Good morning, everyone. My name is Gina Wang. I'm a clinical biotech analyst at Barclays. Welcome to Barclays' 27th Global Healthcare Conference. It is my great pleasure to introduce our next presenting company, Avidity Biosciences. Sitting on the stage with me, we have Mike MacLean, Chief Financial Officer, Steve Hughes, Chief Medical Officer, and Mike Flanagan, Chief Scientific Officer. Before I dive into the specific questions, maybe, Mike, do you want to give a quick overview of the company? Absolutely. First of all, Gina, thank you for inviting us to the Conference. We're always happy to be here at the Barclays Conference. Basically, at Avidity, we've got a very busy year ahead of us. It's a catalyst of each year, but probably the best way to kind of give an overview is just to talk about the fact that we're going to have data readouts in each of our three late-stage clinical trials. We are executing on a regulatory pathway across all of our late-stage clinical trials. Most notably, we are on track to file our first BLA to be commercial in 2026 on accelerated pathway for our del-zota drug that treats DMD44. In the second quarter of this year, we will provide clarity of the regulatory pathway for our drug for FSHD, del-brax, and we expect to have global full approval for a clinical, I'm sorry, global full approval strategy and clinical design for our del-brax drug, as well as an update on the pathway for an accelerated approval in the U.S. for del-brax. Lastly, we're becoming a commercial company. I mean, we have been a research company and development, then added development, now we're adding commercial. We think of ourselves as an RDC company that does all three. We've been spending the time already becoming commercial by putting in place an infrastructure that includes U.S. and ex-U.S. processes, systems, and people. We're actually scaling up things like manufacturing to handle the commercial opportunity ahead of us. We're really excited about 2025. It sets us up for potentially our first commercial launch in 2026. Okay, great. Can you remind us your cash and then the runway? Yeah. We reported, I guess, last month in February, we reported on our 10-K that we had $1.5 billion of cash on our balance sheet at the end of 2024. That is cash that provides runway through mid-2027. What are the assumptions building for the runway? Yeah. So basically, that's essentially the opportunity to launch potentially three drugs through the mid-2027 period. It brings along our neuromuscular pipeline with additional potentially DMD products, as well as the precision cardiology therapeutic area. It also is sufficient to help us build the commercial organization and have product for three commercially available drugs without limitation for potential to exceed our expectations for patients. Great. I will dive into the DMD. Steve, I also wanted to thank you. Earlier today, you were at our DMD panel. Hopefully, you had a fun discussion. Later this weekend or early next Monday, you will have a DMD data update at MDA. Maybe help us understand what should we expect to see. We know that your early lower dose already shows super impressive data. If they already basically check the box, that's good enough. What will we see at the MDA update? Okay, thanks, Gina. Yeah, so indeed, we're presenting data next week from the top-line data from the EXPLORE44 study. The data we presented last year was the 5 mg per kg cohort, where we showed very high levels of delivery to muscle, in fact, three to five times higher than the other targeted delivery mechanisms. We saw extremely high levels of exon skipping and dystrophin levels of over 32%, which is unprecedented, really, really high dystrophin. In association with those really super high dystrophin levels, we also saw near normalization of creatine kinase across all of the patients as well. Subsequent to that, we've shared our data on the 5 mg per kg placebo patients when they switched over to active drug in the open label extension, where, again, we've seen near normalization of creatine kinase. We've replicated that 5 mg per kg data set. At MDA next week, we're going to be including the final data from the EXPLORE44 10 mg per kg cohort, where the focus, again, is going to be on safety and the biomarkers. No surprises on the safety side. The safety still looks really, really good for del-zota. On the biomarker side, we'll be sharing, again, the dystrophin levels, exon skipping, and tissue concentrations. A win for us on that, given that we've already shown really unprecedented levels of dystrophin. Again, it'll be to once replicate the data showing very high delivery to muscle, very high exon skipping, very high dystrophin levels, and again, very attractive safety profile. Okay. Will we see the correlation data between exon skipping versus the protein expression level? I'm going to throw that over to Mike. Yeah. You know, it's a great question. We've talked about it a little bit. What I can tell you is that there's a really tight correlation between exon skipping and production of protein. It'll be a presentation, so trying to pack in all the data. You may not see all of that, but there's a tight correlation. If you skip better, you're going to make better dystrophin, at least for our del-zota program. Okay. Very helpful. The other question is, should we see dose response if you penetrate in theory? Of course, the dosing frequency is slightly different, not just 100%, 5 milligram to 10 milligram, right, because the dosing frequency is slightly different, but still at the higher dose. Should we see higher protein expression at the 10-milligram cohort? Steve, do you want to answer that? Yeah, sure. At 5 mg per kg, we were dosing every six weeks. Traditional PMOs have been dosed weekly. We have managed to push the dose interval out to something that is much more family-friendly, every six weeks. With 10 mg per kg, we actually dosed every eight weeks. The actual increase in dose is not really that much between 5 and 10 mg per kg because of the increase in dose interval. We may not see an increase in or a dose response on the exon skipping or dystrophin as we go from 5 to 10, just because the cumulative dose really does not change very much between those two dose levels. What we would anticipate seeing is very high levels of dystrophin production, very high levels of muscle tissue concentrations, very high levels of exon skipping. Again, commensurate with the fact that we're producing a near full-length dystrophin, that we would see near normalization of creatine kinase again. Okay. That's very good. Regarding the dose that you will move forward to the next one, I know internally you already decided, but you will announce to us. Given what you described, am I right to picking like 10 milligram once every eight weeks, given the convenience of dosing? If similar protein expression, at least that will be the better dose to move forward. Yeah. We are going to provide the information on dose and dose regimen soon, potentially as early as next week. Okay. Okay. What will be, okay, I know you cannot answer which dose, but what are the key factors you are thinking for you to make a decision to pick which dose? I think really the important thing around dose for us is that even at 5 mg per kg, we're seeing extremely high levels of dystrophin production. It's a near full-length dystrophin, and we're seeing near normalization of the CK. It's going to be difficult to improve upon near normalization of CK. In the dose selection, we're factoring multiple things into that. Regulators have their own expectations as well. We've actually already agreed to go forward dose with FDA. They've been in full agreement with our thoughts around dose selection. It's only a few more days until we'll be able to share that publicly. Okay. Related question. I'm pretty sure safety is a very important component there. What will be considered good safety? What kind of measurements will you be looking for that consider this is a good safety? We have seen great safety across our entire platform. All of our drugs are delivered using exactly the same monoclonal antibody. We have hundreds of doses across the platform now. We are seeing excellent long-term safety for all three of our programs and patients being retained in the open label extension studies for very long durations of time, able to tolerate the doses that they have been started on. We are really pleased with the safety profile that we are seeing. We leverage the safety across the entire platform when we are having regulatory discussions as a consequence of the platform technology. Okay, good. I think 4 Q, you also will have open label extension studies. What should we expect to see from that data update? Yeah. We are planning to disclose the data from the open label extension study, EXPLORE44 OLE in Q4 of this year. That will be longer-term follow-up on the patients. We have already got sufficient dystrophin data to satisfy the requirements for the accelerated approval. There will be no additional dystrophin data at that point in time. Because of the longer duration of follow-up, we will be sharing functional data. What kind of functional data will you be sharing? We have not given too much away on the exact measures that we will be sharing. We are measuring quite a lot in the clinical trial, all of the usual things that you would see in a Duchenne study, factoring in that the study involves both ambulatory and non-ambulatory patients across a wide age range from seven all the way up to 27. We have measures of mobility. We have quality of life instruments. We have measures of upper limb function. We may not be able to squeeze all of the measures into a poster or a platform presentation, but the way that we do it is that we work with our KOLs and investigators that have been involved in the clinical trial to agree what are the most meaningful endpoints for a presentation. Importantly, Gina, our mission is to profoundly improve people's lives. We want to show that this drug would be available to patients, whether they're ambulatory, non-ambulatory, across a wide age range. Okay. Should we be worried about safety with the longer follow-up? Any scientific reason could lead to any concern, or should not be any concern with the longer treatment duration? I guess that's a safety question. Yes. Right, right. We've dosed with our platform now for very long durations of time. On our myotonic dystrophy program, the vast majority of patients now are through two years of continuous dosing. Every patient is through 18 months of continuous dosing. On our FSHD program, many patients now are through more than a year of continuous dosing. We've got patients on the DMD program through over a year of continuous dosing. We really haven't seen any safety issues at all across the platform. Because it's a platform technology, we can leverage all of the exposures to inform us about the safety. Really, long-term safety is looking very attractive. Okay. Very good. Now switching gear to your other two very exciting programs, FSHD, because you do have tons of data updates. Maybe if you can run through the second quarter, the milestones, and then how would you like the foreign, how would you share that catalyst? Yeah. I'll kick off here. We call Q2 the quarter of del-brax, right, because we have five milestones or catalysts that we see as important to this program. They're across data execution and regulatory pathway. As you know, we have a global full approval study strategy for this program, right? Our overall strategy is to have this drug approved in the U.S., Europe, and Japan and other markets. That is what we're actively engaged in discussion with global regulators on right now. We expect to share the clinical trial design in Q2, as well as initiate that global full approval study. In advance of that, as we talked about at the end of 2024, we've already started a biomarker cohort because we think that this is a perfect target, and we have the perfect potential drug to treat this disease, and it should squarely fit into the requirements and expectations of the FDA for accelerated approval. That cohort is well underway, and we expect a complete enrollment on that cohort in the second quarter. We'll also be, once we have agreement with the global regulators, talking to the FDA about the accelerated approval pathway, and we'll be providing an update on where we are in alignment with the FDA in Q2. Lastly, the fifth catalyst is that we'll be reporting out the phase I/II A and B cohorts for the FORTITUDE study. We'll be providing the complete information there. As you know, we've already selected our dose, 2 mg per kg every six weeks. We did provide some of the 4 mg per kg data earlier this year so that people can understand why we chose the 2 mg per kg every six weeks. Will we see all this in one press release and conference call, or we will see as it comes? You know, we do get this question a fair amount. We would like to provide an omnibus type update. Without kind of trying to manage the release of data, we'll try and give everybody a lay of the land. If we think that something's material or meaningful, we'll disclose it when it becomes apparent that it is a certainty. I think it would be helpful to the market to kind of understand it all together, but we'll disclose it as it's appropriate. Okay. What could be the scenario that could be material that you have to disclose that individual event earlier? Yeah. It's probably a question for someone who has a legal degree. Look, I mean, if we have global full approval in advance of the accelerated approval, that might be material and have to be disclosed. Okay. More the regulatory front? Yes. Yeah. Okay, good. Maybe a little bit more color on those five catalysts, maybe starting with the phase I/II update in terms of data, oh, sorry, number of patient follow-up, and also the data point, biomarker splicing. Also, should we express some functional data? Steve, do you want to answer that? Yeah, sure. The data update in second quarter is the top-line data from the FORTITUDE cohorts, A and B, so the cohorts that are not the accelerated approval cohort. Those patients will all have completed the one-year study and rolled over into the open-label extension. We will have the one-year follow-up looking at functional data for those patients, also looking at safety over one year of treatment, and of course, biomarkers as well. Okay. Regarding the accelerated approval paths, do you think FDA also will require some kind of correlation data, like what kind of analysis you will be thinking to get the higher chance? Also, do you think you need to show some statistical analysis or some trend that will be sufficient? Yeah. We covered this a little bit at the panel this morning relating to Duchenne. There's no requirement to show a correlation. If you're correlating your biomarker with your functional endpoint with properly statistically correlating, you have a surrogate endpoint. Surrogate endpoint standalone for full approval. The burden of proof for accelerated approval is reasonably likely to predict. Largely, that's based upon having biological plausibility in terms of connection with the underlying disease. That changes in the biomarker are reflected by downstream changes in the disease, that kind of thing. We do anticipate that that is the burden of proof that we're going to need. In addition, we've already seen that patients treated with del-brax do see functional improvements, at least directionally, as compared with placebo. We would expect to reproduce those directional changes in the biomarker cohort as well, and that will be provided as supporting data in the package. If thinking forward, the confirmatory study, the primary endpoint function, do you think more likely is RWS? Reachable workspace has been a nice measure in this disease to capture upper limb mobility and upper limb function. Patients with FSHD in the early to mid stages, it is primarily the upper limb that's affected. We have seen in the data that we shared already last year that we see improvements in other measures as well. We have seen improvements in quantitative muscle testing, improvement in multiple patient-reported outcomes, clinician-reported outcomes. We have seen improvements in other measures that we haven't disclosed yet. Reachable workspace certainly isn't the only endpoint that we can use as a primary endpoint. Ahead of concluding our discussion with the regulators around what's primary and what's secondary for the clinical trial, I can't really say too much more, but we do have a lot of choice. Mike, maybe I wanted to ask you, why I think of both DM1, FSHD, they're all using splicing index in a way. Why do you think FSHD, you will have a chance to get accelerated approval based on the splicing profile while the DM1 should not be? Yeah. For FSHD, just the key things for accelerated approval is that we have a really safe drug. There's high medical need. We have a really good, like Steve said, plausibility between really the circulating biomarker as well as transcripts all the way to functional improvements. We know that DUX4 is the underlying cause of disease in FSHD patients. If you do not have DUX4 turned on, you do not have FSHD. If you can turn off DUX4, then you should at least halt progression and possibly improve disease outcomes. What we are looking for is that link and that direct link. We have that in that we have a circulating biomarker as well as downstream transcripts that are dependent on DUX4. Our circulating biomarker is one of the ones that we are really leaning on. The reason that we're leaning on it is that you can measure it longitudinally. I don't have to have a little snapshot of a biopsy in your leg, but I can look at it over time. I can see that once I deliver a del-brax and see knockdown with DUX4, I see a decrease in that circulating biomarker. That correlates with a decrease in CK levels that are a factor in muscle damage. What you see is you can see that lasts for a long period of time. It doesn't wane, which is an important part of the treatment paradigm, right? One of the reasons that we picked 2 mg per kg every six weeks. It is all those together that just link the plausibility to the disease to improvement that we think it's a really great way forward for FSHD. The DM1, do you think why DM1 is different? Why DM1 cannot, based on those splicing index, would not have a chance to get accelerated approval? Yeah. DM1 is really different. If we just talked about FSHD, DM1 is very different in the sense that there's thousands of genes that are misspliced for DM1. Selecting a small set of genes, for instance, 22 genes that you've had a biopsy in your AT in the front of your leg doesn't get reproduced by a biopsy in your quad or a biopsy in your bicep. There are just so many different genes that are affected in DM1, so there's not a good link between that. That's the first thing. The second thing is when we look at VHOT, so video hand opening, which is a measurement of myotonia across the body. Myotonia is devastating for these patients with swallowing and a number of different things. VHOT is so fast to measure. It's such a tight measurement. We can measure it faster, get it into the database, analyze the data faster than we could do a biopsy, and it's tighter data. If we're really looking to get drugs to patients as quick as possible, that's the path forward. Good. We have less than one minute, maybe one last question on DM1, if you can quickly talk about powering assumption for the phase III study. Anything you think could affect the standard deviation or why you feel confident you designed the phase III study this way? First of all, the power across all of our endpoints, the primary endpoint, the three key secondary endpoints, we got very high levels of statistical power. We have looked at data now from the MARINA program over one year as compared with natural history and seen good separation over a one-year period. We believe that we have really de-risked the program from an efficacy perspective, specifically relating to power. We have used natural history data. We used the data from the MARINA study to power the study. We had statistical significance with 12 patients in the MARINA study. We have 150 patients in the HARBOR study. So loads of power there. We do things like baseline stratification for the key endpoints to make sure that we are well balanced between active and placebo. We have a one-to-one randomization, which is the most efficient randomization for power. As you move away from that, you erode power. As compared with the MARINA program, we've moved the dose interval from 13 weeks to 8 weeks. If there's any extra efficacy to get out, we believe that would be manifest through the increased dose frequency. We're really confident in a positive outcome for the study. We've also seen great safety as well. The long-term safety is looking really, really clean. On the safety side, we think we're de-risked. Of course, we fully negotiated the phase III study with multiple global regulators. From a regulatory pathway as well, we believe we're de-risked. Very good. Thank you very much. We look forward to the second quarter, the FSHD update, and also lots of other progress as well. Thank you. Thanks so much.