All right. We're going to get started here, so welcome, everyone. Thanks for joining. I'm Gavin Clark-Gartner, one of the senior biotech analysts here at Evercore ISI, and I'm really happy to have the Avidity Biosciences team. We have Mike MacLean, who's the CFO and the CBO, and Steve Hughes, who is the Chief Medical Officer. Thank you both for joining. Thanks. Absolutely. So I remember last year when we were sitting here, you guys had just announced the Bristol Cardio partnership. And obviously, since then, it's been an amazing year for the stock and multiple fundamental updates. So maybe you could just kind of quickly reflect on what's happened over the last year. Where does things stand today? Absolutely. Thank you, Gavin, for having us here. We always enjoy this conference. Great to kind of leave the Thanksgiving table and come to the beaches of Miami. So 2024 has been a great year for the company. It's very hard to hear you. I don't know if my mic's coming through. Yep. Hello? Can you hear now? OK. Sorry about that, so 2024 has been a great year, transformational. We're three for three. We have shown great data that's reproducible and consistent across all three of our neuromuscular programs in 2024, and that puts us in a position where we are in potentially registered trials for all of our neuromuscular programs. This is so profound for the company and where we have been and where we're going, and we've also announced that we're moving into a new franchise, a new therapeutic area in precision cardiology, so this is a broadening and deepening of the platform, and we're opening up a whole new space. We can talk about that a little bit. And we've also shown a glimpse of what we're doing for the platform in terms of next-generation technology and how we can profoundly continue to work on delivery and also the potency and durability of the chemistry that we're using as the therapeutic. And lastly, as we head into 2025, we have reported we have $1.6 billion, and that is going to give us a runway to mid-2027. And that allows us to progress all of these trials, as you would expect us to, into approval and commercialization. And we have already begun the commercial infrastructure build that's going to be necessary to bring these products to market. Awesome. All right, let's dive into each of the programs, and we'll go a little higher level at the end. Starting on the DM1 side with del-desiran, I know you guys don't give granular enrollment updates, but what we have roughly said is the trial started around June, and you've noted around 12 months to enroll. Is that all still on track? Yeah, the HARBOR trial is on track for enrollment. This is a global trial, and we're really pleased with the uptake for enrollment. So we have guided that we expect to complete enrollment in mid-2025. Awesome. And thinking ahead for the trial, for the 30-week top line, when you hit that portion, are you planning to announce the data, disclose it there, or is the trial going to keep running? What update should we expect at the 30 weeks? So maybe if I take that one, Gavin. So it's important to remember that it's an ongoing study, and so we do need to be very careful in terms of what we disclose at that time point. In these kind of situations, it's very common to just state whether or not you've met your primary and key secondary endpoints, and then to disclose granular data at a subsequent scientific meeting. Yep, and after you hit that 30-week top line, you're going to move forward and get ready for a filing, et cetera, and let the study keep running. Maybe you could just outline the design of the trial, too. Yeah, so maybe just starting with the design of the study. So it's a pivotal study. It's randomized, double-blinded, placebo-controlled, randomized in a one-to-one fashion, so equal between placebo and active drug. Patients are receiving del-desiran 2 mg/ kg every eight weeks, with the first doses at 2 mg/ kg. And then in our phase one-two program, the MARINA program, we saw very early improvement in the functional endpoints that were maintained out through the 12-month time point. And so we're able to actually look at the efficacy endpoints at a very early time point. So we plan to cut the efficacy data at week 30 and then file with that as soon as possible. And then the continued follow-up is primarily for safety reasons because the regulators like to have a year of placebo-controlled safety data. And so we follow the patients out through week 54 for safety. And our plan would be to provide that additional safety data during the review period at the day 90 or day 120 update time point. Yeah, that makes sense. And I guess even to ask some of these questions a little more explicitly, when you do hit the 30-week top line, you noted keeping it blinded to 54 to generate the safety data. Is there any type of data you could consider providing with the top line, whether that's a pared-down version to not kind of break the blind, like the VHOT effect size, for example? And you might be thinking about this, so it's maybe more to come in the future. Yeah, I'd say it's maybe more to come in the future about what it is that we can specifically disclose there. Yeah. All right. Well, that makes sense. And just for the study overall, maybe you could just kind of say, remind us what the background safety events in general for the DM1 population are that we should be looking out for. And I guess nothing's been flagged on a blinded basis from your perspective, and the DSMB hasn't given you any comments, et cetera. No. So the DSMB reviews have all been "study may continue." The long-term safety data has been really, really favorable. We've got most of it, I think everybody knows, through at least 18 months, many, many patients through two years of follow-up. And all of the patients that went into the open label extension remain in the open label extension after that very long period of follow-up, which really, I think, talks to, one, the tolerability of del-desiran, but also the benefits that the patients are feeling by being on the drug. So all of that is really favorable. In terms of really longitudinal comparative data, that's a more difficult one because there isn't really much out there. What's been really studied is cross-sectional looks at the data. We do know that patients that have DM1 have fairly frequent lab abnormalities. And you can get abnormalities in liver function, abnormalities in renal function, et cetera. So in that respect, having a placebo control is very helpful to have those backgrounds. We're not seeing any safety signals at all out of the clinical trials, which is very encouraging. And in fact, as we look across our platform and all three of our drugs are using the same transferrin-targeting antibody, we have long-term data now across all three programs, and it's all looking really favorable and well tolerated. Yeah, great. And for del-desiran, it doesn't cross the blood-brain barrier. So maybe kind of, and this is a question we get, but maybe discuss your ability to still address the cognition impacts of DM1. Yeah, so that's a really interesting question. And we definitely believe that we will be able to address many of those effects. And the things that are classically described as the central effects of having DM1 are contributed to a large extent by actually the peripheral neuromuscular effects. So if you imagine that weakness and/or myotonia of the muscles of the pharynx, the muscles of the tongue, the respiratory muscles, all of that can contribute to sleep apnea. Sleep apnea can lead to daytime somnolence, problems with concentration, fatigue. The prolonged muscle contractions that come with myotonia can also contribute to fatigue. And all of these things can be addressed by del-desiran. Yeah, great. And I'll sneak in kind of more of a platform question here to your opening comment, Mike. But one of the comments you guys made as you're looking at TfR1 antibodies with different affinity, I believe, one of the things I thought was, is there any way you could look at approaches that could cross the blood-brain barrier to some extent? Would you advance any of these programs in the future, also maybe early on this front? I think the way that we think about crossing the blood-brain barrier is that that, to me, becomes a CNS therapeutic area focus, which is not on our radar screen at the current moment. Obviously, we're very busy with neuromuscular precision cardiology in partnership with Bristol Myers, and then immunology is something that we're dabbling in with Lilly, so we've got our hands full with the transferrin-1 receptor, the monoclonal antibody in its current format. Yeah, I think that's very fair. And moving over to FSHD for del-brax, you could just kind of outline recent data updates and the dose selection, just kind of reframe that update for us. And looking ahead, what's your current status of regulatory discussions, specifically around the accelerated approval path and when we could expect an update for those? Yeah, so maybe if I take that. So we've had two disclosures in recent times from the Fortitude study. The first of those was the data from the 2 mg/kg cohort at four months, where we showed quite marked reduction in the biomarkers indicating reductions in DUX4. So we saw greater than a 50% reduction in the DUX4 gene panel across three different gene panels. We looked at a four-gene panel, a six-gene panel, and a 41-gene panel, and they all behaved very, very similarly. We also saw reductions in a circulating biomarker that we've discovered internally. And the beauty of the circulating biomarker is that it allows us to look at over time. It's very difficult to take multiple muscle biopsies, but we can do multiple blood draws. And we saw very early reductions in the DUX4 circulating biomarker. And those were accompanied by reductions in creatine kinase, which is a biomarker for muscle damage. And then we also looked at clinical endpoints and compared to both placebo and to natural history. At that four-month time point, we were able to show improvements in reachable workspace and improvements in QMT, which is muscle strength, and also improvements in patient and physician-reported outcomes. So really, a data set joining the dots all the way from delivery of the drug through the biomarkers, the biochemistry of the disease, and all the way to the clinical endpoints. And then more recently, we disclosed the data that we used to select our phase three dose for the biomarker cohort targeting and accelerated approval, and then also the functional cohort targeting and full approval. There, the data we shared was around the circulating biomarker because the beauty of that, as I said, is we can track it over time and the creatine kinase. There, we didn't see any greater improvements at 4 mg/ kg than we did at 2 mg/ kg. It seems that's very similar to what we saw with the myotonic dystrophy program. We're at the top of the dose response curve at 2 mg/ kg. With respect to the dose for phase three, in FSHD, DUX4 is due to aberrant expression of DUX4, which is a transcription factor. When DUX4 gets switched on, it basically turns on a whole bunch of different downstream genes. Once those have been turned on, you can't really attenuate the disease. It's very important to keep DUX4 suppressed throughout the dose interval. We went with an every six-week dose interval for our registrational cohorts in order to ensure that DUX4 is always continuously suppressed. Our go-forward dose is 2 mg per kg every six weeks. In terms of guidance around the dose and regulatory, we're going to give more detailed 2025 guidance around the time of the JP Morgan conference. However, what we can tell you is we do plan on showing the 4 mg per kg data at a medical conference in 2025. All right, that makes sense. I was going to my follow-up question. It's very rare to see the first dose you test in a new disease be the right dose. So I was really curious to see the 4 mg/ kg and how you made that selection, but we'll wait for 2025. Yep. All right, let's switch gears then and go over to the DMD side with del-zota because you're dosing at 10 mg/ kg right now, I believe. If I just do some rough math, as of kind of end of July, I think everyone in that cohort had received at least the first dose. So if you just kind of play the timelines forward, understanding that it's three months plus a one-month biopsy, so four months after, presumably, you could be pretty close to having some of that data internally. So what should we expect for timelines of presenting that and also how that fits in with the regulatory engagement side? Yeah, so basically, I think we are pretty close on bringing that to conclusion. Again, we'll give better guidance or more detailed guidance at J.P. Morgan, but you should expect that we'll show that 10 mg/kg data at a medical conference in 2025. And in terms of regulatory pathway, we believe the regulatory path, the accelerated regulatory pathway for DMD is still open. And to the extent we have anything to report on that, we'll report that. Yeah, that makes sense. And I'll just clarify on that point, which is when you say the regulatory path and the DMD exon skipping side is still open, do you mean just for Exon 44 or for all the exons broadly, depending on your product? Yeah, we believe it's open for all exon skipping. Yeah, and that is what Sarepta indicated too, depending on your product profile, of course. Yeah, yeah, all right, that makes sense. Any initial thoughts at this point in time thinking about confirmatory trial design? And it's a little early on this front, but I'm thinking forward to the future when you have multiple exon programs, gene therapy. Can we really run placebo-controlled confirmatory trials in the future? Yeah, so maybe working backwards. At this point in time, it's definitely feasible to run a placebo-controlled confirmatory study that may change in the future. In terms of DMD 44, as you said, it's a little bit early to be talking about the exact design of the confirmatory study, and we'd want to align with the regulators around that. Internally, of course, we're very deep into those discussions right now and the planning for that study. Yeah, that sounds great. And I'll just ask one question on the safety side for DMD since we have gotten some questions on this. Just maybe just kind of reframe on the initial immunogenicity, a little bit that was seen. What exactly was that related to? Was it more around the construct or the antibody specifically? What do we know? Yeah, so for Delzoda, we've been really, really pleased with the safety profile. We did disclose that we'd had a single anaphylaxis event that led to withdrawal of treatment for one of the subjects. We know that these kind of reactions appear to be more common with biological drugs than with, let's say, other classes of drugs. So it's more likely that it's related to the monoclonal antibody component. That allows us to look across our whole platform when we're evaluating for the safety. And across the platform, we've given hundreds of doses now across many, many months and patients out through two years of therapy. And this is the only event that we've seen. So really very reassuring from that respect. Yeah, that's very helpful framing. Switching over to the rare cardio side, just a bigger picture question. Are you going to be pursuing a lot more autosomal dominant diseases here? How rare is rare as you think about that strategy, especially given you also have the Bristol partnership and some larger cardio indications? Yeah, listen, precision cardiology is a really exciting space for us, and this is a new therapeutic area, and the way we see it is we're opening up a whole new space here, right, attacking the genetic diseases of the heart muscle, and so we have started with two relatively small populations in the rare space for phospholamban and PRKAG2. As we said, five targets in the BMS collaboration. We have our first five targets that are wholly owned, and we will be announcing the future targets to your question specifically. The first two areas are small populations on a relative basis to the five that we are pursuing. They are also areas of unmet need, but also importantly, quick-to-proof-of-concept programs, so that's why we started with them, and we will be in the rare space, but not all of the targets are for such a small population. Yeah, that makes sense. And I'll just ask one more scientific question on the G2 side specifically for the preclinical data you have shown, which I thought was really interesting. And this was just one point that took me a little time to understand, which is why I'll ask it, which is why isn't there glycogen accumulation in the heart of the mice with this preclinical model? And does that mean, what does that tell us about the translatability of this model? Okay, so if you think about the purpose of the preclinical models, it's really to show that hitting the targeted pathway has the desired effect. And we've actually shown that in our mouse model. And I'll get on to that in just a second. But mouse models frequently don't recapitulate all of the features of the human disease. Specific to glycogen in the heart, the mouse heart beats at over 200 beats a minute compared to a human heart that's in the kind of 60- 90 range. So the mouse heart likely just burns off the glycogen before it can accumulate. In this particular mouse model, though, in the skeletal muscle, we did see quite marked accumulation of glycogen. And that's due to the same mechanism as in the heart. When we gave our construct to the mice, we were able to normalize the glycogen in the skeletal muscle. We've really shown that pathway engagement there does have the desired therapeutic effect. Great. And we're just about at time. So I'll ask one closing question, which is number one, what are you guys most excited about for in 2025? And secondly, thinking about the buildout of the organization on the back of all these exciting updates, how should we think about that in 2025? I'm most excited about the progression of our neuromuscular franchise, these regulatory pathways being determined and opened up, and the continued data to support the fact that we are going to serve an unmet need in the neuromuscular space. With regard to how we're kind of building out, we have commenced the buildout of our commercial infrastructure. We have commercial people starting to run around the building. The place has a sense of excitement in terms of what's ahead of us, and 2025 will be a very big year for that commercial buildup. Awesome. We'll look forward to future conversations. Thanks for joining. Thanks, Gavin.