Welcome, everyone. My name is Eric Schmidt. I'm one of the analysts at Cantor Fitzgerald, and it's my pleasure to introduce our next presenting company that will be Avidity. We've got with us the company's CEO, Sarah Boyce. We have next to Sarah, Steve Hughes, the company's CMO, and next to Steve, Mike Flanagan, the company's CSO. We also have the company's CFO in the front row, that's Mike MacLean. So thanks for the full team for coming out in all regalia today, and wow, what a year since you were last here a year ago! I mean, this is a very, very different company that we're looking at. So, Sarah, maybe for those in the audience who a little less familiar with the story, give us a state of the union update on where Avidity Biosciences is today. Yeah, you know, it really is. A lot happens in a year, and you know, firstly, thank you for inviting us to the conference, one of the best conferences on the calendar, so thrilled to be here. So if we look back, you know, sort of from where we were last year, we now have three programs where we did three data readouts this year in three different rare diseases. In the case of myotonic dystrophy and FSHD, where there are no approved treatments, and for DMD exon 44, nothing specifically approved, for boys and young men amenable to exon 44 skipping. What we showed as a set of data readouts was where we were able to, in turn, for each program, essentially connect the dots. And connecting the dots both from, you know, we've tackled and have solved delivery to muscle cells, clearly with the data readouts that we have had. So we've shown muscle delivery, we've then shown impact on our genetic targets, and then shown, in the case of myotonic dystrophy, actually reversal of disease progression across a broad range of functional measures. We're now in the HARBOR study, is our global phase 3 study, which is now enrolling, and we're looking to recruit that study within 12 months, and we're on track with that guidance. For FSHD, we were the first program ever to enter the clinic that directly targets DUX4, the genetic driver of the disease. And again, we showed this beautiful connecting of the dots, from muscle delivery to impact on our target, to signs of early functional changes. And now, sort of, you know, it's our guidance for the second half of this year is we're gonna start our first registrational cohort for FSHD, which is a biomarker cohort, and then a functional cohort starting in the first half of next year. And then most recently, for DMD, once again, we've showed muscle delivery. We can deliver more PMO to muscle cells than any other technology. And what we saw was really, you know, game-changing levels of exon skipping and also increases in dystrophin production. And remarkably, and actually for the first time ever seen, was where we also saw serum creatine kinase, a marker of muscle damage, drop by 80% to close to the upper limit of normal and stay there. So we're now set sort of on the aspect of really proving through what we can do from a delivery perspective, engaging targets, and ultimately, to be able to make a profound impact on people's lives. And we're looking at all three of those programs now, either in the registrational phase or entering into the registrational phase. And then we also have our research engine and powerhouse, which has many other targets pulling through. And we're looking to share, which I think last year we weren't even talking about, precision cardiology, and our first look at our efforts in precision cardiology in the second half of this year. And from when we were last here, we'd also signed the collaboration with Bristol Myers Squibb in the precision cardiology space. So incredible progress, and incredible progress across different diseases and now also a new therapeutic area as well. Wow, that's a completely different company indeed. Mm-hmm. I should mention I'm up on stage with my colleague, Michael Bell, so we'll be sharing this fireside chat and its moderation. Maybe, team Avidity, let's start with DM1. Sarah, you mentioned the HARBOR study on delpacibart etedesiran. I know you just recently came off a patient advocacy meeting, I think this past weekend, where you got to engage with some of these families with myotonic dystrophy. What are your key learnings there about this disease and how you can impact its clinical progression? Yeah. You know, I think it's always a deep privilege when you get to meet people from the community of which you're trying to serve. It also reminds you of the deep responsibility that you have as well to make sure that we deliver. The community could not be more excited about delpacibart etedesiran and the HARBOR study. I think for me, one of probably the two most striking impact, two most striking impacts, firstly, it's not about listening to an individual's story, but it's the whole family. And seeing cases where literally it's half the family that are impacted by myotonic dystrophy, and hearing those diagnostic journeys where, you know, in one case the first person in the family was misdiagnosed as having MS. Then ultimately, the first child was born, and it was clear that something was very wrong, and that led to the diagnosis of myotonic dystrophy, and in turn, led to half the family being diagnosed. It's this aspect of the impact, not just on an individual, but the whole families and the communities, and if you find one patient, you actually find a family. I think for me, the second impact, there was a lot of discussion about myotonia. You know, one young man beautifully articulated that people think by myotonia is about the hand. The hand is the measure. The video hand opening time is a way to measure myotonia, but he also talked about myotonia impacts every muscle in my body, both the muscles you see on the outside and the muscles you see on the inside. And in particular, talking about the GI symptoms of the disease. And that's very much where I think we put a lot of focus on video hand opening. That's our measure, but myotonia impacts the entire body. And also, there were a lot of conversations around the fear of choking, because the tongue is a muscle, and you have myotonia in your tongue, and that's like this constant almost terror that people have around that. And then also around the fatigue with the disease, which I think typically we thought of as being neurological and like the daytime sleepiness, whereas a lot of it is related if your muscles are constantly contracting, that's exhausting! And many patients have sleep apnea. Actually, if you can resolve the myotonia and start to improve muscle strength, you actually in turn start to impact the other manifestations of the disease. It's also was just a tremendous reminder. At one point, I was sat in awe around what we have the potential to do as a company and the importance of the work that we're doing. Steve, maybe you can give us an update on the HARBOR study. I know it began just a few months ago. Hmm. But can you talk about how it's progressed, enrollment timelines? And, you know, in particular, Sarah mentioned a number of other endpoints outside of video hand opening. Yeah. How might you collect data and information on some of the other manifestations of the disease? Yeah, sure. Thanks, Eric. We've said that our goal is to enroll the HARBOR study within a year, and it's recruiting really well, really exceeding our expectations around recruitment. We got a lot of interest, both inside the United States and in Europe and Japan, where we're also targeting recruitment as well. So that's going really well. We are, of course, video hand opening time, or vHOT, is our primary endpoint for the study. As Sarah just explained, myotonia is not only the cardinal symptom of the disease, but a very important multisystem symptom. But we're also assessing muscle strength, and looking in particular at hand grip strength, which when we combine that with the video hand opening time, gives us a good overall assessment of gross hand function. And then we have a composite of quantitative muscle testing, looking at the upper limb and the lower limb as a composite as well. And then we have the DM1-Activ, which is a patient-reported outcome, looking at activities of daily living. So that is the primary endpoint and the three key secondaries. They're all gonna be tested statistically, and we've got a lot of power to do that. So we deliberately powered the study for ability to see changes in all of those. Of course, in the MARINA study, where we've already got data now out through the open label extension, we've seen very early improvements in all of those endpoints that continue to improve over the full twelve-month duration that we are anticipating for the HARBOR study. From our perspective, really, the HARBOR study is de-risked from an efficacy endpoint perspective. In terms of what the FDA might wanna see from HARBOR, is video hand opening enough, or do you also, you know, believe that they'll be very willing to consider these secondary endpoints and include them potentially on a label? Yeah, so the... When you're testing things in a hierarchy, statistically, they, you can get them into the label. But I think from just a general registrational perspective, the vHOT is, although an important endpoint, isn't the only thing that FDA are gonna be looking at. Normally, for larger diseases, you'd have two well-controlled clinical trials that validate each other. When you just have a single study, FDA are invariably looking for at least directional improvements in the other endpoints as well. And then, of course, safety. Safety is very important. When we gave our disclosure from the long-term safety data for MARINA, we saw extremely favorable long-term safety. All thirty-seven participants that had enrolled into the open label extension remained in the open label extension after a long duration of follow-up, and in fact, all thirty-seven still remain in the open label extension several months later. So, from a safety side, we're de-risked as well, we believe. And Mike, maybe just paint us an overall picture of the biology. Usually, you start with the biology, but now we have so much clinical data on DM1. I guess we can end with the biology. There's been much made about some of the biomarker movements and how they're supportive or consistent across your therapies and others in the space. Where are you today in your view of del-desiran's potency from a maybe more molecular level? Yeah. So I think, as Sarah said, we've connected the dots. So we've demonstrated muscle delivery. We've demonstrated knockdown of DMPK, which is the underlying cause of myotonic dystrophy. It's this repeat, CTG repeats in the messenger RNA that sequesters muscleblind-like protein, and this muscleblind-like protein goes on to splice RNAs appropriately. So what happens is that, we've been able to knock down DMPK and then release muscleblind-like protein, and what we've demonstrated a nice dose response on an improvement in muscleblind-like protein. That release of muscleblind-like protein then allows normal splicing. That normal splicing allows normal protein production. So for instance, for myotonia, that protein production is a calcium chloride channel, and that's in the disease, there's a stop codon, so it doesn't make the protein. As soon as you do proper splicing, you start making the protein right away, and that's why you start seeing myotonia really early. So we've connected it all the way to the functional endpoints, and then with the functional endpoints, you know, there's been much made about biomarkers. Actually, VHOT is faster to measure and less variable to measure than the biomarkers. So not only do you have a faster measurement, less variability, it's functionally derived measurement. So for our phase three, we don't have biopsies anymore because we really think we've put that story together and have demonstrated all the way from delivery to function. Perhaps for Steve, if we could ask a question about VHOT. How should investors think about changes in VHOT versus absolute VHOT, which may matter more for patients? Most likely it's the absolute change in VHOT that matters. So, for example, if the absolute measures the number of seconds that your VHOT has improved, if you express things in a percentage term, patients with relatively fast hand opening times can have very large percentage changes that are not so meaningful in terms of seconds. So the patients, we think, are more focused and it's more meaningful than to actually have the absolute time, and that's how we've presented all of our VHOT data and the disclosures that we've made. I think the other thing around the VHOT is that there's certainly a ceiling effect. So if your hand opening time's four seconds, the maximum that you can achieve is a four-second improvement. If your hand opening time's 12 seconds, you can see a 12-second opening time. So the cohort mean in terms of improvement in opening time is very much dependent upon what that cohort mean, that baseline was, 'cause that determines the amount of headroom for improvement. On del-desiran, you've noted, I think as a team, that you believe this is not just the first potential therapy for DM1, but also the best. How would you characterize superiority? We know you're well ahead of the competition. Yeah. Yeah, I think clearly, clearly first in class, and we believe clearly best in class, and that's based on an aspect of if you look at the weight of evidence and the data that we have shown, and in particular, across those broad range of multiple different functional measures, and even to the point whereby we're seeing reversal of disease progression, which has not been seen with any other drug. And from an aspect, I think, October of last year at World Muscle, we looked at 13 different measures of functional change and saw a positive impact on all of those. It's kind of this aspect of it doesn't matter which way you look at the drug, you're seeing... We're seeing what we wanna see, which is, being able to make an impact on those functional changes, and then also that coupled, with the safety profile that we're also observing as well. You know, this is the leading drug in myotonic dystrophy from every aspect, both in terms of leading the field, being first in class, and also very clearly being best in class. Good note to end on. Oh, one question from the audience on DM1. Yep. The way it works, in your deck, you mentioned that, the MBNL gets stuck, whether it's first actually having a broken DMPK or more knocked down DMPK. Are you just bringing the MBNL protein off, or you're actually knocking down DMPK? That's a Steve question. For those in the audience who may not have heard it, the question is whether muscleblind is just being released from the hairpins or whether you're actually destroying the hairpins. Yeah. So it's a great question. So the mechanism of action that we've demonstrated is that you knock down DMPK. So you specifically knock it down, and then. So there's two different ways that that can occur. So it either provides foci that are in the cell, that you knock down DMPK there and release muscleblind. The other likelihood is that newly expressed DMPK is being knocked down, which no longer sequesters newly expressed muscleblind-like protein. So you see this accumulation of muscleblind-like protein because there's nowhere it doesn't get sequestered anymore, and then it can do its splicing job just like normal. Okay, let's move on to your second program, for FSHD. Maybe just a quick summary from Steve or Sarah, on what you showed us earlier, just as recently as June it was. Yeah. Yeah. You know, I think the data that we showed in June was also incredibly exciting. It was this aspect of doing something that had never been done before, which is bringing a program to the clinic that directly targets DUX4. And one of the things that we showed, and again, it was this data package where everything connected, both from a delivery to impact on the downstream genes of that are turned on by DUX4. You can't measure DUX4 directly. And we showed that in a range of different ways, using multiple different gene panels. We also showed an impact in creatine kinase. We also showed impact from bulk RNA- Seq in other genes that are not directly regulated by DUX4, so things like inflammatory processes, where we had an impact there. We also identified a novel circulating biomarker, which is incredibly exciting 'cause that allows us to be able to look much more frequently at the impact that we're having versus a one-time muscle biopsy, and then an impact on a whole set of functional measures, even at a very early time point. So you know, really incredibly exciting for us, for the investor community, and most importantly, for the patient community as well. So the data that we saw back in June was at the very lowest of doses, just a single dose cohort. What, what's next for the program? When will we see additional data? And talk about your strategy going forward, Steve. Okay, so next for the program, we've said that we're gonna be very soon initiating Cohort C, which is our biomarker cohort. That cohort is targeting an accelerated approval based upon the tissue biomarkers of DUX4 knockdown, based upon the circulating biomarker of DUX4 knockdown, RNA-Seq data, and also directional changes in the clinical endpoints. We haven't had a discussion with FDA about that, so we're initiating that cohort. The data's compelling, and we've been able to really move up our registrational cohorts, then we'll be having conversations with FDA about our full approval cohort, which is a functional cohort, and we've given guidance that that will start in the first half of next year, so those are our most imminent things that we're working on in that program right now. In terms of in next data, maybe Sarah? Yeah. I think, you know, upon as we said on initiation of Cohort C, we'll issue a press release around that and within that what our dose was, our dose and dose interval, so there's dose and dose frequency. We're also looking at four milligrams. Initially, it's given every six weeks, and then it goes out to every thirteen weeks, and what we're paying really close attention is what happens to the circulating biomarker, which is one of the aspects around, you know, the discovery of that that came out of our lab under Mike Flanagan's leadership. So we're able to look as we go out on a thirteen-week interval, is does that circulating biomarker stay down? If we see it start to come back up, then we can bring in the dose interval. So the dose interval can be anywhere from every six weeks to every 12 weeks. And that circulating biomarker also tracks really nicely with CK as well. So we can look at that also with regards to really sort of dialing in very precisely both dose and dose frequency, 'cause one of the things that's really important to remember for FSHD, this is a prevention model. DUX4 should not be turned on. It should not switch on. When DUX4 switches on, essentially it becomes poison to the muscle. So we're looking to make sure that the siRNA is always there. So if DUX4 switches on, the siRNA is there to block it. That's why the circulating biomarker becomes really important, to make sure that we've always got siRNA on board to block DUX4. The accelerated approval strategy will be based on some measurement of DUX4 activity as a biomarker. Mm-hmm. There's never been an approval in FSHD. Yeah. You have another opportunity to be first and certainly best in class here. How do you make the case to the agency that they should approve this therapy based on a non-clinical endpoint? Yeah. Shall I take that? So the accelerated approval pathway is based upon a reasonable likelihood to predict a clinical benefit, and really, FSHD is a perfect disease for an accelerated approval. We completely understand the biological basis of the disease. There's only one cause. It's aberrant DUX4 expression. There's a whole range of different endpoints that you can use. You can look at the downstream gene signature, and that's been done in multiple different labs, and we've shown it across three different gene signature panels, that we can dramatically reduce the DUX4 downstream signaling. We can use RNA- Seq to look at the downstream biology of the disease, and we've shown that across many, many different genes using the RNA- Seq. We see improvements in the underlying disease biology. We have a circulating biomarker that tells us what DUX4 activity is doing over time. So we not only see it in a muscle biopsy at one time point, we see it over time as well with the circulating biomarker. CK, creatine kinase, which is a measure of muscle damage, tracks very nicely from a time course perspective with the circulating biomarker as well, and then we see directional changes in both clinical endpoints and in the patient-reported outcomes. So we've really got a full package, there isn't any outliers in the data, and that totality of evidence, we believe, makes a compelling case for accelerated approval. Can you share a little bit more about the excitement and reaction from physicians and patients on the FSHD program and, you know, share anything that you've experienced from communicating with the FSHD Society? Yeah, maybe if I start, and Mike and Steve, please feel free to add. You know, essentially for FSHD, and I don't mean this to in any way exaggerate. I mean, it's this is what the community has been waiting for. I mean, the it is an incredible community. The FSHD Society is one of the most well-organized patient advocacy groups I've ever seen, and the data we saw is what they've been waiting for, from an aspect of something that can target the underlying cause of the disease. There's also a lot of excitement around the identification of the circulating biomarker. If ultimately, in the longer term, we can move away from muscle biopsies, that's incredibly important, when you, particularly when you have a disease where you're losing muscle. And, we have a lot of it, as a lot of our questions that we get asked now is, you know, "When's the study opening? How can I get into your studies?"... and that's also in part why you've seen us lean in and with a real sense of urgency around we're starting the biomarker cohort, and we've been very clear about the fact that we're starting that cohort without the agreement from the agency around it. We believe we have a compelling case. We also accelerated through the functional cohort and are looking to initiate that in the first half of next year, again, also as part of that. And, you know, we do have a lot of requests for access. Obviously, we're conducting placebo-controlled trials, and we'll be doing placebo-controlled trials right now. You know, it's a... This is the sort of stuff like you wait your whole career for, around being able to make the potential impact that we can make in people's lives. Last question on FSHD. I know we've got to get to DM1 as, sorry, to DMD as well, but what, if anything, did you learn from Fulcrum's unfortunate failure last week? It was unfortunate. It was, I think, a huge deal for the patients. They've been very much looking forward to having a near-term drug approved. At the moment, they have no treatments available, so it's been extremely disappointing for them. We were most interested really in the placebo arm of the Fulcrum dataset, and using that to build in overall how we do our sample size calculations for our full approval cohort. We triangulate on multiple different data points. I really think that their placebo arm was likely not severely enough affected. Based upon comparison between their eligibility criteria that are in the public domain and our eligibility criteria, we clearly have a more severely affected cohort. That's important because we know that in this disease, in terms of measuring change over time, that if you're too mild, you don't see those changes over that one-year period. If you're too severe, you don't see the changes over a one-year period. You need to be kind of right in the middle to be confident of seeing changes. And within the FORTITUDE study, we've got our selection criteria to really get the patients that are in that kind of sweet spot based upon MRI muscle fat fraction, based upon the disease severity score as well. Great. How big will that Cohort C be? We haven't finalized the sample size calculations. To some extent, it's gonna depend on what we negotiate with FDA, but we're anticipating that it will be somewhere between 150 and 200- Oh, sorry, Cohort C. Oh, Cohort C. Cohort C is gonna be around forty patients. Great. Maybe just to follow up on Michael's question about FSHD in patients. You know, I think I would sum it up in two words: Hurry up. Yeah. Yeah. It's like, really, and that's kind of been our why we're doing that two-prong approach of accelerating a biomarker cohort, as well as looking for full approval. So I think we take that to heart and really are trying to meet that goal. Yeah, we've got. We're getting a lot of requests from patients. We've actually got more interest in the biomarker cohort than there are slots in the biomarker cohort at this point. So, obviously, that interest will carry over for the full approval cohort as well. So we're anticipating that we'll be able to recruit those really easily. Great. Okay, I didn't mean to shortchange DMD, and in some ways, this could potentially be your first approval. Mm-hmm. Del-zota is the drug we're talking about. These are patients with exon 44 mutations. What did we learn and what's next? I guess we'll have to keep it pretty quick here. Mike, do you wanna take what we learned, and then, Steve- Yeah, I mean- ... for what's next? I think, you know, I hate to repeat it, but again, we've just connected the dots, right? Delivery to muscle, unsurpassed delivery to muscle, to robust exon skipping that led to unprecedented levels of dystrophin production. So, and then that dystrophin production, as we go out longer, will hopefully show up into those improvements that we're starting to see trends in that. So I think, again, it's just that consistency, we just follow the same playbook at this point. Just the consistency of delivery to target engagement, to a biological effect. And, you know, what we saw was 32% in mean levels of dystrophin, which is amazing amounts of dystrophin, as high as, as high as 54% dystrophin. So just to put that in perspective, moms who are carriers for the gene are around 50% dystrophin and are asymptomatic. So we're starting to approach what would be considered kind of a normal range of dystrophin for some of these, boys and young men. So super exciting. I guess the other thing is that, we measured at the four-month time point, so we almost certainly are at steady state then. If we measure it at later time points, we'd see even higher dystrophin levels. The creatine kinase also came down to near normal levels, that just hasn't been seen before, and it came down and stayed down in everybody. Everybody that was treated with delpacibart, with delpacibart zotadirsen at least. Next steps, the data is so unprecedented and creates such hope for patients and their families that we're really moving to have conversations with FDA about how we expedite the accelerated approval for this drug and get the drug to patients as quickly as possible. If this is gonna be your first approval, what, what could that accelerated strategy look like? You know, one of the things that we're, we've said is, you know, we're gonna get in, have those discussions with the agency. Once we've got real clarity on that, we'll then share it. We're very mindful that we talk to the, you know, we'll talk to the investment community, but we're talking to the broader community, and we wanna be, you know, make sure we've got that, had that discussion with the agency before we get into what an approval timeline could look like. As soon as we have something meaningful, we'll share it, because whilst we're talking to you here today, we're also very mindful that we're talking to families as well.