Great. Maybe we can get started? Okay, see the clock is running. Could we get started? Great. Thanks everyone for being here. Welcome to day one of the Healthcare Conference. We are fortunate to have Avidity Biosciences management team with us here. We have CEO, Sarah Boyce, Chief Medical Officer, Steve Hughes, and Mike Flanagan, Chief Scientific and Technical Officer. Thank you for being here. You're welcome. It's a pleasure to be here, Yanan. Great. Sarah, can you start us off by providing a brief overview of the company's platform and program? Absolutely. So I mean, firstly, it's been an incredibly exciting time for us at Avidity, in that this year we have read our data from our three clinical programs, del-desiran for myotonic dystrophy, del-brax for FSHD, and most recently, del-zota for boys and young men amenable to exon 44 skipping, living with DMD. From a platform, one of the things that we set out to do quite some time ago now, we had two goals and these continue to be our vision. Firstly, is to revolutionize the RNA space, and secondly, is to make a profound impact in people's lives. The revolutionizing of the RNA space was cracking what has been one of the fundamental challenges, which is that of delivery to a thousand tissues outside of the liver, and we've done that, and we've shown categorically that we can do that with our technology, which is Antibody Oligonucleotide Conjugates. We conjugate an siRNA or a PMO to an anti-transferrin antibody in the case of our skeletal muscle and precision cardio programs, that gets the SI or the PMO to precisely where it needs to be. You know, we're now on the cusp of having all three of our drugs in the pivotal phase of development. Now moving full steam ahead with regards to commercial preparations as well. Great. Yeah, as you said, it's quite amazing you achieved proof of concept, if I may say, come to that conclusion, you know, for all three of your- Mm-hmm ... your programs, only four years after IPO. So, you know, can you talk about your level of confidence on, you know, the platform's ability to deliver to the muscle? And also, how far are we from commercialization, and how are you thinking about investment on that front? Yeah. It is, you know, actually, recently I was looking at our S-1 from four years ago, and we did everything we said we were going to do and more. So we certainly over-delivered on that one. You know, in terms of today now essentially being three for three, and it's just a great example of when you really understand the biology of a disease, through Mike's team, we are able to have, you know, very potent siRNAs, and great sequences with regards to PMO, so we can precisely target the underlying cause of the disease. And our goal has always been to develop and commercialize our rare disease drugs ourselves. So we have been building for a long time now with the goal of doing that, and, as you said, now moving towards commercialization. We're in the process of building our, continuing to build our global commercial team. I use global very purposefully, in that when you have more than one drug, actually commercializing yourself globally, you know, makes very good sense, 'cause it's the same infrastructure that we'll be layering one program after the other onto, which gives great economies of scale from an organizational efficiency perspective. Wow! Thanks for that message. That's a lot to look forward to. Mm-hmm. I can't imagine what happens, you know, over the next four years of the company's journey. Yeah, this is just the beginning. It's just the beginning, and, you know, we have several other skeletal muscle programs. The targets are not disclosed yet, as well as also a precision cardiology program that's actually bigger from a number of targets perspective than our skeletal muscle. Wow! Can you touch on that cardiology area? Because that's something you said you will tell us more about by the end of the year, right? Yeah. Yeah, Mike, do you wanna talk about that a little bit? Yeah. - and what's to come? Yeah, yeah. So I can talk about precision cardiology. So, you know, our technology is perfectly suited for precision cardiology, right? We can deliver it to heart, we can deliver genetic medicine such as siRNAs or perhaps PMOs, to the heart. We've demonstrated that preclinically, and now we have a wide open space in precision cardiology. So if you look at the precision cardiology field as a whole, it's really been underinvested in because it has relatively low POS, or probability of success, given the huge trials that people have had to do in the past with, you know, cardiovascular type of drugs. Whereas we're doing precision cardiology, so we can use our siRNAs to directly target gain-of-function diseases in the heart. For instance, hypertrophic cardiomyopathy is a great space where, you know, there's over a million patients in the U.S. that have HCM, and as you go down, there's a large proportion that are already genetically defined. ... and those genetic definitions are all treated with kind of common drugs that affect blood pressure and things like that. Whereas now we can go in with siRNAs and directly target that genetic, you know, abnormality. So we're, we're in a perfect position where we have delivery, we have flexibility of modalities that we use. We know we can deliver to heart. We have a safety profile that we've demonstrated through three different programs. We can manufacture, we can scale. I mean, we have all the pieces in place, and it's a wide-open field for us to really start looking at. And you're just starting to see the beginning of it with mavacamten from Bristol Myers Squibb, right, who's one of our partners. I see. Wow! Very exciting. Looking forward to unveiling that program. Us, too. Great. So, let's talk about del-desiran for DM1. That's the lead program currently in phase III. Could you talk about, you know, you're enrolling, you're, you know, initiating the study? Wanted to see how many sites have you opened, and how's the enrollment going? What's the interest, you know, from those sites? Yeah. So one of the things that we've never done is we don't do status updates for ongoing clinical trials, but here's what I can say: You know, firstly, the excitement in the myotonic dystrophy community, it really is incredible. For del-desiran, you know, we've been able to show reversal of disease progression. No one's ever done that. We're the first people ever to show that. So in terms of from finding patients, site enthusiasm, no issues whatsoever. I would say our operational team, calm, confident, they know what they're doing. Our goal is to recruit that study 150 patients within 12 months. We're on track to do that, and really pleased with the progress that we're making with HARBOR, the HARBOR study, and no end of enthusiasm from the sites and from the patient community. Got it. So the study is designed to have a primary endpoint and all the secondary endpoints analyzed at week thirty. Mm-hmm. But the safety follow-up goes to one year. Mm-hmm. So, there is, you know... Will you take advantage of the earlier analysis for the primary and secondary endpoints and move the program quickly without having to wait for the study to completely finish? Yeah. Yeah, Steve, maybe if you want to talk about that one. Yeah, sure. So, in the HARBOR study, we, as you know, we saw very early improvements in all of our key endpoints, and those are the same endpoints, key endpoints that we're measuring in the HARBOR study. The fact that we saw very early improvements allows us to measure our primary endpoint and all of our key secondaries at the week 30 time point, and we certainly plan to file based on that data and then provide the week 54 data during the review period. So it's a very efficient filing. We call it a, an accelerated full approval strategy because we're able to file early based on that early cut of the data. Got it. Got it. Very helpful. So, the study's primary completion, according to clinicaltrials.gov, is October 2026. Does that refer to the 30-week, or the full one year? Yes. So, we're already enrolling, and as Sarah said, our guidance has been that we plan to enroll the study within 12 months. So that means that 2026 timeframe relates to the full completion of the 54 weeks. Got it. Got it. Very helpful. There have been some cross-validation from a competitor in the space, Dyne. So I was wondering, how do you see the competitiveness of del-desiran versus DYNE-101? Based on data we have seen so far, do you think that there could be a read-through from Dyne's future updates to the del-desiran program? If I start in terms. Very simply, we believe del-desiran, two things: First in class, we are currently enrolling a global phase III study targeted for global approval, and secondly, best in class. The data that we have seen with del-desiran really is unsurpassed, and if you look across the functional readouts we've had from the MARINA study and then the MARINA open label extension study across a broad range of measures, we were remarkably able to see reversal of disease progression. And in particular, when we looked at the HARBOR study for both the primary and all of the key secondaries, we were able to look at those from the MARINA open label extension study. That really shows you what to expect, and essentially, we view HARBOR as being fully de-risked. But I don't know if Steve or Mike, if you want to expand on further. Yeah, maybe if I just jump in, and then Mike can maybe add some. So we showed earlier this year data from the MARINA open-label extension study. That was data out through one year, where we showed not only that we had early improvements in all of our key endpoints in the MARINA study, but those improvements were sustained and even improved as we went out through one year of treatment. Really, for the competitive programs they've shown, they've only really shown the longer-term data for the lower dose cohorts, and really, the sustained improvements were only seen in the low end there. The higher dose cohorts have only shown very early data, so we have yet to see whether they can see a sustained effect over time. As Sarah said, we're well ahead in a phase III study, and so really we're leading the field. I think also just, you know, we're seeing reversal of disease, and that's supported by the mechanisms of action also, right? Delivered in muscle, right? The knockdown of DMPK, which is the underlying cause of the disease with the sequestration of Muscleblind. We've shown a dose-dependent increase in Muscleblind, so the release of Muscleblind to allow you to do the splicing. We've shown improvement in splicing that leads to then the change in myotonia. We've shown not only a 22 gene panel, but a specific muscle gene panel that we affect by splicing. So we have all the functional endpoints, the reversal of disease, and all the mechanism of action to back it up as to the way the drug works. I mean, we are the first ones to demonstrate delivery to muscle, right? The first time in thirty years that someone's been able to deliver RNAs outside of the liver, you know, and then to be able to connect all those dots repeatedly, not only for del-desiran, but for del-brax, right, for FSHD, now with del-zota. I mean, we've really... The platform has been proven, and now it's just a matter of how are we gonna use it. Yeah. And I think there's that, you know, aspect across the platform, and, you know, we talk about this all the time as a team, around the incredible opportunity and also responsibility that we have in that, all three of our programs, these are drugs that can really change people's lives. And making sure that, excuse me, and making sure that we take that responsibility to the patient very seriously, and we look to move our development as quickly as possible, and also have a fully built organization ready to commercialize and bring these drugs to people as quickly as possible. Right. This really is a paradigm change, and yeah, looking forward to further development of all three programs, of course. Just maybe a last question on the DM1 program. You know, you talked about the MARINA, which is a proof of concept early study. Are we going to see any further follow-up data from that study in the coming months and, you know, coming year? And also, there was a clinical hold on the study, a partial clinical hold on that study. What's the status on that, and does that have any implication for HARBOR phase III? Yeah. Yeah. Steve, do you wanna talk to that one? Yeah. So we in terms of additional updates, we've not given our guidance yet as to what our disclosures are gonna be through 2025. That will come later in the year. So we haven't looked at any additional efficacy data cuts at this point in time. We do track safety on an ongoing basis, and what I can say is that the long-term safety profile for del-desiran remains very safe, very favorable. No meaningful changes at all since the last update, and all 37 patients that enrolled in the open-label extension remain in the open-label extension still, with many of them now through two years of continuous treatment. With regard to the partial clinical hold, it has zero impact at all on the HARBOR study. We're dosing in that study at four milligrams per kilogram. The study's enrolling. We're tracking to our guidance. It really is an administrative technicality in reality, and we plan to be off hold very soon. Okay. Yeah. You know, the other thing I would say as we talk about data updates from the MARINA open-label extension study, I mean, firstly, just calling out again what Steve said, 37 out of 37 patients remain in that study. It's quite remarkable that, and I think that's an aspect of you see where people are voting with their feet, so to speak, about how they're feeling on del-desiran. The other aspect is, going into twenty twenty-five, we have a wealth of catalysts. There's a lot of data, obviously, with three programs in the clinic. So we would expect that an update from the MARINA open-label extension study and all of our open-label extension studies would be you know, in the 2025 data plan. And for MARINA, for the open label, it's really looking at, as we go longer and longer term, both from an efficacy and a safety perspective. Great. Yeah, looking forward to those updates. Yeah, I can see it's going to be a busy calendar for- Yeah ... 2025. Maybe let's touch on the second program, the FSHD program, with del-brax. I think you, after you... You know, recently, you reported positive data, initial data. And perhaps you know, talk about that data and why that, you know, you're excited about that. And then you, you did something, I think, very you know, accelerated in terms of your drug development path. Yeah. I mean, you're pulling forward the program essentially, right? Mm-hmm. So I was wondering, have you got a chance to talk with regulators and see if, you know, those measures, you know, is okay from that perspective? Yeah. So maybe let's talk about the data first, and then we'll come back around our strategy and what we're really leaning in around how to accelerate. I think, you know, Mike summarized it really well from an aspect of, with del-brax, once again, we connected all of the dots. And, once again, the first to ever directly target the underlying cause of the disease, which is the aberrant expression of DUX4. But maybe, if you want to elaborate more on what we saw? Yeah. So for FSHD and del-brax, we saw, right, delivery to muscle. So that was and we saw really good delivery of our siRNA to muscle. Then we showed effect of knocking down DUX4 by looking at a downstream gene signature. So we picked a set of four genes. As you know, it's really hard to measure DUX4 in muscle, so what you do is you look at the downstream effects of DUX4. DUX4 is a transcription factor, so that you can look at the downstream genes that are turned on by DUX4. And if those genes are turned off, then you know you've hit DUX4. So we've looked at a specific set of genes. We looked at what we like, a set of four genes, but we've also looked at what others have looked at, and then we looked at a panel of 41 different genes. If you're DUX4 regulated gene, you're gonna go down with treatment on del-brax, and that's what we saw. In addition, we spent the last two years looking for a circulating biomarker, and what we've discovered is a circulating biomarker that we know is regulated by DUX4, and we've shown that that also decreases. Along with that decrease of that circulating biomarker, we showed creatine kinase, which is a marker of muscle damage, and we see that that creatine kinase goes down, indicating that we have reduced muscle damage in those patients, and then that's translated into functional data that Steve's seen in the clinic. Patient-reported outcome. Yes. Got it. Do you wanna talk about the functional? We’re really pleased. Again, we saw very early improvements in a number of functional measures. We saw improvements in the reachable workspace, compared with not only the placebo within the FORTITUDE study, but also compared with an early time point in an external natural history dataset. We saw the reachable workspace improve no matter which of the quadrants that we looked at, whether you looked at the dominant arm, the non-dominant arm, the average, so very consistent data. We also saw improvements in muscle strength as measured by quantitative muscle testing across a composite of seven different muscle groups in the upper and lower limb. Also, when we looked at muscle groups individually in the upper and lower limb as well, we saw improvements there. And then lastly, we saw improvements in patient-reported outcomes, three different patient-reported outcomes that we looked at, including the EQ-5D visual analog scale. And those were mirrored in the equivalent physician-reported outcomes as well, showing improvements as compared to placebo. So really, as Mike said, we've joined all of the dots up through delivery to muscle, target engagement, affecting the DUX4 genes, all the way through to how the patient's feeling at the end of the day. So really a very consistent story for the drug. Yeah. So, you know, obviously, given the data that we saw, and when we shared the data, we talked about our regulatory strategy. So within the FORTITUDE study, it was always designed to add additional cohorts to that study, which allows us to be very efficient from a timeline perspective. And what we announced was two additional cohorts. One is Cohort C, that we're referring to as Cohort C. That is a cohort that is focused on biomarkers and that is designed for potential accelerated approval. And then Cohort D, which is a larger cohort that is designed for a full approval strategy, looking at functional endpoints. What we have said with regards to Cohort C, and, you know, remains consistent, is that, you know, we're really leaning in, and, that we would very likely be initiating the cohort before we had agreement with regulators with regards to that strategy. But given, you know, the incredibly compelling nature of the data and the fact that we can look at multiple ways to look at the biomarkers, we feel sort of that, one, simply from a patient perspective, it was the right thing to do to look at how we can accelerate. But also from a strategic perspective, this gives us a real opportunity to pull forward the whole program. So the next update from the program will likely be around initiation of the cohort, dose and dose selection, rationale for that. And we guided that that would be in the second half of this year, and we're on track for that. But that, in all likelihood, will not be with us or with us having agreement from a regulatory perspective. Got it. Does that mean for the Cohort D, that one will be initiated after you had something back? Correct. Correct, yeah. Cohort D will be after we've had feedback. And look, you know, the way that we view it, for Cohort C, it's kind of like a win-win regardless, in terms of, it gives us more data, it expands our safety database, it allows us to learn even more about our program. And of course, you know, on having data from Cohort C, that would also enable us to go back and have another discussion with regulators as well. So we kind of have two strategies in play, both the acceleration and also the full approval strategy, which is earlier than we anticipated as well. Right. Got it. Got it. And in terms of Cohort C's biomarkers that are to be followed, I think there are a few- Mm-hmm. Actually, the DUX4 biopsy data, and also, I think you've talked about this. ... normal serum biomarker that you discovered- Yeah. In your work, and perhaps also the CK. Mm-hmm. I'm not sure if that's considered part of the biomarker. So, any updated thinking about which one might be your favorite? Yeah. Mike, do you want to talk about the biomarker? Yeah, we can. I'll start and then you can. I think, you know, it's gonna be a holistic view of all of them together. So it's going to be, you know, as anyone, you'd want to know, like, okay, does it actually hit the target? And does that target lead to a clinical improvement or benefit, right? And I think what's clear is that DUX4 is the underlying cause of the disease. We can demonstrate that we knock down DUX4 by looking at a downstream gene panel. So that'll be part of it, right? We can also demonstrate that we're hitting DUX4 by looking at a circulating biomarker. So we'll be able to see that biomarker, not just in that small little biopsy, but over time. That shows a continuous improvement or continuous decrease in that biomarker. And then, and then finally, the CK will add into that, that you're actually having some improvement in muscle. So that, that set of data will go a long ways, and then I think there'll be some probably implication of a functional, just like we've seen early on. Yeah. So FSHD really is a perfect disease for an accelerated approval. The underlying cause of the disease is known without a doubt. It's aberrant DUX4 expression. If you don't have aberrant DUX4 expression, you don't develop FSHD. There's a well-accepted group of downstream biomarkers of DUX4 activation. No matter how we measure those biomarkers, and we looked at them three different ways, we see profound reductions of greater than 50%. Very, very consistent data. When we look at the circulating biomarker, we're able to track DUX4 activation over time. We can show that we're not just hitting DUX4 at one time point, but we're seeing consistent reductions over time. We're seeing improvements in creatine kinase, as Mike said, a measure of muscle health and muscle damage, and we see that go down in a consistent fashion over time. Then we're also seeing very strong trends in the clinical endpoints as well. Really a very strong package, we think, to justify an accelerated approval. We think we can make a compelling case. Great. So great to hear that confidence and perspective. Appreciate the insights. So I think at the time of the presentation for the first human study for the FORTITUDE study, you know, you had two-month PET data. I think you also mentioned four-month PET data is close, but not quite there. Mm-hmm. Is that something we will hear more about this year or next year? Yeah. So I would say for this year, it'll be initiation of Cohort C, and at the time we do that, we will have done our dose selection. So that will be the dose selection, dose frequency, and also the rationale for that. I think, you know, one of the really exciting things with the discovery of the circulating biomarker, as Steve said, it allows us to look over time and to be really able to see really able to use that data and the creatine kinase to inform the dose frequency. So whether or not every 12 weeks or whether we need to do something shorter, because we can look at if there's any sort of return of the circulating biomarker as we look out at 12 weeks. So it really is an aspect that allows us to now dial in our dose and dose frequency in a way that is very unique, and in a way that, you know, we haven't been able to do before, 'cause otherwise you're just relying on the muscle biopsy data, and obviously you can't do muscle biopsies every single month, the way we can look at the circulating biomarkers. So that's the area that we'll be really leaning on very heavily when it comes to dose and dose selection. Got it. So more to come. Okay. Got it, got it. Maybe one, one other thing that I would add is that what we know with FSHD is that unlike our other programs, it's due to expression of a gene that just shouldn't be there. And when you express the DUX4 protein, which is encoded by that gene, is a transcription factor. When it's expressed at all, it turns on a whole bunch of downstream genes, and the products of those downstream genes are extremely toxic to muscle. So what we need to do is maintain enough siRNA in the cell throughout the entire dose interval so that we keep the DUX4 suppressed. Whenever any DUX4 siRNA is made, it's immediately freed by the siRNA, so we just don't get that downstream cascade of events that leads to the muscle damage, and that's going to factor into our dose and schedule selection as well. Got it. Great. Great. I think one event investors are watching for in the FSHD space is the Fulcrum's data. Like, I think they said by the end of October. Mm-hmm. I was wondering, as you, you know, look at that upcoming data, how... what's, you know, what's your -- what will be your focus? And hypothetically, if the data is indeed positive, what... how should the investor think about the risk to, del-brax? Yeah. Steve, do you want to take that one? Yeah, sure, so FSHD is a relentlessly progressive disease, leads to disability. It hits people in the prime of their life, and there are currently no treatments at all for this disease. If losmapimod gets approved, that's great for patients. It means they've got a treatment choice. That said, it doesn't target the underlying cause of the disease directly, the DUX4 expression, and del-brax DUX4, we hit DUX4. By knocking down DUX4, we would anticipate that we would have a better treatment effect on the disease than losmapimod. Got it. Yeah, that totally makes sense. So let's touch on DMD. Yeah. This is the most recent data. Congrats on that positive data reported in August. So I think if you, you know, I think you talk about the accelerated approval path. I was just curious, does the full approval of the Elevidys, obviously a gene therapy, does that have any implication for accelerated approval path for exon skipping drugs? No, there's no implication. The accelerated approval pathway remains open, and we're planning to take full advantage of it to get the drug to patients as quickly as possible. Got it. Got it. So obviously, in your data, you had a very impressive dystrophin expression. I think that's higher than any of the, the- Mm-hmm ... drugs approved to date. So certainly looking forward to that, you know, discussion with FDA and, you know, the next steps for that program. But how do you... I guess, how is there a way to think about how this might translate to additional, exon, exons? What's your confidence level? Or could this be just a case-by-case, you know, exon-by-exon situation? Yeah. Mike, maybe you wanna talk about delivery here. Yeah. So, yeah, the first thing, well, like you said, I mean, it was unprecedented data. I mean, the delivery to muscle, which was, you know, and we've surpassed everyone on delivery to muscle, which is the first key step, right? The exon skipping was amazing, and now we're seeing, what? 32% mean amounts of dystrophin in patients. And then just to put the 32% in perspective, you know, moms who are carriers make about 50% dystrophin. So we're really starting to approach normal levels of dystrophin at 32%. So we really think that that level of dystrophin production will, you know, help the muscle cells, and we saw that with the decrease in creatine kinase, right? Then we as we go longer and longer, we should see, you know, hopefully an improvement in people, in boys and young men. That dystrophin level is amazing, and we may not even be at the top level of dystrophin because our time point was at four months. The longer half-life of dystrophin, you should expect to see some accumulation. That is really amazing. The I think, you know, for del-zota, it's just, it's all about delivery. It's about delivery, and it's about a really good sequence, and how that translates to other exons, we believe that the delivery is really gonna be key to that, and we've cracked delivery. And what we're expecting to see as we move into exon 45 and to others is that we expect to be able to make dystrophin levels that are clearly in the Becker's range, so above 10%, where we think we'll have a meaningful effect or profound improvement in people's lives. So that's really what we're looking for. If we don't see that kind of level of dystrophin, you know, we have lots of programs that we're gonna be able to invest in, but that's the kind of profound difference that we wanna be able to make. Even if we're only half as good with the other exons as we were with del-zota, we're still well within the Becker's range and streets ahead of the other exon skippers out there. So really, we've got a high degree of confidence about the other exons that we're targeting. Got it. Got it. Yes. Yeah, that's very, very helpful. And lastly, I wonder, there was some breaking news yesterday from your competitor, Dyne, in their DMD program, but I think what caught investors by surprise is some safety findings in that data set. Do you think there could be, you know, any, you know... How do you think about those findings, and could there be any read-through to the broader space? Yeah. So maybe I talk about what we observed with del-zota. I think, you know, Steve and Mike have already talked about really, truly unsurpassed levels of exon skipping and then increasing in dystrophin production. First time for any program to see serum creatine kinase getting close to near normalization and sustained. From a safety perspective, we're really pleased with the overall safety profile that we've observed, and we have not observed any thrombocytopenia, any pancytopenia, or any signs of renal injury or any hint of that in the del-zota program. So we're, overall, you know, we have that combination of both a drug, you know, that clearly is making a profound impact by increasing dystrophin, but also with an overall very favorable safety and tolerability profile. Great. Great. Thank you for those thoughts and updates. I think we're out of time, so thank you so much for a very enlightening session. Thanks so much, Yanan. Great to see you. Yeah, thanks for having us. Great.