Second day of the BofA Healthcare Conference. My name is Geoff Meacham. I'm the Senior Biopharma Analyst here at BofA. We're thrilled to have Avidity Biosciences with us on stage. So, with me, Sarah Boyce, President and CEO, Mike Flanagan, Chief Scientific and Technical Officer, and Steve Hughes, Chief Medical Officer. So thank you. Thanks for inviting us. Welcome. Of course. We're thrilled to be here. So, Sarah, maybe talk a little just to give us, like, set the stage, give us kind of the five-minute background for those on the webcast or here that may not be as familiar, and then we'll get into some questions. Sure. So at Avidity Biosciences, we are the leaders of RNA delivery. If you look at the vision of the company and what we're trying to do, it's two things. Firstly, we set out to revolutionize the RNA space by cracking what's been one of the fundamental challenges in the space, which is that of delivery to cells and tissues outside of the liver. We've done that. And then the second aspect is also to look to make a profound impact in people's lives. That aspect of the profound impact really directs where we direct our technology, and that is typically in rare diseases where we lead fields, where we're in spaces where there's been no other drugs approved, or nothing specifically approved for that indication. In many cases, we're carving the way in regulatory pathways and looking to make a profound impact in people's lives. The way we deliver is through our antibody oligonucleotide conjugate technology or AOCs. So the antibody, as we all know well, antibodies are wonderful at targeting receptors on the surface of cells. We use a transferrin antibody to get our RNA to where it needs to be. As we sit today, we have three programs in the clinic. Our lead program, del-desiran, is for myotonic dystrophy. We are on the cusp of initiating our first phase III study, which is the HARBOR study. We received breakthrough designation last week. Was it last week? It was last week. Time goes so fast. So we were thrilled to have received breakthrough designation last week. Also this year, we have readouts on our two other clinical programs this quarter on FSHD with AOC 1020, and in the second half of the year, for our first DMD program, targeting boys and young men amenable to exon 44 skipping, and that program is called AOC 1044. So let's, before we get into the pipeline, let's talk a little bit more about the platform. What have been some of the technical challenges and what, maybe give us kind of the history of, you know, the AOC platform and, you know, how you guys, you know, came to, you know, came to develop it. Yeah. So we have Mike with us, he's our scientific and technical officer, so that is a great question for Mike. No, we've been working on this, this technology for over 10 years. So, you know, and really looking at every aspect of it, from the siRNA or the morpholino oligo that we deliver for skipping, to the linker, whether we use a cleavable linker or non-cleavable linker, looking at the antibody and different antibody formats. So every piece of the AOC technology, whether we're targeting transferrin or a different receptor, we really use this kind of 10 years of learnings to really hone in on what we think is the best drug candidate. And, so that's how we've done it. You know, along the way, of course, we've developed a lot of inventions, and have a good grasp of how each different part of the technology works. That's exciting. Yeah, I think when you're looking at the indications, I mean, obviously, you know, you guys have an orphan focus, but for some of the larger orphan indications, talk about, you know, being able to scale up, you know, using the AOC platform, as you move from, you know, kind of phase I to phase III and then beyond. Yeah, that's a good... You know, we don't get that many questions kind of on manufacturing. Yeah. So yeah, we've been able to do that. It was one of the reasons why we really like full-length monoclonal antibodies. You know, there's over 100 monoclonal antibodies approved to date. There's a tremendous amount of ability to make monoclonal antibodies across the world. So that's. And they generally give you very high titers. So being able to scale up from, you know, phase I kind of clinical trial, where you're not treating that many patients, to being able to treat thousands of patients, I think that is really a key thing, to be able to scale that. And then along with the siRNAs now, interestingly, you know, there's a lot of nucleic acid firms out there that can make siRNAs, so we've been able to tap into those. So the technology and the ability to have multiple sources of where you get products has really helped us to be able to go from, you know, those hundreds of patients to thousands of patients. Right. Makes sense. So let's talk about the DM1 indication. So maybe catch up, you know, where we are today, and then we can talk about phase III and the market, et cetera. Yeah. As I said, we're on the cusp of initiating the HARBOR study. Yep. On Monday, the study went up on ClinicalTrials.gov. As we speak, we are initiating multiple sites, so that initiation of the study is very imminent. From an aspect of maybe just pulling back and talking a little bit about myotonic dystrophy, and Steve... It'd be great if you could expand on it as well. Myotonic dystrophy is a devastating rare disease. It's actually, it's orphan. You know, we have orphan drug status, as well as breakthrough and fast track. And it, there's estimated to be about 50,000 people living in the U.S. with myotonic dystrophy today, and the same in Europe. There is no treatments available, and we were the first people ever to put—ever to start a phase III program. So we're leading the field, and we were also able to have very successful discussions with the regulators around the world to get alignment on the phase III design for the HARBOR study. But maybe, Steve, if you want to talk a little bit more around the disease to give people context. Yeah, sure. So, excuse me. Myotonic dystrophy, as Sarah said, is a relentlessly progressive disease. It actually doesn't just affect muscle; it's a multisystem disease. It's caused by a trinucleotide expansion, and the RNA that's a consequence of that expansion in the DNA sequesters muscle blind, which is an essential splicing factor. And so thousands of different RNAs and subsequent proteins end up being abnormal, and that causes multiple different difficulties for the patient. So, from a muscular perspective, they have progressive weakness over time. They also have a symptom called myotonia, which is an inability to relax the muscles, and that's one of the cardinal symptoms of the disease. It's in the name; myotonic dystrophy comes from the myotonia that they experience, and that myotonia can affect just about every muscle in the body. So it doesn't just affect day-to-day activities, and it can affect breathing, it affects mobility, so a very significant symptom. It's an autosomal dominant disease, which means that multiple members of the same family are affected, and it also has something called anticipation, where successive generations can have it longer and longer and longer trinucleotide repeat tracts, which makes the disease more severe. So you can find that parents are looking after affected children, as well as looking after their own parents within a single family. So really, it's a disease with a huge potential impact on families as a whole. As Sarah said, we're the first people to really be able to demonstrate in the clinic that we have a therapy that's potentially able to make a profound difference to these patients' lives. We shared data earlier this year from our MARINA program, which is a phase I/II study. We've been following patients in that study for a long period of time now. Most patients have had at least 18 months of continuous treatment, many patients with more than two years of continuous treatment. We showed really great long-term safety and tolerability, which is great for the patients. But also we were able to show that we had really quite remarkable improvements in myotonia that occurred very early on in these patients. We showed improvements in muscle strength across multiple different measures, and also improvements in a patient-reported outcome measure for activities of daily living. All of those endpoints that we were able to show improvements in the MARINA program are actually the key endpoints in the HARBOR study, our phase III study. So we really think that we've essentially de-risked that. One of the comparisons that we did was with the END-DM1 natural history dataset, which is a contemporary natural history dataset. We were able to match patients to the patients in our study and showed that not only compared with placebo were we seeing improvements, but also compared with the natural history. We were merely essentially reversing the course of the disease in for those patients, which is great news. Well, then let me follow up on that, 'cause if you, The longer a patient goes on, do you see a broader, sort of breadth of, and depth of clinical benefit? I know obviously the primary endpoint, you know, you have the, the hand test, but beyond that, though, if you look out six months, 18 months, you know, do you expect to see, you know, a broader, more robust benefit? Yeah, it's a great question. So, the data that we presented recently was follow-up, was a year of follow-up- Okay. ...for the patients, and we saw that in the natural history dataset, patients relentlessly declined for most of the endpoints. We showed improvement for all of the endpoints that are gonna be the key endpoints in our phase III study. But perhaps most importantly for the patients, those improvements occurred really, really early, with a lot of the improvement just occurring within weeks for the myotonia and within a few months for the muscle strength endpoints. They did continue to improve out from the six month to one year time point as well. It does seem that we're able to show continuous improvement over time for patients as compared with the natural history, which is great. Was that captured in the HARBOR design? I guess the question is: what new elements of HARBOR can you introduce to show the totality of the benefit? As I mentioned, though, the endpoints that we've already shown improvements on are the ones that we're testing statistically in HARBOR. Yep. What that means then is that we've been able to do really robust power calculations, and we actually have a lot of power for our primary endpoint and our key secondaries. We are looking at other endpoints as well in order to capture the many different facets of the disease. We just haven't disclosed the other endpoints within the study, but we are looking at a number of things. The clinical trial was a year long, so there's a year of follow-up, but because we see improvements in patients very early, we're able to cut the primary endpoint before the one year time point. So we're actually doing the primary endpoint at 30 weeks, and our goal would be to file with that 30-week data and provide the final data from the study during the review period. If anything, it's a really simple study. You know, from a phase III perspective, primary endpoint, we have, you know, three key secondaries. We've already seen that we can hit those in the MARINA and the MARINA open label extension study, and we designed it to be a really patient-friendly study as well. So there's no muscle biopsies. And we're also very aware that getting a drug approved and getting a drug reimbursed are often two different things. So we've made sure there's that quality of life endpoint in this study, and this study is also designed to really optimize the market access strategy as well. Sarah, as you have progressed, you know, to phase III, talk a little bit about the investments you're going to have to make now from a commercial reimbursement access perspective. You know, I imagine that that was incremental previously, right? Yeah. In the phase I, II, but now it's a different evolution, right? Yeah. So, you know, I as a leadership team at Avidity, we all have deep experience in developing and launching rare disease drugs. So it has been our intent from the very beginning, from when we IPO'd, to in the rare disease space, commercialize our drugs ourselves. So a lot of that work has already started quite a long time ago. You know, we've had patient advocacy established now for almost five years within the company. We brought market access on early medical affairs and, you know, some of those key functions that you need from a marketing aspect. We recently hired one of our board members, who joined us as our Chief Strategy Officer. He has deep commercial experience and, you know, sort of now you'll see where we start. We have MSLs in the field now. So we're really locked and loaded from that aspect of launch preparation work, and that starts very early, and then you continue to build and grow. It's really about you establish the piping work in the company and establish the work patterns, the matrix patterns, and then from there, you build out. So... And we're about to actually have our first person in Europe as well. So also building out around the world. Well, let me ask you that. Yeah, so when you think about the market and the opportunity, help us with kind of the geographic kind of rollout, because I know for a lot of rare diseases, right, I mean- Mm-hmm. You know, the patient in the U.S. maybe have better, more streamlined, seamless reimbursement, but the real patients by numbers are, you know, outside the U.S. Yeah. Yeah, you're exactly right. You know, in many ways, it is, the inequities that happen in the rare disease space is one of those aspects that we're really looking to do our best to... We're developing this drug globally. We have 40, we're looking to recruit, have 40 sites in the study, and by having, you know, a global study to set the foundations in those key markets for ultimately your launch in those markets. And a big part of it is building out strategically, and also, it also really helps when you have a transformational drug like del-desiran on your hands as well. So don't get me wrong from, from that perspective. But, you know, it's always been our intent from the very beginning around to look at this from a global aspect. Right. Right. And so you, Europe, you said, just started, but, have you, you know, built out, you know, MSLs and, and, you know, patient identification, you know, type of specialists, in other geographies? Yeah, you know, some of that is really starting now. Okay. Okay. Okay. So we have been in discussions with multiple global regulators, and, you know, and that includes U.S. and Europe, as well as multiple other countries as well. And a lot of that work is starting now from an aspect of really understanding the nuances of those different countries. Last question. When you think about the HARBOR study, because you're blazing sort of a new trail, you'll have somewhat of a, you know, you have to build the, you know, the execution of the study. Yeah. You have to train the, you know, physicians and, you know, again, around the world. How do you see that, you know, playing out? It's also your, you know, first drug, so there's a lot of firsts, right, that you have going on. Yeah. But, I mean, as you said, I mean, at least you have a drug that's unequivocally effective, so that makes things easier, I guess. Yeah. Yeah, like, I mean, this is, you know, what we hope the first of many. And our sort of clinical operations team for the HARBOR study, they got this. It's interesting, there's a very kind of calm confidence. They know what they're doing. They've got their plan. They know how to execute. They're locked and loaded. All right. Sounds good. All right, so let's turn to DMD. So when you look at, you know, biomarker data, I mean, this has been, you know, a bit of a tough indication for, you know, for many companies across the board. So kind of help us with kind of the, you know, your biomarker data, you know, the level of sort of confidence as you, as you progress. Yeah, I would say that we demonstrated earlier this year that it's unsurpassed delivery in healthy volunteers. And that delivery matters because the amount of morpholino oligo that you can get into cells that then allows skipping is really a key driver. And we just have unsurpassed levels, and that's led to statistical difference in exon skipping in healthy volunteers that generally don't skip that well because they're healthy patients. But what others have seen is that with high levels of PMO into cells, that then translates into better exon skipping and then dystrophin production. I mean, like Sarah said, we're making profound differences in patients' lives, so we're not looking for like incremental changes of like 1% dystrophin to 2%. We're looking at differences that are above 5%. You know, we're hoping to get to kind of Becker's type of phenotype or beyond, so we're really trying to make a big difference. Makes sense. And then, when you progress to, you know, phase I, so just walk us through kind of the, you know, what are the steps from here? What should investors focus on in the DMD program as you go through the clinic? Steve, do you want to take that one? Yeah. Thanks, Mike. So at this point, we've completed the healthy volunteer portion of the study. We're well into the patient portion of the study. We'll be disclosing data from the first patient cohort in the second half of this year, which will focus on muscle delivery safety, but more importantly, dystrophin levels in the patients. And then, all of the patients that are in this first study have the opportunity to progress on to an extension study where they'll continue to receive active treatment. And then, as part of that process, we'll be having conversations with the regulators as to next steps to move towards approval in the United States. And, as you know, the United States is an accelerated approval market, so you can get approval, just on the dystrophin levels, and then as we move further forward with the development program, initiating a confirmatory study looking at, at clinical endpoints. So all of those things will play out over the next couple of years. What does success look like? You mentioned, you know, you're not looking to incrementally add dystrophin. Are you looking to meaningfully, you know, show performance better than, you know, standards of care which are, you know, suboptimal already? Or is it, you know, sort of transform-- I mean, is there sort of a, an outcome that you're looking for that would really be, you know, highly confidence to go into a registration? So, as Mike mentioned, we're really looking to significantly improve over the current generation of exon skippers, which have really had fairly mediocre levels of dystrophin production, and push patients into the Becker's range or hopefully even higher. That would be the initial bar to getting approval in the United States. And then, as we are able to treat a broader range of patients in a confirmatory study, really see meaningful differences, slowing down the rate of decline over time or perhaps even improving some patients. So that's really our goal. Yeah. I, I think it all, you know, what you hear is how it all comes back from, being consistent with our vision around we're looking to make profound differences. When you have a technology like ours, and we have been able to open up new spaces, you know, when we go after, you know, we're typically going after, for our own programs, diseases where there's nothing approved, there's nothing available, or where we think we can make a big difference. And if we can't, then that's not something we'll do. You know, if we find that we can't, then... But we've seen real reproducibility and consistency in the platform from a delivery perspective. But bottom line, we're looking to be able to make a profound improvement. Given the AOC platform, is there anything that you're thinking about, you know, as you look to a registration study that you can capture that's, that's novel, that could, you know, maybe expand the breadth of the, of the benefit? I guess progression to Becker's, you know, could be maybe a more, a more novel endpoint. Yeah, but I wasn't sure if you're thinking about any other? So, the transferrin receptor antibodies don't just deliver to skeletal muscle. We have really good delivery to cardiac muscle as well, and of course, myotonic dystrophy and Duchenne muscular dystrophy, as well as being skeletal muscle diseases, are also cardiac muscle diseases. So we would hope that we would see improvements in that aspect of those diseases as well. Even though those aren't the endpoints that we're looking at in our pivotal trials, there is great potential to benefit patients in that respect as well. Similar to the, you know, to the myotonic dystrophy indication, can you pretty rapidly advance to a, you know, to a phase III? Like, what breadth, I guess, of phase I experience, you know, phase I, II experience do you want to have before you go into a phase III, bigger population and maybe FDA is a little bit more experienced, you know, in Duchenne? So I wasn't sure if that factored into the development plans. Yeah. For the accelerated approval, your phase III confirmatory study needs to be ongoing prior to getting your registration. Yeah. Our development plan kind of factors that in, in terms of timing of the next study. We'll have a very good idea of how we're performing in patients later this year when we do our- Yep. ... first readout. And of course, we've already shown unsurpassed delivery to muscles, and as Mike mentioned, the exon skipping and dystrophin production is really a game of numbers. The more PMO you put in, the better the results that you would anticipate, and we know that PMOs work. Makes sense. Okay, so FSHD, maybe we'll start off with kind of the market opportunity and, you know, it's been. We haven't had a lot, you know, in development, but it hasn't been zero. So I just wanted to compare and contrast, right, the AOC platform. Yeah. So, you know, this is, again, where, you know, we're leading the field of RNA delivery- Mm. and we're doing things for the first time. So for FSHD, we're the first program, and AOC1020 is the first drug ever looking to precisely target the underlying cause of the disease, which is the aberrant expression of DUX4. We know we can deliver to muscle cells. We've shown that twice now. You know, obviously, we'll be looking to see reproducibility of that, but it's really an aspect for FSHD, where it's again a you know devastating rare disease. Today, there's nothing approved and available for people living with FSHD. It's a large orphan disease. It's not that dissimilar in size from myotonic dystrophy. So also presents an opportunity, you know, we hope to be able to make a profound impact in a lot of people's lives. Maybe Steve, do you want to set a little bit of context for the disease, for everyone again? Yeah. So, FSHD, again, is a devastating disease, another genetic disease, autosomal dominant, multiple members of families affected. Also, unlike with myotonic dystrophy, about a third of cases are de novo cases with no family history at all. It can take patients, particularly the de novo cases, quite a long time to get diagnosed. They tend to bounce around before they get an accurate diagnosis. The muscles that it has a predilection for, kind of in the name, again, it's facioscapulohumeral, so disease often starts in the face. It affects the muscles that stabilize the shoulder blade, and it affects the muscles of the upper arm very early on. And what patients experience is real difficulty in raising their arms above the head, and that can cause a lot of difficulties with self-care. For example, just doing simple things like brushing your teeth, washing your hair, putting on a shirt, all of those kind of things. And that progresses over time, and then more muscles become affected, and the muscles of the lower limb as well. About 20% of patients end up with requiring a wheelchair over time. Some patients have onset in childhood as well and can progress very, very quickly to significant levels of disability even in their late teens and early 20s. So really a devastating disease. There is a voice of the patient that's been put out within the past few years that really gives a very nice overview. People would like to read it from the patient perspective of how the disease affects them, and I really would encourage people to read that to get a great idea of how significant this disease is. Can you talk about data, you know, initial data disclosure and maybe what, again, success looks like there? Yeah. So, suppressing a sneeze 'cause I really don't want to sneeze on camera. So I'm, like, holding my nose, trying not to sneeze. Anyway, aside from suppressing the sneeze, so in terms of we're really looking forward to reading out, this is the first look at data from the FORTITUDE study, which is our phase I/II study, this quarter, so coming soon. From an aspect in, in terms of that look, well, it's an early time point, so it's the four-month time point. And what we have said is we'll, when we have a full cohort, we will read out a full cohort. So obviously, at a minimum, people can look forward to the 2 mg cohort. And, you know, a big part of this, and maybe Mike, if you want to talk about it, is around, looking at the biomarkers and this aspect of what happens when you directly target DUX4. Yeah. So we FSHD is a perfect disease for, I mean, for siRNA technology, and that's because, you have to think of the disease as a prevention disease for siRNA. So we're gonna deliver siRNA to the muscle, and then whenever DUX4 is apparently expressed, siRNAs are gonna be on board, and we'll just destroy the DUX4 messenger RNA. So really, because DUX4 is sporadically expressed in a few muscle cells but causes damage across a wide variety of muscle cells, probably due to inflammation and other things, if we can suppress that signal, which siRNA technology is perfect for, AOC technology is perfect for because of the delivery that we know that we can do to muscle, it's a perfect type of disease or indication for our technology. So having that as a background, then what we expect is that by knocking down DUX4, we should see a change in the downstream gene signature. Realize that DUX4 is intractable to measure in biopsies, so we won't be measuring DUX4 specifically. That's due to its low expression and sporadic expression. But what you can do is, measure the downstream gene signature. DUX4 is a transcription factor, so it turns on hundreds or even thousands of different genes downstream that we can easily measure with qPCR, RNA- seq data, and the like. So we're expecting to look at a gene signature that we've chosen. We have a specific biomarker panel that partially overlaps Fulcrum's biomarker panel and is consistent with the academic panels that have been used. So we really like those downstream gene signature. And then, of course, just like DM1, we're also gonna look at RNA- seq data, and that gives you a broader view of that. We're also doing some exploratory biomarker work to see if we can get a circulating biomarker. So, you know, there is this technical challenge of a fine needle biopsy in your leg to be able to capture DUX4. So we would like to look broader if we can, with, like, a circulating biomarker. So we'll be looking at all those different aspects and expect that our technology, because of the unsurpassed delivery to muscle, that we should have an effect on the disease and hopefully a benefit to patients. Perfect. In just the minute that we have left, These are, you know, orphan diseases, you know, muscular diseases. Looking forward, you know, what's the, Is, is there, is, is this an area that you want to evolve into other indications? The AOC platform obviously could work not just in muscle diseases but, you know, pretty broadly. Yeah. So when I talk about being the leaders in RNA delivery, that expands way beyond muscle. So we have a precision cardiology portfolio. We have a partnership with BMS, and they have five targets. We also have our own targets, and that's where you potentially see some of the expansion into the larger indications. You'll probably see us do that with a partner, and when it's rare and orphan, that's the sort of thing we're gonna look to develop and commercialize ourselves. Yeah. We can also deliver to immune cells, and a whole range of other cell types as well. But probably the next kind of franchise you'll see us build will be in the precision cardiology space. Perfect. Okay. Thank you. Thank you. Thank you. Thank you. It's great.