Good day, everyone. Thank you for joining the 23rd Annual Needham Healthcare Conference. My name is Joseph Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, Avidity Biosciences. Joining us today from Avidity is President and CEO Sarah Boyce and CMO Steve Hughes. For those of you joining on the webcast, if you want to ask a question, please do so at any time. You can submit a question using the chat box at the bottom of your screen. So with that, we'll get started. Sarah, Steve, thank you so much for joining us today. Thanks for inviting us, Joe. Pleasure to be here. Sarah, just wondering if you could provide us with a brief high-level overview of Avidity, its technology, and pipeline before we get into the specifics of the programs? Yeah. So, Avidity, we are an RNA delivery company. If you look at our vision and mission, it's around revolutionizing the RNA space and looking to make a profound impact in people's lives. That revolutionizing the space has been around cracking what's been one of the fundamental challenges in the RNA space for a long time, which has been that of delivery. We are able, and we've shown this now in more than one program, to very effectively deliver either an siRNA or a PMO to our target cells, which is the muscle cells for our muscle program. And today we have three programs in the clinic. All three are for diseases where there are no specific approved treatments. Our lead program is a drug called del-desiran, which is being developed for the treatment of myotonic dystrophy, and where we are on the cusp of initiating our phase III pivotal study, the HARBOR study. Just a month ago, actually, we shared both the study design as well as also a look at the data from the MARINA Open-Label Extension study, where really excitingly, we have actually seen reversal of disease progression and saw really striking separations when compared to natural history data for both our primary endpoint for the HARBOR trial as well as our key secondaries. We have a lot of data also coming this year. So we're really looking forward to sharing this quarter data, our first look at data from our FSHD program. Again, where we're really pioneering the space, being the first treatment to directly target the underlying cause of the disease, which is aberrant DUX4 expression. And then in the second half of the year, actually, a first look at our patient data in myotonic dystrophy, sorry, DMD, in boys amenable to exon 44 skipping. So this is where now we're starting to see sort of the robustness of the pipeline and really what we can do and what we're able to do when we've been able to tackle the challenge of delivery. Great. Well, we'll start with del-desiran and DM1. Can you summarize some of the key data points from the OLE that you announced in early March? Yeah, of course. And Steve, why don't you—Steve's on the screen, but we're actually sat next to each other. But Steve, why don't you share the open label data? Sure. Thanks, Sarah. So as Sarah said, at a very high level, we showed that we're reversing the course of disease progression as compared with the natural history data set. So the END-DM1, which is a very contemporary data set, largely with assessments taken at the same centers as we're conducting the clinical trial. So these improvements were in the video hand opening time, which is a measure of myotonia. Myotonia, of course, is a very important symptom of this disease. It doesn't just affect the hand. It affects just about every muscle in the body, causes multiple disabilities and problems for the patients. We also showed improvements in measures of muscle strength with hand grip strength and a composite measure of upper and lower limb muscles for quantitative muscle testing and improvements in a patient-reported outcome for measurement of activities of daily living. So that's DM1-A ctiv. Importantly, all of these measures are the key endpoints in our phase III study, the HARBOR study. So the video hand opening time is the primary endpoint, and the other assessments are key secondary endpoints that will be assessed statistically. These measures, we've also got agreement with both global regulators, including EMA and phase III, for the HARBOR study. And we've now, of course, shown that we see improvements compared with placebo across these measures in the MARINA study in the shorter term, and then in the longer term, also improvements as compared with the natural history data set. Importantly, the END-DM1 natural history data set now has got a few hundred people in it for a year. So we were able to actually match the patients that we selected for that analysis with the baseline characteristics for the patients in the MARINA-OLE cohort that we were comparing them to. So it really was a match comparison. So really, we de-risked the phase III study, both from the efficacy side, where we've seen great improvements, and we're actually incredibly well-powered on all of our endpoints. But also the last thing that we saw in the OLE data was the safety. And we've got really favorable long-term safety and tolerability through over 61 patient-years follow-up, many, many doses in these patients. And the majority of patients now are through over 18 months of continuous treatment with many patients through two years, which really speaks well to the tolerability of del-desiran. As you said, you announced the phase III HARBOR pivotal trial design, and you touched on vHOT as the primary endpoint. But what are the key design elements of HARBOR that give you the confidence that the impressive data you saw in the phase I/II trial will translate into phase III? So I think there's a few things there. One, as I mentioned just now, we're very well-powered for all of the key endpoints in the study. And we haven't used best-case scenarios to power the study. We've taken pretty conservative estimates in order to do that. So that gives us some kind of power in the bank, if you like, for the study. The HARBOR patient population also will be broadly similar to the MARINA study. The MARINA study was a pretty broad population. There's a couple of key differences. One, we're now for HARBOR going to be going down into the pediatric group. So the regulators have approved for us to treat patients that are 16 years and up. But really, for the most part, a very similar patient population for which we already have very good data across multiple different comparisons that show improvements. I guess the final piece is that we've got approval from regulators who've looked at our data and also will have a degree of confidence in allowing us to move forward as well. Yeah. And I think maybe just to build on Steve's points, it's really a pretty simple study from an aspect, and we think also design-wise pretty elegant that allows us, from the functional endpoints, to do that data cut at 30 weeks. So it allows us to move quickly. There's no muscle biopsies in the study. There's no MRIs in this study. So from a patient perspective, it's also one that is really amenable from a patient perspective. And the sites and the patient community are incredibly excited as we to get this study going. We're also guiding that it's our goal to recruit the study within 12 months. So we're going to move very, very quickly, which is really important because this patient population, there's nothing approved. We have a drug that we know already. I mean, we're making a big difference with regards to the data we've already seen. So our goal is to move as swiftly as possible through this to get del-desiran to the people that need it. Where do you stand in terms of the safety and exposure requirements needed for potential regulatory submission? Is this something that could be gating for a submission, or are you pretty confident that you'll have the required exposure once phase III wraps up? Yes, that's a great question, Joey. We really designed the HARBOR study with this in mind. If you remember, the design of the study includes about a year of a placebo-controlled follow-up, even though we're cutting the primary endpoint at week 30, which we're able to do, of course, because we're making patients better rather than waiting for the placebos to decline. That's all baked into the study. Also, we've got approval from multiple regulators on the study design that it's suitable for registration purposes. When they are doing their assessment of the study, it's very clear that it's a registration or pivotal trial, and that's factored into their assessment when they get the approval to move forward. Yeah. When we say multiple regulators, that includes the FDA and EMA. Got it. Last one on DM1, any quick update on the FDA partial hold and any impact at all to the phase III pivotal trial? Yeah. So the simple answer is from the HARBOR study, there is no impact whatsoever with regards to the partial clinical hold. Those two things have completely separated. So the HARBOR study is not in any way impacted. It is not on hold, and we are full steam ahead. From the partial hold, there's that very narrow aspect around it, which is in relation to first dose being 4 mg, which we largely view now as being an administrative technicality that, as we've guided to, we'll loop back and expect to resolve that in the summer. But from the HARBOR study perspective, not in any way impacted, and we are full steam ahead and couldn't be more excited about that. Great. Well, let's move on to FSHD. AOC 1020 have a big data readout coming this year. First, let's take a step back and maybe level set everyone on FSHD as an indication. What's the prevalence, disease progression, standard of care, etc.? Yeah. So FSHD, there's actually a lot of similarities with DM1 myotonic dystrophy. It is a rare disease, but a large one, bigger than cystic fibrosis, as an example. There are no approved treatments available for people living with FSHD. There is a very high level of medical need. It is a devastating rare genetic disease that, as we often see with rare genetic diseases, impacts not just individuals, but their families. And this is, again, we're really pioneering the space. We are the first program ever to directly target the underlying cause of the disease, which is the aberrant expression of DUX4. It's, in many cases, ideal for an siRNA approach. One of the challenges up until this point has been that of delivery, which, of course, we can deliver to muscle cells. And that really long durability of action that we see from siRNAs, we think, is going to be really important for this patient population. So we're really looking forward to sharing that first look at the data from the FORTITUDE study in this quarter because we are now in April. I paused there because I was like, "We're still in March." But no, we're in April. So I'm not saying this quarter. In terms of the diagnosis of FSHD, how are the patients diagnosed, and what type of specialists are seeing these patients? Yeah. I think one of the very tragic aspects around FSHD is, a lot of the time, people are diagnosed in their prime of life. So in their 20s, early 30s, obviously, there's variability on the side of that, but that's what we hear a lot. So it's that time of life when you want to be invincible, and then you find out that you're not. It's largely treated by neuromuscular specialists. So actually, there's a lot of overlap in clinical trial sites and actually a lot of overlap with specialists that are treating this disease. Steve, I don't know if there's anything you'd want to add to that as well. Yeah, maybe just a couple of things. So diagnosis is typically by a neurologist or a neuromuscular specialist, as Sarah said. But because of the presentation, patients often bounce around for quite a few years, and it can be nine or 10 years before a diagnosis is actually made. And we hear this from the patients that we talk to, that they presented with this thing, and it was diagnosed as neck spasm or a trapped nerve, and then they went to see somebody else. And then eventually, they saw somebody that had seen FSHD patients and put two and two together and was able to make a diagnosis. Over time, because it's a progressive disease, though, they tend to have their care coordinated by the neurology or neuromuscular team. There's a whole bunch of other people that they need to see: orthopedic specialists, rehabilitation specialists, etc., just to manage the progressive nature of the disease. Of course, over time, about 20% of these patients will end up wheelchair-dependent as well. Yeah. How organized is the patient community? Are there patient registries? Yeah. I would say the FSHD community is probably one of the most organized that I've seen in my time working in rare diseases. And Steve and I have worked on a lot of different rare disease programs. The FSHD Society does an incredible job. There is a patient registry that has been established for some time now. It's called MOVE. And then there's also the MOVE Plus, which is an expansion of the registry looking more at reachable workspace. As part of our collaboration with the MOVE and MOVE Plus study group, we have access to the raw data, and we can mine that. And that really helps sort of inform aspects of our design. So very well-organized patient community. They're really incredible to work with. And from that aspect, that's incredibly important in rare diseases. Really grateful and commend the community, both the FSHD Society and the KOLs, for getting in front of drugs coming into clinical development with regards to putting together the natural history studies like MOVE and MOVE Plus. What differentiates your approach, Avidity's approach, relative to, say, competitive clinical programs in FSHD? You just named a couple. Fulcrum's got a phase III oral agent, Roche phase II antibody. There are other mRNA-based approaches out there. What do you believe you have the right approach in this indication? Yeah. Simply put, I mean, firstly, we're the first people to take a drug into clinic that is directly targeting the underlying cause of the disease, which is aberrant expression of DUX4. It is ideal for an siRNA approach. Think of it almost like a prevention model where if you get that aberrant expression of DUX4, the si is always there to shut it off. We know we can deliver to muscle cells. Obviously, we will look at delivery this quarter when we look at the data from the FORTITUDE study. But this is ideal for an siRNA approach and we're the first to do that. So pretty different from the Fulcrum program, which is in phase III, completely different mechanism of action. Got it. That makes sense. The FORTITUDE trial, can you give us an outline of the trial design there? And we'll have a couple of follow-up questions there. Yeah, sure. Steve, do you want to take that one? Yeah. It's a dose escalation study with then an expansion cohort at the selected move forward dose. So we have three dose escalation cohorts. The first one, patients receive a first dose at 1 mg/kg, and then all subsequent doses at 2 mg/kg. The second cohort is a 4-mg/kg, and the third cohort is an 8-mg/kg cohort. 12 patients in each of the cohorts with 2-1 randomization. So eight patients on active drug, four patients on placebo in each of the cohorts. And then we pool the placebos together so that we have similar-sized groups for the comparison. Patients have multiple assessment time points through the study. And the dosing regimen in terms of the dose schedule is very similar to what we did in the MARINA study. So the first three doses are given at six-week intervals so that we load the patients with the siRNA to get very rapidly to steady-state tissue levels. Then it's every month-month dosing. The placebo-controlled follow-up period is a year. Then patients roll over into the open-label extension study. Of course, we have the expansion cohort where we'll expand at one or two doses to get additional experience at those doses. Then those patients have a similar duration of follow-up and roll over into an open-label extension. Have you disclosed what data you plan to announce in the upcoming topline readout? Will this include measures of clinical activity such as muscle strength and function? This first assessment is patients through the first assessment time point, which is four months into the study. So for this disease, four months is a little early to see movement on the clinical measures. So we're obviously looking at measures of muscle strength, very similar to what we did in the MARINA study. We're looking at measures of mobility as well and also the reachable workspace. And we're also looking at MRI scans for changes in muscle fat fraction, etc. But for those kind of endpoints, it's a little bit early. We would expect to be able to see separation from placebo as we go a little bit further out into the study. So this four-month time point is really focused on delivery to muscle. Now, we know we can deliver to muscle. So what we want to do there is to see exactly how much in this disease we're getting into the muscle, how well it correlates with our animal studies, etc. And that overall for the platform helps us get better predictions. We'll be looking at the biomarkers. As you know, DUX4 is very sporadically expressed. So not turned on all of the time. When it does turn on, it turns on in one in 1,000 or less muscle fibers. So technically, we're not really able to measure DUX4 directly. So DUX4 is a transcription factor. When it is switched on, it activates a whole bunch of downstream genes. So we'll be looking at the biomarker signature of DUX4 expression where we would expect to see that we see a reduction in that gene signature over time. And then, of course, we'd be also confirming the great safety and tolerability for the platform that we've seen with the other programs. In terms of the DUX4-related gene panel, how reliable is that? How predictive is that? Maybe just a little bit additional color on that so that when you do release the data, we'll have some idea, a little bit of context around that. So the biomarkers are known targets or known to be turned on by DUX4. So we know that all of the genes that we're measuring in the gene panel are DUX4-regulated genes. And then other things that we look for is good dynamic range, reliability from assessment to assessment so that you can reproduce the measures, etc. So the panel itself should be extremely reliable. The issue that we have isn't with the panel. It's with the technical challenges of the muscle biopsy. So DUX4 is sporadically expressed. And in order to measure the signal, you need to have the DUX4 expression both in the baseline biopsy and in the post-baseline biopsy. We're doing everything that we can to do that. So we select the muscle group to biopsy based upon what we see on the baseline MRI scan. But to some extent, it's not precise science. There are some technical challenges with the biopsy process. In this, we would anticipate that we'll see a signal for some of the patients in the cohorts, but maybe not all of the patients. But because of the mechanism of action, basically, it's a prevention model. We know that we're getting good drug tissue concentrations into the patients, and that will be all patients. That if we see it in some patients, then we can really extrapolate that and assume that we're having the same effect in all patients. It's just that we weren't able to detect it. Got it. Could you elaborate a little bit more on what are the most important functional endpoints? I understand that the data it will be early data in terms of the treatment period, but any additional details on that would be helpful. So really, all of the functional endpoints, from our perspective, are important because it's not a disease that just affects one muscle. It's a disease that over time affects multiple different muscle groups. And it affects not just muscle strength. That affects mobility and a whole bunch of other things. So we're taking a really broad look at these endpoints, including patient-reported outcome measures as well in this study so that we can select what's best to measure in a phase III study. We are, of course, in addition to those measures, looking at reachable workspace. That's something that's pioneered by Fulcrum. So that's in there in the mix. But we wouldn't prioritize one of those endpoints over another at this stage. Yeah. Like said, Joe, it seems to have been doing a very similar type of approach as we did with myotonic dystrophy. In the phase I/II, well, we go broad. We're looking at a broad range of functional measures with a goal to ultimately be able to narrow that down to something much simpler and much more straightforward from a registrational study perspective. We do like reachable workspace. We think it's a potentially really good endpoint for this disease. But design-wise, it's go broad. And then from there, we'll come in and ultimately look to narrow down. I see. Makes sense. Yeah. Mentioned Fulcrum had the reachable workspace, certainly in their phase III. And so that's sort of a natural question that investors ask. Would that be a registrational endpoint? Yeah. I mean, it could be. And I mean, clearly, it is for the Fulcrum program. We do like it as an endpoint. It's one that potentially makes a lot of sense for—I mean, it makes sense for FSHD. But approach-wise, go broad, look to narrow down. Steve, do you see that? Yeah, that's exactly right. It's important not to focus too early on any one measure because we're looking at all things that are being captured in the natural history studies as well. And so the natural history studies capture things that are relevant to the patients. Yeah. Yeah. And again, this is the first time anyone's doing this. This is where we're pioneering and leading the space again by directly targeting the aberrant expression of DUX4. So we're going to learn a lot. Okay. Great. Well, we have a few minutes left. I want to ask a couple of questions on the DMD program. First, just briefly outline your approach here in DMD, patients amenable to exon 44 skipping. Yeah. I mean, our approach here is pretty simple. I mean, I think we all know that PMOs are ideal from a skipping perspective. The challenge around PMOs has been delivery and getting them into muscle cells. Obviously, we cracked that. We showed healthy volunteer data last year that was really unsurpassed delivery of PMO to muscle cells. It's a pretty straightforward approach. We're targeting. We have a PMO that targets Exon 44. Looking forward to sharing our first look of patient data in the second half of this year. Yeah. You mentioned the EXPLORE trial. It's ongoing. Just to remind everyone what the trial design is there and a quick summary of the healthy volunteer data that you announced last December. Yeah, sure. So as you alluded to there, this is a combined healthy volunteer and patient study. The first part of the study was in healthy volunteers with single-dose cohorts that allowed us to very rapidly dose escalate to doses that we thought would be well within the therapeutic range, which is 5 mg/kg and above. And now we bridged across last year into the patient cohorts at 5 mg/kg. So testing five different dose levels in the healthy volunteers and then bridging across our patients in 5 mg/kg, and then the patient cohorts we had at 5, 10, and 20 mg/kg. The data that we showed from the healthy volunteers was drug delivery to muscle. And as Sarah said, we showed unsurpassed delivery there, 50 times more than been seen with the PPMO constructs. We also saw exon skipping in the healthy volunteers. We saw exon skipping in every single healthy volunteer that received a dose. Those changes were statistically significant. That is something that hasn't been shown before in other studies in healthy volunteers. Exon skipping up to 1.5% at the 10 mg/kg dose level and not far behind that, actually, at the 5 mg/kg dose. So really encouraging data on the exon skipping side. Of course, you can't look at dystrophin in healthy volunteers. That's something that you look at in the patients and also very favorable safety as well, as we've seen with our other program that we've seen favorable safety in the healthy volunteers. As we look forward to the data disclosure that we'll be making later this year, that's going to be in the first patient cohort. So the 5 mg/k kg patient cohort, we'll be looking at very similar things to what we looked at in the healthy volunteers in terms of delivery to muscle, safety, exon skipping. But in the patients, the most important measure really for these early studies is the amount of dystrophin that's being made and whether that dystrophin is being incorporated correctly into the membrane complex. So we'll be looking at that. Importantly, the patient cohorts are multiple-dose cohorts. So whereas in the healthy volunteers, we were just looking after a single dose, in the patients, we'll be looking after three doses. Got it. And you mentioned the Dystrophin levels. What would you consider clinically meaningful change in the Dystrophin and any other details around the data readout from Part B? So we're, as we've said all along, looking to make a meaningful difference to patients' lives in diseases where there's few or no treatments. So the changes in dystrophin that we're going to be excited about are really stepwise improvements over the current generation of PMO drugs. And what we've seen from the tissue concentration levels in the healthy volunteer studies is that at both the 5 and the 10 mg/kg doses that we showed the data from for the healthy volunteers, that the tissue concentrations were well above what's needed in our animal model of this disease to achieve at least 5% exon dystrophin levels. So we're really going to be looking at dystrophin levels that are well above that level. Great. Well, last question from us. It's on cash position runway. What's your current cash position and runway expectations? Yeah. So going into the pivotal study now, we have just under $1 billion in cash. Obviously, that is a great cash position. And that takes us through our top-line data from the HARBOR study, as well as also it's our plan to have all three of our programs in pivotal studies next year. That is factoring in there as well as the development of our precision cardiology pipeline, which we haven't really focused on today, which we're also incredibly excited about and believe can also be game-changing in that space. Great. Well, thank you so much, Sarah and Steve, for participating. It was a very useful discussion. Thanks, Joe. Thanks, everyone, for joining us on the webcast. Everyone, have a good day and a good rest of the conference.