Okay, great. Let's go ahead and get started with this session. It's my pleasure to introduce the management team from Avidity Biosciences. With us here today, Michael MacLean, the CFO, Chief Business Officer. We've got Mike Flanagan, Chief Scientific and Technical Officer, and Steve Hughes, the CMO. So welcome, gentlemen. This is a fireside chat, and if there's any time at the end for questions, we'll try to answer those for you. Mike, let me start with you. Maybe just provide a brief summary of you know, what's happening at the company year to date. You made a lot of progress. Yeah, thank you. And, thank you for inviting us to the conference. Like, we really always enjoy being out here at Chardan, and, we were just talking about how you picked us up for coverage in our early days, so Chardan has really been along for our ride. Where are we today from a view of Avidity? We're three for three, right? We have, three profound data readouts and three programs focused on three different rare neuromuscular diseases. So, we're thrilled, for, you know, progression of our mission and for the patients that we look to be able to bring therapies to. And we, are going after diseases that have no available treatment today, right? Whether that's for myotonic dystrophy, FSHD, or DMD for young men and boys that are amenable to exon forty-four skipping. The power of the platform is showing through. We are continuing to connect the dots. We are showing delivery to muscle. We're showing knockdown of the intended target, downstream biomarker changes. And in the case of myotonic dystrophy and FSHD, we're showing signs of functional benefit. So, we're not only showing signs of functional benefit for myotonic dystrophy, but also the reversal of disease compared to the natural history data. So, we're really excited about all of that. As to where the company is right now, we remain on track for enrolling the HARBOR trial, which is focused on myotonic dystrophy. It's a pivotal trial. We commenced that enrollment in July of this year, and we expect to complete enrollment in a twelve-month time period. With regard to FSHD, the FORTITUDE study, you know, showed, you know, that by focusing on the root cause of the disease, DUX4, that we can make a profound impact, and we're looking to initiate a biomarker cohort by the end of this year, and a full approval functional cohort in the first half of 2025. Lastly, for DMD, the EXPLORER 44 trial showed unprecedented delivery to muscle, which resulted in profound skipping and dystrophin creation for patients with DMD 44. The neuromuscular franchise is off to a fabulous start here, and we're now expanding into precision cardiology. We will announce our first and lead program in precision cardiology by the end of this year, and we're really excited for the platform and what it can bring to the patient populations that we can affect. All right, we'll save those thoughts because I have a question for you at the end of this. Well, Mike, let's switch to your first program in DM1. And when I first picked up the company, I used to have these interesting discussions with Art about your approach. And especially for DM1, we're in the field, we're seeing different approaches to knock down the toxic DMPK in the nucleus. You guys obviously using an siRNA to engage a RISC complex, others delivering a gapmer to induce RNase H degradation, still others trying to have the effect of steric blocking to achieve that same effect. So talk about why you think your approach is advantaged here. Yeah. So we spent a decade of really honing our approach, and first, it starts with the antibody, that transferrin antibody. Really have done a lot of work on selecting that antibody, having a high-affinity, good delivery mechanism, and we continue to do antibody engineering. Second is a linker. So we've selected the linker for a non-cleavable linker, so it has high stability in plasma, so you can get very good stability of your drug and therefore better delivery to muscle. And then finally, the silencing RNA. Now, the silencing RNA is probably the biggest differentiator in the sense that it's highly potent, right? It binds to AGO2. You need very small amounts bound to AGO2, and it's catalytic, so it identifies its target, degrades its target, finds a new target, degrades that. So it's really a remarkable, not only potent, but durable, mechanism. And then, if you just look generally, there's been, what, maybe six different siRNAs or maybe more now that have been approved. siRNAs perform really well, both safety-wise and just in general, for patients, so it's a really great modality for using that. I think when you contrast that with others, is that, again, the potency is with siRNA, the safety profile is with the siRNA, the convenience of dosing is with siRNAs, compared to ASOs or a PMO, where you're basically wallpapering a DMPK to try to block muscleblind. So I think, you know, our technology, not only like Mike said, we've shown delivery to muscle, we've shown knockdown of DMPK. We've actually shown increases in muscleblind. So if you remember, Muscle blind protein is what's sequestered by DMPK, and by releasing Muscle blind-like protein, then you allow the normal splicing to occur. So we've seen that normal splicing, and you've seen those videos where you see improvement in myotonia early on, so that's just measured by hand, but of course, myotonia is throughout the whole body. So I think those, all these different attributes of del-desiran make that selection of the antibody, the linker, and the siRNA really valuable. Okay, so, you know, going back to March of this year, you presented data from the MARINA open-label extension study, and this really built on the prior findings from the MARINA study. Then you also had some natural history study data that helped to support what you were seeing. So maybe highlight the key findings and how that's informed the design of your HARBOR phase lll. Steve, do you want it? Yeah, so maybe if I take that one. So, yeah, so we really did have a lot of data to inform the HARBOR phase lll study. The data that we disclosed earlier this year was through one year of a follow-up, so that was through both the MARINA study and the first six months of follow-up in the open label extension study. And there, across multiple clinical endpoints, we showed essentially reversal of the natural history of the disease, and those endpoints formed the primary and key secondary endpoints for the HARBOR study. So we saw very early improvements, first of all, in each of the endpoints, so VHOT, hand grip strength, muscle strength, and activities of daily living. Those improved within the first three to six months, so very early. They were sustained over that one-year period. We did comparisons both with natural history data set and with placebo, and we saw exactly the same thing. So we really believe that from an efficacy perspective, the HARBOR study has been de-risked. We've already followed up patients for the same duration as the HARBOR study. We've seen the changes in that phase ll cohort that we expect to see in HARBOR. Our eligibility for HARBOR, criteria for HARBOR are very similar to what they were for the MARINA study, so they're gonna be similar. And then I guess the last thing is just the, the safety database. So, we've got long-term safety data now with just about, well, all patients through eighteen months of continuous follow-up, many patients through two years of continuous follow-up. All of the patients that enrolled into the open label extension remain in the open label extension with long-term follow-up. So all of that provides a very reassuring package as we move through the phase lll program. So, as you've described, you know, VHOT is your primary endpoint in this study, but how important do you think the findings for the secondary endpoints will be in, you know, perhaps both the approval decision and then obviously the commercial marketing? Yeah, so in rare diseases, where you typically file with a single pivotal trial, not with two pivotal trials, the secondary endpoints do become extremely important as confirmatory evidence. So, FDA and other regulators will typically want to see at least directional improvements in those, in those key secondaries to back up the primary endpoint findings. Based on the data that we've got, and as I said just now, we've got a lot of data now to inform how we design the HARBOR study. We're really well-powered for both our primary endpoint and all of our key secondary endpoints, so a lot of confidence that we're gonna hit those as well as the primary. I guess just qualitatively, the fact that the study doesn't require biopsies, you know, how is that affecting both the interest in the study and perhaps the pace of enrollment? So, the not requiring a biopsy definitely makes the study easier on the patient, and we've got a lot of interest in the study. As Mike mentioned, we've guided that we will enroll the study within a one-year period, and we're on track to do that. We're very pleased with the level of interest that we've got and the enrollment. The other piece, of course, is that by not requiring biopsies, that increases the pool of sites that we have available to us because we don't need sites that have expertise in biopsying and also uncomplicates the logistics of the clinical trial because we don't need to arrange ultra cold chain transport for biopsies from one continent to another to a central lab, for example. So definitely an asset. Maybe just to touch a little bit on why we've set the study up in that way. One, essentially, the regulators haven't really shown a lot of interest in the biopsies in the biomarkers as indicative of what's gonna happen in the disease. They've done their job in terms of informing target engagement, informing the downstream biology, et cetera. We've kind of already joined those dots. What the patients care about and what the regulators care about is really the functional improvements in this disease. Okay. So, you know, we look forward to hearing about your progress there and obviously, ultimately, the readout of the top-line data. But, it's really great to see your progress there. Let's move on to your second candidate, del-zota for DMD amenable to exon 44 skipping. As Mike alluded to, I guess from our perspective, based on what we saw in your preclinical data, the fact that you were able to deliver more drug, this was resulting in more exon skipping, and then obviously, more production of dystrophin. I guess we weren't surprised, but happy to see that that was the effect. So what else can you highlight from the data that you've presented thus far? Yeah, I think the other key thing, just like you said, right, again, we showed delivery to muscle, unprecedented levels of PMO into muscle at our lowest dose of five mg per kg, dosed every six weeks. So that was amazing. That translated into skipping of 44% skipping of that exon 44. And then that translated into 37% kind of mean levels of dystrophin. And just to put 37% dystrophin into proper context, carrier moms would have about 50% dystrophin level. So you can see at our mean levels, we're really starting to approach what would be considered kind of normal levels of dystrophin, and we saw as high as 54% dystrophin levels in some patients. So really remarkable data. I think the other thing that you know, while that's really amazing, I think when we started sharing it with some of the docs that were running the investigators that were running, they were most impressed by the CK levels and the creatine kinase levels going down from around 5,000 to near background or near normal levels of creatine kinase, which is a marker of muscle damage. So we dramatically and quickly reduced CK levels down to near normal levels. I don't know, Steve, if you want to add to that? Yeah, so we definitely had a lot of interest from the investigators and also from the patient community in the data. As we move forward, we've disclosed already, we're planning to enroll an additional 10-15 patients into the open-label extension study to build out our safety database into the range of other approvals within this disease, and we've got a lot of interest in those additional slots in the clinical trial. When might we see some data on functional benefit improvement? So, in terms of our guidance on what we're going to show next, we're certainly measuring functional measures as part of the trial. But remember, as Mike said, this is the five mg per kg cohort that we've shown. We have announced that we've fully enrolled, that the 10 mg per kg information will be coming out. That's going to be sometime in 2025. Remember, like, the cutoff was four months, right? So that's very early to be showing functional benefit for this for people with this disease. So the functional benefit will likely come out of the open-label extension data that certainly will be in the future. So we can't kind of guide to exactly when that will be at this point in time. But as Mike mentioned, with the creatine kinase levels coming down to near normal, we have a lot of hope that we're going to see functional benefit, given the fact that the biology is leaning towards normal in that instance. Okay, great. So we know that the accelerated approval pathway for, you know, PMO-based DMD remains open. So how might the study become registrational? So maybe if I take that question. So we regard the study as registrational already. We're very close to the number of exposures for other PMOs that have been approved for Duchenne muscular dystrophy. At this point in time, we're working diligently to have conversations with FDA about what is the most rapid route to an accelerated approval. We're not giving guidance at this time as to exactly what we think that is, in order just to avoid any speculation around that. But, as we get more concrete guidance, we'll be able to provide an update on timing and what the exact path is. Okay. And while there are some nuances between the different exons that would be amenable to skipping, you do have other programs addressing other exons, exon-skipping programs. So how do we think about how rapidly you might accelerate the development of those programs, given the confidence you have in what you've seen, not only for the platform, but specifically for exon skipping with forty-four? We've already disclosed that we are accelerating the additional exons. Exon 45 is our next one. That's already in IND-enabling studies, so that will be the first one out of the other exons that we're looking at to go forward into the clinic, and then we're accelerating the path through to IND for additional exons as well. Okay, well, great. So then let's maybe talk about your third program for FSHD. Again, we saw a nice tranche of initial data here. Obviously, the ability to measure the effect on DUX4 can't really measure it directly. So talk about the way that you were able to assess the effect of your drug here. Yeah. So I can take that. So, yeah, the data from FSHD were. You know, we're really pleased with that, those data. So just to give you, just to set the context right, DUX4, which is the underlying cause of FSHD, and DUX4 is a transcription factor that is turned off after the two to four stage kind of embryogenesis, never to be turned on again. Yet within FSHD, DUX4 gets apparently expressed and is poison to muscle. So when DUX4 is expressed, you get poison of your muscle, and that's really due to activation of a downstream pathways that include apoptosis, kind of, some early cell death, and other targets that are activated. So it activates a cascade of events. And what our drug does is that, del-brax basically hits DUX4. It knocks down DUX4 and prevents it from being expressed. If you prevent that expression, then you don't get poisoning of the muscle cells. And what we were able to show is that DUX4, because it activates a downstream signal, we can show that those downstream signals are blocked. And it doesn't matter which ones you look at. We had a group of just four transcripts that we looked at. Those were knocked down by greater than 50%. If we looked at another set of transcripts that another sponsor had selected, we saw, again, greater than 50% knockdown. And then, when we looked at a broader set of DUX4-regulated genes that included 41 different genes that were de-identified by academic groups, we again saw knockdown. So what this points to is that if you're a transcript that's regulated by DUX4, and you're dosed with del-brax, you're going to see a decrease in that transcription because we're blocking DUX4. So that's really the key, a key point of that. In addition to that, we were able to identify a novel circulating biomarker. So this is a plasma-based circulating biomarker, never been identified before for this kind of biomarker plasma-based. And what I can tell you about this protein that's in the plasma is that it's DUX4 regulated, and that we can measure it by a number of different ways. So using that circulating biomarker, we can then, instead of having, like, a fine needle biopsy in your thigh, just at a single time point, we can look at all the muscles in your body using this plasma circulating biomarker, and then also follow it over time. So it really provides us this really nice picture of what del-brax is doing, in these patient populations, and just following the decrease of that. That decrease in that biomarker also was translated to decreases in CK again. So we also saw decreases in creatine kinase, which again is a muscle damage marker. So, you know, I think I probably sound like a broken record again. What we did was we showed delivery to muscle, we showed target engagement with DUX4, we show it effect on both muscle health, and then Steve can describe some of the things that we saw early signals of functional benefit. So, again, connecting all the dots, and I think this is what happens when you have a genetic medicine, right? That you're delivering to muscle, specifically targeting the genetic effect. So do you want to speak to the functional benefits? Yeah, sure. So, as with all of our programs, we're looking at a range of clinical endpoints, including measures of muscle strength, mobility, and patient-reported outcomes. In the FORTITUDE study, we showed again very early improvements in patients, so we looked at reachable workspace in the right arm, in the left arm, or dominant and non-dominant arms, both combined, looking at the upper quadrants, looking at the lower quadrants, looking at all quadrants combined, and saw very consistent improvements compared with both the placebo arm of the FORTITUDE study, but also compared with natural history as well, essentially showing again reversal of disease progression, and we showed improvements in muscle strength, both as a composite of upper and lower limb, so that's a measure of total body strength. When we looked at upper limb muscles and lower limb muscles separately, again, we saw improvements versus placebo there, and we also saw improvements in a range of both patient-reported outcomes of disease severity and disease progression, as well as the equivalent physician-reported outcomes of those measures as well, so really, a full package of data from both the target engagement and biomarker side, all the way through clinical and through to how patients are feeling at the end of the day, so joining all the dots up again. Yeah. So, you know, we found the biomarker to be really intriguing. What additional data do you think it would take for that to be accepted as a validated biomarker and possibly be able to use that for an accelerated approval? Yeah, I think I can start and then Steve. But I think for us, when we think about accelerated approval, so if you remember, we have a two-prong approach. So we have, we've initiated or will be initiating a accelerated pathway for approval, and then we'll also have a full approval pathway that we'll discuss next year. So what we think for the accelerated approval, and just to remind everyone, is that we don't have, we haven't had buy-in by the FDA, by regulatory agencies, so we're really looking at the totality of the data. So then, again, going to the DUX4 gene score, going to a circulating biomarker, going to early effects on CK. We also have RNAseq data, looking at the disease biology downstream, even of the next level of DUX4, and then looking at the functional data. So we think that's the totality of data that's going to allow us, reasonable, you know, a reasonable likelihood that we're going to see clinical benefit is kind of the bar that you have to hit. So it's not gonna be any one thing. It's gonna be a composite of all those data that, again, I think the key thing, and Steve can expound on this, but DUX4 is the underlying cause of disease. I mean, I think everyone agrees that DUX4, if you knock down DUX4, you're gonna see effect. If you don't have DUX4, you're not gonna have FSHD. So I think that really provides a good background for that accelerated approval. ... Steve? Yeah, so, the accelerated approval pathway is based on reasonable likelihood to predict clinical benefit, and for all the reasons Mike said, the underlying cause of the disease is known without a doubt. We know the downstream biomarkers that tell you whether you're hitting that, et cetera, et cetera. Maybe just to clarify on one point is, which is that, we're initiating that biomarker cohort prior to having any regulatory interactions. We will get alignment with the regulators downstream. We think there's a very compelling case for an accelerated approval in this disease based upon DUX4. And so we plan to have those discussions subsequently. They're just not gating on initiation of this cohort. Okay, well, I know you have other catalysts upcoming. Maybe briefly talk about the first candidate on your BMS. The precision cardiology. So yes, by the end of the year, we will present our lead candidate. And we did enter into a collaboration around this time last year, actually, with BMS, and there are five targets, one of which we've been working on with them for quite a while. Those targets are totally separate from our targets. So we have a similar number of targets that are, I'll call wholly owned, which are after different disease types, right? So what we're going to announce by the end of the year is our lead wholly owned target that we look at as a proof of concept for really both AOC and BMS in terms of the precision cardiology space. So we're really looking forward to it. It's a, it's a huge opportunity for the technology, and we can bring some therapies to patients that are meaningful and necessary. Okay, so here's my final question for you. It's a question I get a lot these days from investors. The stock's up 400% this year, so they're asking me, have they missed this opportunity? At the beginning of the year, I made the bold case that, you know, this is a platform technology. The company's gonna present a bunch of data this year. If it's positive, it's gonna validate that platform. So Mike, what's the bold case now, for investors who think they may have missed it? Yeah. Listen, I think the bold case is what it has always been, right? It's not too late. If we just look at myotonic dystrophy and our del-desiran drug, this is an area of unmet need with a large for rare patient population. We are going to be the first to have a commercial drug. We will be first in class and best in class. It's a multi-billion-dollar opportunity, so you need to think about this like where Alnylam was, where Vertex was, right? That's on this. Without even thinking about any other drug coming through, this could build a company on its own. Then you add in del-brax for FSHD, similar patient population size, area of unmet need. We expect to be first in class and best in class. Now you're looking at Alnylam and Vertex combined, and that's before we even get into precision cardiology, other neuromuscular programs, and what else we will bring this platform to bear for. So I think there's tremendous value creation ahead of us. This is a likely time to get in if you're someone who looks and, really wants to make the bet on the commercial opportunity that we see ahead. Great. You certainly made me look smart by nominating this as my top pick this year, so thank you. Thank you, Gang.