Good afternoon, everyone. Welcome to the Barclays Global Healthcare Conference. My name is Gena Wang. I cover U.S. SMID-cap biotech. It is my great pleasure to introduce our next presenting company, Avidity Biosciences. With us today we have Sarah Boyce, President and Chief Executive Officer. We also have Steve Hughes, Chief Medical Officer. Sarah, maybe before I went to, you know, dive into the questions, why not you give a brief overview of the company? Yeah. And firstly, thank you so much for inviting us to this wonderful conference. And it's nice to be in Miami and have a bit of sun, although we're based in San Diego, so we got the sun anyway. Sorry. So Avidity, we are if you look at our vision, there's two things that we're aiming to do. Firstly is revolutionize the RNA space. We are an RNA delivery company. And through our technology, which is the antibody oligonucleotide conjugate technology, we have shown more than once that we can effectively deliver siRNA or PMOs to muscle cells. As also a part of our delivery technology, we can also deliver to the heart. And we have a precision cardiology portfolio that is preclinical. And we have a collaboration with BMS as part of that. We also, with our partners Lilly, have a collaboration where we look at, genetic targets in the immunology space as well. So we are an RNA delivery company, and we've been able to revolutionize, actually, from an aspect of opening up new therapeutic areas for RNA by cracking what has been one of the fundamental challenges in the space, which is that of delivery to tissues and cells outside of the liver. The other aspect of our vision is that we're looking to make profound improvements in people's lives. That speaks to where we direct our technology. You find us in spaces where we lead the field and where we are the first in what have been previously untreatable diseases, whether it's a very high level of unmet need, where we know our genetic target, and where we can precisely deliver, our siRNA or a PMO. Today, very excitingly, we are now transitioning into our first pivotal study, which is in myotonic dystrophy. And I know we'll, I'm sure we'll talk about that more. As well as also, over the course of this year, we're also seeing readouts for our FSHD program in the second quarter, where we are the first people to directly target the underlying causes of disease, which is aberrant expression, DUX4. And then in the second half of this year, we're really looking forward to sharing, for the first time, our data in DMD in patients, in boys and young men who are amenable to exon 44 skipping. So a lot happening from a pipeline perspective and some really exciting spaces where there are very high levels of unmet need. Great. Thank you. So, Sarah, so maybe, like, you know, the antibody, oligonucleotide conjugate. Yeah. Platform, like, what is the uniqueness of the technology and key modifications for muscle, target RNA delivery? Yeah. So firstly, this is a proprietary technology that was developed entirely in-house, so by our team of scientists at Avidity. And think of it like we have the GalNAc for liver. What we were looking for, having sort of developed the antibody oligonucleotide conjugate technology, is what other professional transport systems in the body can we tap into to deliver our siRNA? And that led us to transferrin. So we conjugate to the transferrin antibody. That antibody, think of it as simply as a delivery vehicle that gets our siRNA or our PMO to our target cell, and in this case, muscle cells, both skeletal. And we also use the transferrin antibody to deliver to cardiac tissue as well. It's a really simple concept. I remember when I was first introduced to the company, I was like, "Why has no one thought about this before?" In actual fact, people had and couldn't get it to work. What we were able to do at, at Avidity is apply our bioengineers, our chemists, our biologists to figure out precisely how to do it. Every single component matters, both the antibody, the linker, and the siRNA or the PMO. But it's really looking at think of it, it's like a it's like the GalNAc approach for liver, but we're doing it for other tissues and cell types, and we're using the a-an antibody as a delivery vehicle. Mm-hmm. So can you, you know, give a quantitative, you know, description how much more improvement by using this, you know, target delivery to the muscle? No one had been able to deliver siRNAs to muscle cells before. So it, it's not an aspect of it. I mean, it's a complete change of the game. Mm-hmm. In that, this delivery challenge had never been cracked. Mm-hmm. That's what we did. So I think on the. Yeah. On the PMO side, we do have a comparative. Yes. Yes. So we're delivering 50-fold more drug into the muscle. Mm-hmm. Than the pPMOs. The pPMOs are also targeted delivery technology. Compared to the PMOs, we're many multiples above that as well. So really able to get lots of drug into the tissues. Mm-hmm. So really a giant leap forward in terms of muscle delivery. Okay. And then, kind of thinking of regarding the safety, and we know pPMO, you know, first-gen has some safety issue. And PMO, because there's not really targeted, passes intake, and then the uptake rate is pretty low. So, like, in your case, how do you address, you know, also one, the tissue specificity, and also the safety part? We've got a good amount of safety data now. We've got three programs that are in the clinic, two with siRNAs and one with the PMO. All three have been really well tolerated. Mm-hmm. We presented data very recently, for our lead program in myotonic dystrophy, where we've given over 265 infusions. We've got over 61 patient years of continuous treatment. Many patients now through, well, in fact, the majority of patients beyond 18 months of continuous dosing, many patients through 2 years of continuous dosing. We looked at the most frequent adverse events that are related to the technology. So adverse events, basically, that are occurring in more than one person. And, they were headache and nausea, really common adverse events that you see in any clinical trial. So it's been incredibly well tolerated and has got a great long-term safety and tolerability profile, as we move forward into phase three. Mm-hmm. Okay. Very helpful. So, I mean, you do have, you know, important, you know, phase three study about to start. And. Mm-hmm. Maybe before that, we wanted to discuss about the DM1 as a disease and also the phase 2 data. Yeah. You shared. So maybe if I start on the disease and then Steve, look for you to bring your, your clinical perspective as well. So for myotonic dystrophy, it is an area where there are no approved treatments. So for people living with myotonic dystrophy, they have not had anything available to them. In many ways, because it's been ideal for a siRNA approach, but no one's been able to deliver. It's estimated there are about 40,000 people living with myotonic dystrophy in the U.S. and about the same in Europe. So a large orphan disease, I mean, bigger than cystic fibrosis, and, you know, when we look at part of our vision about making a profound improvement in people's lives, you know, we'll get onto that with our with our data. But it was a program that was ideal for an siRNA approach and where we hope to be able to make a transformative difference. We're the first people ever to move into a pivotal study for myotonic dystrophy. So we're incredibly excited and proud to be playing such an important role in the community. And, you know, from a market potential, you know, we view this as being a multibillion-dollar indication. But maybe Steve talk more about the devastating impacts on people's lives, and those living with myotonic dystrophy today. Yeah. So, it's that neuromuscular disease. The myotonia in the myotonic dystrophy is prominent. Myotonia is a inability to relax muscle once it's contracted. That actually affects just about every muscle in the body. So it can affect speech, swallowing, breathing, ability to just do day-to-day activities. It affects the gut. So really does have multiple different impacts on the patient's lives. And then along with the myotonia is a progressive muscle weakness that deteriorates over time. And with that comes all of the deterioration of quality of life. It ends people's lives early. It, the most frequent causes of death are cardiac. So it also can affect the heart. But also, its impact on respiratory muscles increases the frequency of pneumonias and other respiratory complications that can be fatal. So really a devastating disease. Because it's genetic, many members of the same family are affected. And it has something called anticipation, which is where subsequent generations have the disease worse than the previous generation. So within families, you'll find one member of the family that's caring for their children and maybe their grandchildren that have the disease as well. And we certainly have people on our patient advisory board that are in that situation. So really a devastating disease. We've recently released data, showing that we can have a dramatic impact on the disease. So we showed really profound improvements in the myotonia, improvements in muscle strength, and also improvements in patient-reported outcomes of how they can go about their activities of daily living, all of which were extremely positive. We showed those improvements first in the MARINA study, which was our phase 1/2 study, where we disclosed data at AAN and at World Muscle last year. Then more recently, we've shown the longer-term follow-up of those patients in the open-label extension, where we've shown that the substantial improvements that they had in the MARINA study actually continue to improve throughout the duration of the open-label extension. We're very lucky in this disease that there's a well-organized treating community where they have an ongoing natural history study called END-DM1. We were able to compare our clinical trial data with a matched group of patients from the END-DM1 natural history data set. There we showed substantial improvements, in fact, reversal of the course of the disease as compared to natural history. So this is the endpoints that we showed there were myotonia, hand grip strength, quantitative muscle testing across the upper and lower limb muscles, and the DM1-Activ patient-reported outcome. Those are the primary and the key secondary endpoints in our phase 3 study. So that data combined with the really great long-term safety and tolerability data that I mentioned earlier, really we think has de-risked the phase 3 program for us. We really have a really good idea of what we're gonna see as we run that phase 3 study out. Yeah. And just to add, you know, and I would say to people, if you haven't seen it, on our website, if you go to the events section, you'll see our latest corporate update as of March. And we actually are still in March. I'm like, "What month is it? Right. As of March, and there's a video in there. It's of the video hand opening time. That tells you almost everything you need to know from the disease. 'Cause you'll see and, you know, imagine what it's like living with the level of myotonia that the study participant had. And then you'll see after delpacibart etedesiran, where it's pretty much a normal hand opening. And then also in the presentation, there are quotes from patient interviews that really, you know, no one can articulate better the impact of any drug than someone who is receiving it. And you can see direct quotes from participants in the study around how their lives have been impacting. It really is quite profound. Very good. So, regarding the video hand opening time, and also you have the muscle strength endpoint. So maybe if you can elaborate a little bit how you measure that and how consistent. Okay. The outcome will be. Okay. Mm-hmm. The video hand opening time is how we measure myotonia. Mm-hmm. It's measured in the hand. But of course, myotonia, as I explained just now, doesn't just affect the hand. It can affect just about every. Mm-hmm. Muscle in the body. But we do know that what we observe in the hand is also improvements that are occurring in the other muscles as well. Mm-hmm. The video hand opening time was actually developed by experts in the disease and is one of the endpoints that's being measured in the END-DM1 natural history data set. We've adapted it slightly, not in terms of the video of the hand opening element, but we use an independent adjudication panel. Mm-hmm. To actually score the hand opening. So that removes any subjectivity in terms of the hand opening. We have two independent adjudicators that are blinded to the patient's treatment assignment. They each score the hand opening time. And they have to score within a certain range. Otherwise, it goes to an adjudication panel where they meet and actually get consensus around what the actual hand opening time was. So there's essentially a tie-break procedure. At each assessment time point, patients have two measurements of hand opening taken. And there's a rest period before each of those assessments so that there's no warming-up effect that can be had. And then those two results are averaged to get the overall hand opening time. You don't measure it for the whole hand. We're measuring it for the middle finger. And so it's the time taken for the middle finger to go down flat to the table. Other things are to make sure that the hand is identically placed for each of the assessments. So, you'll see on the videos on our website that, the patient's hand is on a piece of white card in a certain position. And there's a line that's been drawn along the edge of their hand. And that was done at the baseline assessment. And they position the hand exactly up against that line for all subsequent assessments to make sure the hand is in exactly the same position, again, to remove variability from the test. Yeah. It's a very, like, systematic, rigorous methodology. Mm-hmm. around how it's done. Mm-hmm. So that's in the clinical study, right? Mm-hmm. And then from the natural history data, you know, were they also done under, you know, similar rigor? Yeah. To collect the data? Yeah. So the test is performed in a similarly rigorous fashion. Mm-hmm. in the open label extension in the natural history study as well. I see. Okay. Okay. So then, well, thinking about your HARBOR phase 3 study and the primary endpoint, like, regarding the study design, was that aligned with the FDA? Yes. So we actually have been in communications with multiple regulators because. Mm-hmm. It's a global study. We have alignment with FDA, with EMA, other regulators as well. I see. About the study design. So the primary endpoint, the secondary endpoints, the duration of follow-up, the timing of the primary endpoint assessment, all of those, we have regulatory agreements on. Okay. That's very good. Then what is your, like, say, powering assumption for this? I know you do have a placebo control on it. Yeah. So the primary endpoint and the secondary endpoints are all incredibly well powered. We were extremely lucky. We had the data from the MARINA study. But we also had the END-DM1 natural history data set that we could use to inform our assumptions about placebo response rates and things like that. So, we've been able to do a very reasonably sized study of 150 participants, but with still maintained very good power, certainly the sort of power that you would expect for a phase 3 pivotal study. So what is your placebo assumption there? We haven't given guidance on all of the elements of how we did our placebo assumption. One key difference between the MARINA study and the HARBOR study was that in the MARINA study, patients were randomized in a 3-to-1 fashion. So your probability of getting active drug was three times greater than your probability of receiving placebo. We know from multiple other studies that the higher your randomization ratio, the greater your placebo effect 'cause people will assume that they want active drug. And as we move into the HARBOR study, it's a 1-to-1 randomization. So the calculations that we've used and the data set that we've used from the MARINA study will almost certainly have a higher placebo effect than what we will actually see in the HARBOR clinical trial. And so that adds onto our calculated power as well. Mm-hmm. Okay. And then regarding the dose, do you have a first dose like 2 mg per kg before you're scaling up to 4 mg per k? Yeah. So the dose in the clinical trial is 4 milligrams per kilogram ongoing throughout the study. Mm-hmm. But the first dose is at 2 milligrams per kilogram. Mm-hmm. The other thing that we've been able to do in the HARBOR study is to move the dose interval up to eight weeks. Mm-hmm. In the MARINA open-label extension study, drug was given every 13 weeks. But because we've got a really great safety profile, we were able to compress that into an approximately every two months, receipt of drug. And we're hopeful that by giving the drug even more frequently, that we'll be able to see even greater clinical benefits in the HARBOR study than we saw in the MARINA-OLE. Mm-hmm. Yeah. So, just so, first dose two milligrams, all subsequent doses four milligrams given every eight weeks. We have also aligned with global regulatory authorities on the dosing and the dosing schedule. That includes FDA and EMA. Okay. What's the reason why you start at the lower dose, the first dose of 2 milligrams per kit? Essentially, that was the quickest route to getting into a phase 3 clinical trial. And our goal is to get the drug to patients as quickly as possible, particularly given the really great data that we've seen in the MARINA and MARINA open-label extension study. So it was really just about getting the phase 3 pivotal study up and running as quickly as possible. Okay. Sorry. Maybe I did not make my question clear. The why you give a first dose as a 2 milligram and a subsequent as a 4 milligram? If you remember in the MARINA open-label extension study. Mm-hmm. We've already, it dose escalated half of the patients that were at 2 milligrams per kilogram. Uh-huh. Up to 4 milligrams per kilogram. Earlier this year, we announced that we were dose escalating the remaining patients up to 4 milligrams per kilogram now that we'd selected our phase 3 dose at 4 mg per kg. That was an already tried and tested dosing paradigm of starting at 2, moving to 4. That's why it was really the quickest route to getting into a phase 3 study. We'd already negotiated that dose measurement with the regulators. Yeah. And maybe also, I can add here that we do have a very narrow partial clinical hold, which is around initiation at 4 milligrams. So think of it as you have the HARBOR study and you have the partial clinical hold. So those two things have completely separated. The HARBOR study is not on hold. So we are all systems go getting the HARBOR study up and running as fast as possible, getting the study recruited as quickly as possible, and getting delpacibart etedesiran to people who need it. We then have the very small sort of narrow, what we view now as really an administrative technicality, on first dose of 4 milligrams. And, you know, we expect to resolve that in the summer. But the HARBOR study is not in any way impacted. And the HARBOR study is not on it. The HARBOR study is not on hold. So it was a very elegant way for us to separate the two factors completely and for the HARBOR study to be able to move as swiftly as possible, which is what we're now doing. Okay. Okay. I think that makes sense then. So then you do have a primary endpoint at 30 weeks. Mm-hmm. Then, 54 weeks. Maybe rationale to have an early assessment? Well, maybe we start with the 4 weeks first. So regulators like a year. Mm-hmm. Our placebo-controlled follow-up for safety reasons. So, running the placebo-controlled period at week 54 allows us to give the regulators that one year of placebo-controlled safety data. Well, the reason we cut the primary endpoint at week 30 is because we see very early improvement. Within the MARINA study, within weeks of starting the drug, we were already seeing separation from placebo in the active treated groups. And so, because we're essentially reversing the course of the disease, improving the patients, we don't need to wait for the placebo patients to get worse in order to see that separation. So, we're able to measure it early. Mm-hmm. And we got agreement from the global regulators to cut the primary endpoint at that week 30 time point. So we would plan to file at that week 30 time point and then provide the safety data as during the review period. There's a natural point at day 120. It's called the day 120 safety update where you provide your updated safety information. And that's the point at which we would provide the full data from the clinical trial. So it essentially allows us to move the filing up considerably by almost half a year. Mm-hmm. And that's aligned with our goal of getting the drug to the broader patient community as quickly as possible. Yeah. Yeah. I mean, it's a—I think, you know, just to build on what Steve said, you know, it's pretty unusual where you see a drug that's actually reversing progression of disease. And where you see movement on these functional measures so quickly and so consistently, you know, in treatment. And our goal is to get delpacibart etedesiran to the myotonic dystrophy community who very much need it and we're very acutely aware of the responsibility that's on us around that and to move as quickly as possible. It's a pretty simple study from an aspect. There's no biopsies. There's no MRIs. It's a global study. And we're extremely well powered for both the primary and the key secondary endpoints. It's you, you can see what we already did in MARINA and the MARINA open label and the comparison to natural history as well. This is a really important drug. Thank you very much. Thank you. Oh, time. Yeah. Yeah. Thank you. Thank you, everyone. Thank you.