OK, welcome everyone. My pleasure to be hosting this fireside chat with Avidity. I'm Joe Schwartz from the BioPharma Equity Research Team at Leerink, and I'm very pleased to have Sarah Boyce, CEO, and Steve Hughes, CMO, with us today to give us an update. Maybe we can start at a high level and have you give us an overview of the technology and how you've decided to apply it in the various programs that you have underway. Yeah, sure. I'll take that one. Firstly, thank you for inviting us. It's wonderful to be here in Miami. We were just saying it's nice to be on the East Coast somewhere where it's warm. We're based in San Diego, so that's that reason. Avidity, we are an RNA Delivery Company. Our vision is to do two things. Firstly, to make a profound impact in people's lives. This is very relevant because it's where we direct our technology. The second aspect of our vision is to revolutionize RNA Therapeutics. And we're doing that through cracking what has been one of the fundamental challenges in the space, which is that of delivery. Through our technology that was entirely developed in-house, which is the antibody oligonucleotide conjugates, so we use an antibody as a delivery vehicle to get our siRNA or our PMO, in the case of our DMD programs, to the cells that we want it to. That has opened up the musculoskeletal space, where we now have three programs in the clinic, each of which are for rare diseases where there are either no approved therapies for DM1 and FSHD, or in the case of our DMD program targeting boys and young men amenable to exon 44 skipping, where there's nothing directly approved for exon 44. We've also expanded that work further, and we're also directing our technology to delivering to the heart, which is another space where there is a greenfield of genetic targets that we're also looking to address both through our own programs and through our partnership with BMS that we signed at the end of last year, as well as adding additional musculoskeletal programs. So that's kind of, at a high level, what we're doing and our philosophy around which spaces we choose to go into. Great. All right. So how have you designed these conjugates in order to accomplish an adequate penetration into the target tissues, as well as the cellular machinery that you need to have adequate exposure to in order to have an effect? Because a lot of these RNA targets, some of them have been tried in the past, to no avail or little avail, because they didn't get adequate penetration into the tissues. And can you talk about the different levels of de-risking that you see for the technology in order for it to achieve its end goal? Yeah, yeah, absolutely. And maybe, Steve, if you want to talk to some of that. And firstly, we can deliver RNA to muscle cells. We have shown that with an siRNA and have shown it with a PMO. But maybe, Steve, if you want to talk a little bit more around the technology and how we do it. Yeah, sure. So all three of the drugs that we currently have in the clinic for myotonic dystrophy, FSHD, and DMD 44 are all based upon an antibody, it's a monoclonal antibody that targets the transferrin receptor. Transferrin receptor is ubiquitously expressed. It's highly expressed on muscle, so that allows us to get whatever is attached to the monoclonal antibody inside the muscle cell. What happens is that the antibody binds to the transferrin receptor. The transferrin receptor gets internalized into the cell, into an endolysosome, and pulls in the siRNA or the PMO, whatever's bound to it, inside the cell into a lysosome. The lysosome actually acts as a storage depot, and then the RNA leaks out over time. So once the drug is inside the cell, the antibody component gets degraded, and that leaves the RNA. And then the RNA slowly leaks out of the endosome. And in the case of siRNA, it will load into the RISC complex. In the case of PMOs, it will bind to its target and cause exon skipping. So that, in a nutshell, is how the technology works. We've used the transferrin antibody across all of our current programs that are in the clinic. The transferrin antibody is also subject to our deal with BMS. So all of the cardiac targets that are part of that collaboration will be based upon the transferrin receptor antibody as well. OK, great. And let's talk about the lead program next in DM1. And maybe talk about the target and what you've seen in terms of the ability to hit the target on both a biomarker basis as well as functionally. Yeah, so maybe I'll just start off at a high level, and then Steve, maybe you talk about the data that we shared at our most recent update, which was Monday of last week. Firstly, DM1, myotonic dystrophy is a rare genetic disease. There's about 40,000 people in the US living with myotonic dystrophy, about the same in Europe. There are no approved treatments. We are leading the field. We are the first people ever to start a phase lll program, a pivotal study program for this disease. There is a very high level of a medical need. It has a devastating impact on people's lives. And from a potential, this is an indication that is larger than cystic fibrosis. So we view this as being a multi-billion-dollar indication. We are able to precisely deliver an siRNA to muscle cells to be able to impact DMPK, splicing, and then, most importantly, releasing Muscleblind. Really, sort of as you look to our phase lll design, it's the functional data. It's really all about the functional data where we're seeing those changes and where we're seeing reversal of disease progression. Yeah. Can we talk about that a little bit more? It's such an interesting disease, and you're trailblazing here. So what must they deal with in terms of the clinical manifestations? And what have you investigated in your MARINA trial in order to see whether you can improve those? Yeah. OK, it's maybe hard to kind of start at the beginning with the disease. The term myotonic dystrophy talks to one of the cardinal symptoms of the disease, which is myotonia. Myotonia is an inability of a muscle to relax once it's contracted. You see that in the videos that we showed and the videos that are on our website, where we ask patients to contract, or the investigators ask the patients to make a fist, squeeze, squeeze, squeeze, and open. The patients just can't open their hand. It takes many, many seconds. That's really debilitating for the patients. Myotonia doesn't just affect the muscles in the hand. It affects all of the muscles in the body. It can affect speech. It affects the tongue. It can affect swallowing. It can affect the respiratory muscles. It affects the gut. A big part of the disease is gastrointestinal issues as well. So it really is a multi-system disorder that has a massive impact on patients' lives. And then the other thing that goes along with the myotonia is just gradual wasting of muscles over time. That causes progressive muscle weakness, and many patients end up in a wheelchair. It shortens patients' lives because it affects their respiratory muscles. They can get pneumonias and die from pneumonia. It also affects the cardiac muscle. And patients the two leading causes of death actually are pneumonia, respiratory complications, and cardiac complications leading to death. So it really is a significant disease. In the data that we showed well, the first data set that we showed was back at AAN last year. And that was the top line data from the MARINA study. So the MARINA was a six-month study. In multiple doses, we looked at 2 and 4 mg per kg. We showed that across several different muscle strength endpoints, together with measures of mobility and also myotonia, as we measured with the video hand opening time, we showed improvement in disease across all of those endpoints, particularly so at the 4 mg per kg dose. Then a little bit later last year, in September, we presented data at World Muscle, where we looked at a range of other muscles as well using an orthogonal test of muscle strength. We showed improvement across all of those, so very good correlation between the different muscle measures. Then we also showed data on the DM1-Activ, which is a disease-specific patient-reported outcome measure for activities of daily living. We showed improvement in the DM1-Activ. So the improvements in myotonia, the improvements in muscle strength, the improvements in mobility that we'd seen and presented earlier were translating into improvements in how the patients are able to go about their daily lives. And then more recently, all of the patients that were in the MARINA study had rolled over into an open label extension study. And the data that we presented very recently was data from the open label extension study, where we showed two things. First of all, that the improvements that the patients at 4 milligrams per kilogram saw in the MARINA study continued out through the open label extension. And we looked at the data after one year of continuous dosing. And across the measures of muscle strength, the DM1-Activ, and the myotonia, they all continued to improve over time. And then the other thing that we were able to do was to take data from the NDM1 natural history study, which is a contemporary natural history study that's ongoing at the moment, and match patients from that study to the baseline characteristics of our 4 milligram per kilogram cohort and do a comparison of what happens after 1 year. And the patients in the NDM1 data set declined over that 1-year period. And the patients in our study, we knew that they'd improved, but we showed really good separation between our 4 milligram per kilogram dose and what happened over exactly the same period of time in the natural history study. So on the efficacy side, that gives us great confidence in our phase lll study because the endpoints that we were showing, which is the VHOT, that's the primary endpoint for our phase lll clinical trial, our HARBOR study, and then hand grip strength and a muscle composite score of muscle strength together with DM1-Activ, they are our key secondary endpoints. And all of those improve versus natural history. So that's great. We think that that's really de-risked the efficacy side of our phase lll study. And then the other thing that we showed was our safety data. And we now have data through over 235, I think it is, infusions, 61 years or more of continuous follow-up, so patient years of follow-up. Most patients are now through at least 18 months of continuous dosing, many patients through 2 years of continuous dosing. We saw no related serious adverse events. We've had no discontinuations due to adverse events. In fact, all of the patients that went into the open label extension study remain in the open label extension study after a long duration of follow-up. That's highly unusual to have 100% retention over that period of time. What that tells us is two things. One, the patients are feeling better, and they want to stay in the study. Secondly, the drug is extremely well tolerated, and they can stay in the study because they can take the drug. All of those things together, really, we think, has de-risked the phase lll. We've got a very good idea of what our phase lll study will look like. OK. And I would just add one thing. If you haven't and you want to understand a little bit about the disease and the impact it has on people's lives, if you go to our website and embed some presentations, you'll see our latest corporate presentation. Watch the video. There's a video of the hand opening. You watch that. It will tell you a lot of what you need to know about this disease, about how severe it is, and also the impact that Del-desiran makes. OK, great. Can you talk a bit about the phase lll design now in terms of endpoints, inclusion criteria, and then the dose level and schedule? Because some things are changing. I want to make sure that we cover that. Yeah, so maybe if I start off, and then Steve, you can go into the details of the design. A couple of things from last Monday. Firstly, we have pulled forward our guidance for initiation of the HARBOR study. We were guiding to mid-year. We're now guiding to the next quarter. Secondly, it is we are going to run very fast and very hard in getting this study up and running as quickly as possible. This is a really important drug for patients. It's our goal to recruit it within the year. I would say the third element of it, as well as both the primary and the key secondary endpoints, we are extremely well powered for those endpoints and given, obviously, what we've seen from the data so far. Maybe, Steve, if you want to go into a bit more detail about the designs as well as the dosing and the dosing schedule. Yeah, sure. So I think the other thing, just to remind everyone, is that we've got agreement from the regulators globally on the phase lll study design. It's quite unusual to get agreements pretty much simultaneously from multiple regulators. Often, you're waiting around for one regulator after the other, or you're going at risk hoping that the other regulator is going to say the same thing as the first one. We've got agreement about our phase lll study design that we presented at the beginning of the year. So we're going to randomize 150 patients. And it's a 1:1 randomization. So an equal number will go into the placebo group or into the active treatment group. Our dose is 4 mg/kg. The first dose is given at 2 mg/kg, and all subsequent doses at 4 mg/kg. The dose interval, we've moved from being every 13 weeks in the MARINA-OLE. In the HARBOR study, it's going to be given every 8 weeks. Two reasons, really. One, the safety data is awesome in the MARINA open-label extension study. And so it means that we are able to dose more frequently without having to worry about side effects from the drug. And secondly, if there's any more efficacy on the table to be had in the patients, we would hope that by dosing more frequently, we can see even better results than we've already seen in the MARINA open-label extension data. The placebo-controlled follow-up period is about a year. The reason for that is that regulators like to have a year of placebo-controlled safety data. And we're able to cut the primary endpoint for the study at week 30, though. And the reason for that is that we don't have to wait for the placebo patients to deteriorate over time. We're seeing improvements across the board in the key endpoints that we're testing. And so we can see those improvements with adequate separation from placebo very early on at week 30. So what that actually allows us to do is to cut the data and hopefully file at that week 30 time point. And we can potentially file then and then follow up with the week 54 safety data as part of the ongoing review process. So the way that the study is designed is with efficiency and getting the drug out into the broader population as quickly as possible. And so this cutting the data at week 30 potentially allows us to get the filing done even sooner. I would also add, in this study as well, there are no MRIs. Importantly, there are no biopsies. So that is very amenable from a patient perspective. This is functional. This is about functional data. From a regulatory perspective, they're interested in functional data. You see the functional changes move so quickly that there isn't an interest in the biomarkers. There's interest in the functional data. So really, what that means is that for any of the people that are following on behind us, the regulatory bar is set now. It's functional. It's not based on biomarker data. Right. Yeah, that's very interesting. And will you report data to the street and investors and the treatment community at 30 weeks or end 54 weeks? Or will you wait for 54? We haven't given guidance on that at this point in time. We'll give some guidance on that in due course. OK. How are you thinking about balancing enrollment size in order to ensure adequate statistical power with speed to market, which I've heard you mention a few times? Yeah, so it's 150 patients. Our goal is to recruit within a year. There is an enormous amount of excitement in both the clinician and the patient community, as you would expect. Del-desiran is a really important drug. From our powering, I think, as we've already said, we are extremely well powered both for our primary endpoint and for the key secondaries. And all of that was taken into account into our statistical calculations. And then the other thing is that we have more sites than we had for the MARINA program. So there we had nine sites. And for the HARBOR study, we're going to have around 40 sites globally. And we've actually done all of our site selection now. And when we do the site selection, one of the criteria is how many patients have you got. So we select the sites that have the highest enrollment potential as well as the expertise to do the assessments. So we're very confident that we'll be able to enroll very quickly. Yeah, OK. Interesting. And you were or maybe still are technically on partial clinical hold for certain doses. But yet, it's not a gating factor for the phase lll, which makes sense because you're starting at 2 milligrams and going to four. And you were able to up-titrate everybody in the MARINA-OLE from 2 to 4 without any issues. So what's next on that front? Will the partial clinical hold be officially lifted at some point before the trial starts, do you think? Or could that be even after the trial? And will you make an announcement on that front? Yeah, so really good question, Joe. Thank you for asking. So in terms of, as you say, for the HARBOR study, it's not in any way impacted. So think of it. You had a partial clinical hold and the HARBOR study. Those two things have separated completely. So the HARBOR study is not on hold. Let me be really clear. The HARBOR study is not on hold. If we had a site open and we could initiate drug tomorrow, we could. Our dosing schedule, first dose is 2 milligrams and then 4 milligrams every 8 weeks. We are running fast and hard to get that study enrolled and get this drug to patients as quickly as possible. The partial clinical hold is very narrow. The partial clinical hold is solely about first dose being 4 milligrams. We do expect to resolve that and anticipate doing that in the summer. But the HARBOR study is not on hold. These are two completely separate things that are not in any way impacted. Really, we think of the partial hold and that narrow nature of it as an administrative technicality that we'll work through. But the most important thing is the HARBOR study is not on hold. Yep, cool. All right. And so let's see. You're clearly in the lead for DM1. But I'm wondering, and many people are wondering, how you think about competitor positioning in the space and how you're differentiated versus some other approaches that are being taken both to degrade DMPK as well as to block it. So can we hear about your thoughts on that front? Yeah, maybe if I start us off, and maybe, Steve, if you want to add. Clearly, we're leading the field and continue to do so. I think the other thing that is now also very clear, as we've said consistently, is this is about functional changes. We have set a very high bar for anyone who is following. We saw functional changes very early in the MARINA study and very consistently across a broad range of functional measures. We've also shown now what the regulatory path is, what measures are important. And we've also shown that we're reversing disease progression when we look at those measures. I think for those following us, seeing they need to see, I would be looking for those early signs of functional change and the consistency across them. No one else has shown that yet. Steve, is there anything to add? Or does that cover it? Well, clearly, the great clinical data that we've got is a massive differentiator from the competition. There's only one other program that's got any human data out there at all. It's nowhere near the level of data that we've already shown, nowhere near the duration of follow-up that we have, which, as I said, is at least 18 months now for the majority of patients across our program. In terms of the technologies that are being used, really, siRNAs, in terms of the knockdown approach, are the way to go. They have long duration of action. The RISC complex is highly efficient in catalytic cleavage. They're not associated with the high-dose toxicities that you see with ASOs, such as renal toxicity and thrombocytopenia. There's several siRNAs now that have been licensed. They've been shown to be very safe and well tolerated as a class of drugs as opposed to the ASOs that have been registered to date. So really, a lot of efficiencies from the technology. In terms of the other approaches which are coming to the clinic, which is the steroid inhibition approach of basically wallpapering the DMPK so that muscleblind can't bind to it, we know, based upon PMOs and Duchenne muscular dystrophy, that these steroid approaches require much higher tissue concentrations in order to be effective. We also know that from what we've seen with the peptide conjugates, that you start seeing some renal toxicities. I think it remains to be seen whether those drugs can be dosed high enough in humans in order to be effective. OK, makes sense. So we've talked a lot about AOC 1001, del-desiran. Where should we go next? Do we want to talk about DMD or FSHD, which we have data for in the second quarter? We've got lots to cover in six minutes. Yeah, so why don't we start with FSHD because that's the one that's the next one, which is we're really looking forward to sharing sort of initial data from our FSHD program. We are the first people ever to directly target the cause of the disease, which is aberrant expression of DUX4. So once again, we are leading the field, leading the field in an area where today there are no approved treatments for an orphan indication that's larger than cystic fibrosis. Now, in terms of we are leading the field and, from an aspect, first people to directly target DUX4. So one of the things that we'll look at for our first look is impact on biomarkers. And maybe, Steve, if you want to talk to those. And also, of course, muscle delivery. But we know we can deliver to muscle. Maybe if you want to talk about what to look forward to in this initial look at the study. Yeah, so as you know, DUX4 is sporadically expressed in FSHD. It's not supposed to be there at all in adults. And when it is expressed, it's expressed in a very small fraction of the overall muscle fibers within any individual muscle. So we can't measure DUX4 directly. What we can measure, though, is the downstream impact of DUX4 expression. So DUX4 is a gene product is a transcription factor. And that turns on a whole bunch of different genes downstream of that, the products of which many of them are toxic to muscles and cause muscle death. So we'll be looking at a number of different biomarkers of DUX4 activation. A question that we get a lot is Fulcrum didn't show anything with their biomarker data. So why are you so confident that you'll see a change in your biomarkers? Of course, we directly target DUX4, which is the root cause of disease, whereas Fulcrum's drug is more of an orthogonal approach as a kinase inhibitor. So by targeting the root cause of the disease and with a very highly potent siRNA, we're confident that we'll see downstream changes in the biomarkers in at least some of the patients. OK. And what is your current thinking on the merit of the target DUX4 in FSHD? I think there's just a host of downstream things that happen as a result of DUX4 being upregulated. And so I'm wondering, do we know whether, if we turn it off, the horse hasn't already left the barn, so to speak? Yeah, so maybe I would describe it. We think of this as more of a prevention approach. When you have aberrant expression of DUX4, the siRNA is there. The siRNA is there to block it. We are looking at the downstream gene signatures. We're actually also planning to do bulk RNA-seq as well. I would expect that we'll probably see other genes that we're also impacting. But DUX4 is something that's really only expressed in a tiny number of cells. Then it switches off. From that aspect, we know we can hit DUX4. It's a prevention model that you always want the siRNA there. If DUX4 switches on, we can switch it off. We've got a really good animal model as well, where we have a mouse where we can switch on the expression of DUX4. If you switch it on in the absence of having an siRNA on board, the mice get weakness. They get less mobile and don't do very well. If you have siRNA on board and then you turn on the DUX4 gene, then we massively attenuate those things in the mouse model. And because, as I said, the treatment is essentially a prevention model, the mouse really recapitulates the disease well. OK. What are your thoughts on clinical endpoints in FSHD based on what we know about the disease and what these patients must deal with, in particular the RWS primary endpoint that Fulcrum's using? Yeah, so in phase one and two, we're looking at muscle tissue concentration, downstream gene signatures of DUX4. We'll look at bulk RNA-seq as well. And we have all of those functional measures. So similar to what we did in MARINA, there's a broad range of functional measures, which we'll probably then narrow down. And that includes the Reachable Workspace. So that's can you. I'll start waving my hands around now. So can you put your hand above your head? And And how you move, it's a way of measuring the shoulder mobility. And that has been an endpoint that has been acceptable to regulators. But we'll look at other functional measures as well. Yeah, so Fulcrum, of course, have agreed Reachable Workspace as a phase lll endpoint already with the regulators. So we're fortunate in that they're ahead of us. And we can learn from their experiences on the regulatory pathway. The Reachable Workspace really is a nice endpoint for this disease because it's pretty sensitive to changes in the upper limb, particularly the shoulder and facioscapulohumeral. It's a scapular muscular problem, at least in the early to mid-stages of the disease. Other things that we're looking at are MRI scans and looking at the muscle fat fraction and the muscle volume over time as well. So we'll have those readouts in due course as well. You are measuring RWS in FORTITUDE? Yes. We'll get that data in the interim. I would say, though, in the interim, it's 4 months. So this is a disease that is complex in its progression. So we are not expecting to see any changes there at this point. OK, makes sense. Well, moving to AOC 1044 for about a minute. Yes. Apologies. Got hung up on everything else. The target product profile you're going for, can you just give us your vision for this agent and where you hope to end up in terms of dystrophin expression? So maybe I'll put this really simply. And I can do it in 30 seconds. I said at the beginning, our vision is to make a profound impact in people's lives. So we are looking, with AOC 1044, to make a big impact on dystrophin. We're very encouraged by the healthy volunteer data that we saw at the end of last year. We can deliver more PMO to muscle cells than anybody else. And we're looking to be able to make a big impact. Fantastic. Well, we look forward to all these updates. Thank you for the update today. Thanks, Joe. Thanks.