. But in addition to that, they also lose mobility over time, and the weakness becomes a significant issue. It's a multi-system disease, so it doesn't just affect the skeletal muscle. It affects smooth muscle. It affects the cardiac muscle. So patients can get cardiomyopathy. And quite a lot of these patients actually succumb to cardiac problems as they get a little bit older. And also, it has quite profound gastrointestinal effects. So it can affect swallowing. It affects the speed at which the gut moves. So the patients often have very severe gastrointestinal symptoms. So really, quite a lot of different areas that this disease impacts. And del-desiran, really, we know gets into smooth muscle, gets into cardiac muscle, gets into skeletal muscle. So we're hoping that actually it will create a significant improvement in all of those areas. As we think about the Phase III design of HARBOR, which is initiating any day, I think, very soon. Initiated last week. It initiated last week. Okay. Patients are lining up for enrollment as we speak. Can you walk us through the Phase III design, especially as it relates, Steve, to those four elements that you talked about, the myotonia, the strength, cardiovascular, and the GI as far as endpoints? Yeah, sure. So as you'd expect for a Phase III study, it's double-blind, randomized, placebo-controlled. Patients are randomized in a 1:1 fashion. And there's about 150 people going to be going into the study. So that will be 75 in each group. The doses of del-desiran is 4 mg/kg, which will be given every eight weeks, although the first dose is at 2 mg/kg. Patients have assessments performed at intervals, but the primary endpoint, which is video hand opening time, which is a measure of the myotonia element of the disease, together with the key secondary endpoints, will be assessed at the week 30 time point, which is just a little bit over 6 months. So primary endpoint, video hand opening time. And then we have secondary endpoints that are looking at hand grip strength. The video hand opening, together with hand grip strength, really gives a good idea of improvements in hand function. We have a composite of quantitative muscle testing, assessing muscles in the upper and lower limb. That tells us about improvements in total body strength. The last of the key secondary endpoints is the DM1-Activ, which is a patient-reported outcome measure that looks at activities of daily living. You'll remember that earlier in the year when we shared the data from the one-year follow-up in the open-label extension study, we showed improvements in all of those endpoints. The Phase III study is really very well statistically powered to look at all of those endpoints. From our perspective, we've really de-risked the HARBOR study in terms of the endpoints that we're measuring. Additionally, it's a one-year. I should have mentioned the follow-up in the study is actually one year of placebo-controlled follow-up. That's really to provide the regulators with one year of safety data, which they like to see in these sorts of studies. But we're cutting the primary endpoint and the key secondaries, as I mentioned early, at week 30. And we would aim to file at that time point as well. So although the HARBOR studies are targeting functional endpoints, it's actually targeting a full approval. Our filing strategy has actually been accelerated with this potential for early submission. Sarah, have you worked out what your disclosure strategy around that primary endpoint disclosure and filing versus full unblinding of the study will be, both for FDA and for the public markets? Yeah. So in terms of at the time of unblinding and proceeding with filing, we'd then do an announcement that we had done that. And then the data would then be shared once the 12-month portion of the study is complete. And they'll probably go in concert pretty quickly. So there shouldn't be much delay between one and the other. And that's pretty much the standard approach in this type of strategy. Investors will hear that you have filed, but that the full unblinded data will come at 12 months, at which point investors could assess the viability of the application. Is that fair? Correct. Correct. I would expect we'd say we'd met our primary, we'd met the endpoints. I see. Okay. That's very helpful. So Steve, you mentioned cardiovascular and GI as well. Is that something that are covered as part of either exploratory endpoints or in the PRO that you mentioned? Will we get signals on those aspects of the disease? So just talking to cardiac first. So cardiac studies are typically many hundreds of patients, i.e., in order to measure cardiac-type outcomes. So we haven't included any of those in the study. But over time, we would anticipate that as we do kind of post-marketing follow-up, that we might be able to see some signals there in terms of reporting. In terms of the gastrointestinal effects, they're not really in the DM1-Activ PRO, but we'll be doing the same as we did for the MARINA program. We'll do exit interviews for all of the patients as part of the study. That's where we would anticipate teasing out improvements in those sorts of symptoms. Got it. And we saw that even with the open-label extension study and the interviews we did with MARINA. I mean, Steve, I'm sure you recall we had one patient who they actually could not leave their house because of their GI symptoms. And now, being on del-desiran, is able to leave the house and travel. And so some of that also comes in in the exit interviews that you do as well. I see. Okay. What were the final conclusions on safety heading into HARBOR? What were the points of focus as you got through all of the IRBs for all the additional sites? There's just continuing discussion, I would say, of potential cerebrovascular. I think many, many investors are very comfortable with the profile generated by all the additional patients with all the additional follow-up. But it was just perplexing. And also the hemoglobin compartment. Can you just sort of run through what you're seeing there across the FSHD program with the transferrin antibody? Yeah, sure. So maybe if I just start at a high level. You'll remember that earlier this year at World Muscle, we presented the one-year follow-up that I mentioned just a little bit earlier. And in that data, we had a lot of safety. So at the time of that data cut, which I think was back in the spring, we had over 61 patient years of follow-up. Most of the patients were through 18 months of continuous dosing. Many patients through more than two years. All the patients that were eligible to go into the OLE actually remained in the OLE, so nobody had discontinued. And in that study, we'd had no related serious adverse events, no discontinuations. We've just about finished dose-escalating the remaining patients from 2 to 4 mg per kg in that study with no issues. So really, del-desiran over long-term dosing has really shown that it's got a very favorable safety and tolerability profile in the long term. Talking more specifically to maybe the neurological event first, that was just a single, very rare neurological event. It occurred quite some time ago now, and we haven't seen anything like it at all since. You'll remember that back at the time, we pulled together an independent panel of experts that evaluated the case with us. And they couldn't find any plausible link to either the siRNA or the antibody component of del-desiran. We've also conducted extensive MRI scans in the MARINA and the MARINA OLE, including scans both before and after infusions. And we've not seen any issues at all. So as we move forward now in the MARINA study, we're not needing to conduct any further MRI. So that issue from a regulatory perspective has really gone away now. With respect to hemoglobin changes, the AEs relating to hemoglobin changes are expected based on using the transferrin receptor as a method of delivery. They've all been transient. They're really clinically unimportant. No patients have discontinued dosing. All of the events have been mild or moderate. None have required transfusion. And actually, as patients have been on del-desiran for longer and out through into the open-label extension, these events have really pretty much disappeared in the safety. So rebound of the hemoglobin levels with continuing treatment? Well, so the events were transient. The hemoglobin levels rebounded after each dose. So what happens is when you target the transferrin receptor, you remove it from the cell surface, so it can't transport iron. And that has an impact on the hemoglobin. The periods of depressed hemoglobin levels are small, not chronic. No. Okay. So they were transient. And then as patients have gone out longer in the open label extension, you'll recall that back at World Muscle, we presented the most common related adverse events. That was ones that occurred in two or more people, and none of them related to hemoglobin. So really, they've kind of gone away. So it's not been an issue at all. And patients are continuing. As you recall, I mentioned that pretty much everybody is beyond 18 months of dosing. And at this time now, everybody is beyond 18 months with many, many patients beyond two years and no discontinuations. I would also just add, Ritu, because I know you said about the process and with regulations and IRBs. I mean, with regulations, obviously, we were able to get pretty much simultaneous alignment with the FDA and EMA on the study design. With data like we had, that process went very effectively. With IRBs, I mean, the Phase III team that is in place for the Harbor study within Avidity, they're very calm, very confident. They're like, "We got this. It's locked and loaded." Very smooth sailing through IRBs, through central IRBs. So all of that is just working really, really well. Are there any training effects that we should be worried about between VHOT and muscle strength and these others? No. There aren't any training effects with those. We've got a lot of that. We've got an awful lot of data now from the HARBOR study and from the HARBOR OLE that supports that. You mean MARINA? Sorry, MARINA. That's okay. Is there a HARBOR OLE? Are you going to be? There will be. Okay. All of the patients will come over. Got it. And then last question. Steve, you mentioned the patients that titrated from two to four. When will we get that data? And when could we get timelines, some guidance on HARBOR enrollment and data? Yeah. Steve, do you want me to take some of the enrollment and stuff? Yeah, sure. Sure. So for Harbor, we've said it's our goal to recruit the study within a year. We feel really good about being able to do that. There is a huge amount of enthusiasm within the DM1 community, as you would expect, to get onto the Harbor study. Then in relation to further data from the MARINA open label, we certainly won't be seeing any more data from the MARINA open label this year. We've not set up our 2025 guidance at this point yet. So that's something that would be part of that, but certainly no data this year. Got it. Okay. That's helpful. Let's move now to FSHD. Again, let's start with just the market numbers. This is one that doctor feedback has suggested. There's a wide variety of severities among patients. How do you see the addressable patient population within the larger FSHD patient population in the U.S. and Europe? Yeah. So again, it's also rare disease, no approved treatments. So we always have to remember that the epidemiology is going to continue to need to be better understood. The estimate is there's about 30,000 people living in the U.S. with FSHD and about the same in Europe. Anecdotally, we get a lot of information that leads us to believe that it may be even more common than that, but that's sort of the base numbers. From, as you say, there's a range of severity of disease at time of diagnosis, but we also have to remember that this is a relentlessly progressive disease and that DUX4 should not be expressed, anything beyond the early multicell stage. And while the body can tolerate, it seems, a certain level of DUX4 expression, once you go past a certain point, that is poison to the muscle. And that then causes a whole range of issues. And I have to tell just a little anecdotal story because it was so cool. This morning, so I'm in the U.K. at the moment in my sister's office trying to figure out what the hell's going on with the sunlight, but that's an aside. So I'm at the train station in Wigan, in north of England, and I'm wearing an orange sweatshirt because it's World FSHD Day. A lady comes over to me who's also wearing orange, and she says, "Are you wearing that because of FSHD?" And I said, "Yes, I am." And then she said, "Are you Sarah Boyce from Avidity?" To which I was like, "Yes." And we had this beautiful moment. We had a hug. Some tears may have been shed as well. But it was this aspect of, she talked about the hope that had been brought to the community. But also, for me, it was this aspect of, I've never before worked on a rare disease where I've met people just through a range of social encounters. And we see that a lot with FSHD. So like myotonic dystrophy, from a commercial perspective, it's a large commercial opportunity. Again, probably about the same size as cystic fibrosis. So if you look at our pipeline today, we have two programs, one of which is in phase three, which we view as being fully de-risked. And then for delpacibart braxlosiran, you saw how beautiful the dots connected with regards to, I mean, just beautiful, the sort of thing you love to see with a genetic medicine. Again, for another opportunity that's about the same size as cystic fibrosis. We got a lot of work to do. So as we think about the gene panel data that you guys generated, the consistent gene panel data, and your mysterious biomarker, can we talk about how those gene panels compare to what's been commonly used, whether by Fulcrum or by investigational studies in FSHD? And then any additional data on that or features of your biomarker that you can discuss at this time? Not to complicate your IP, but you mentioned it's not related to CK and muscle damage. It's related to DUX4 itself. And I believe it has a binding site for DUX4 you mentioned. But why wouldn't the panel be able to be used as a biomarker versus your novel biomarker? Or could it? Before Steve gets into it, I would say, Ritu, we view the biomarker approach. It's using the panel and the circulating biomarker and looking at the CK as well because it's like four different ways to look at it. The circulating biomarker, the beauty of it is it allows us to dial in our dose and dose frequency in a way that we've never been able to do before because you're not just one moment in time from a muscle biopsy. We can look at it over time. Steve, why don't you talk more about sort of the gene panel, why it was selected, and then also the work we did in looking even broader? Yeah, sure. So there's a number of different gene panels that have been used, as you mentioned, the two. But they all seem to kind of converge around a few genes where there's overlap. And our four-gene panel has overlaps with the ReDUX4 panel. There's by about two genes. The 41-gene panel, which is an academic panel, all of our genes are included within that panel. Although there's a number of different genes that you can measure, we selected our panel really based on the genes that we found to be reproducible from measurement to measurement. Also, ones with a large dynamic range so that you can actually easily measure changes. Some of the gene expression just isn't very high for some of the other genes. And so it's difficult to measure changes. And small changes can result in very large percentage improvements. So those were really the main features of our gene panel. As Sarah mentioned, we're targeting an accelerated approval with this. And really, the beauty of our data is that we've got multiple gene panels that we can use on the muscle biopsy. We also have the circulating biomarker, which allows us to track over time what's happening with the muscle. We see changes in CK, which are a known measure for muscle damage as well. So all of this. And also, I was forgetting, we've got the RNA-seq panel, which looks at the downstream biology. After you've impacted the DUX4 regulated genes, what happens after that, where we see improvements in the underlying disease biology as well. So we really believe that all of that creates a compelling package for a potential accelerated approval. Is there a level of correlation that you need to show between some of the functional markers that you detailed, or is correlation between the three, including CK, which is pretty well understood, enough? So at this point in time, the number of patients that we have is a little small for us to actually do statistical correlations. If you look on the slides on our website where we display both the circulating biomarker and the CK side by side, you'll see that the changes in the circulating biomarker are reflected very closely by similar changes in the CK over time. The time courses are very, very similar. So we would anticipate a high degree of correlation with those. And then, of course, as we get more patients into the biomarker cohort, then we'll be better able to do the statistical correlations. Understood. We are at time, but I still have stuff to talk about. So I'm going to take two extra minutes, operator, forgive me. Quickly, your DMD program, Exon 44, program 1044, we have data coming later this year from patients for the first time. How much detail are you going to give? Can you give us the parameters around patient numbers, endpoints, and follow-up at that point? Yeah. So what we pulled forward, actually, the guidance for that data, so it's now Q3, it is the first of the patient cohort. So it's at the 5 mg/kg dose. Obviously, we'll look at safety, muscle delivery, exon skipping, dystrophin. And in terms of the patient cohorts, Steve, can you just remind me of the size? Is it 12? Yeah. So each of the patient cohorts is eight participants. Eight. Okay. In size. Two of those, two of each cohort are placebos. Okay. So six and two. Got it. And what do you hope to see in these patients? Are we going to get functional, or is it really just expression and levels? So this is the four-month biopsy point, which is focused on the expression levels. We all know for DMD, this is something that we would expect to take time. So it's really, and I can see you smiling at me, Ritu, because I know we see that for myotonic dystrophy. Yeah. These cultures have done more with less, I'll just say. Yeah. But at this point, sort of we're guiding it. It's focused on all the various biomarkers as well. All the various biomarkers that are well understood in DMD. Precision cardiology. You teased an update. What will we get by the end of the year, Sarah? Yeah. So that's a look at our lead program. So our first target, so we'll disclose the target. And then also it will be focused on all of our preclinical work. So that will include non-human primate work. And it's kind of like connecting your dots preclinically from an aspect of muscle delivery, in this case, obviously delivery to the heart, and then engagement. And we're really excited. It's really kind of the tip of the work that we've been doing. So this is kind of opening up some of that. Understood. Will that be like an investor event? Yeah. We'll probably do one of our webcasts. Got it. Great. Well, we are over time now. Thank you, everybody, for bearing with us. Thank you, Sarah and Steve for taking us through everything. Looking forward to all the updates through the end of the year. Yeah. Absolutely. Thanks, Ritu. Take care. Bye. Bye.