Good day everyone. Thank you for joining the 23rd Annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham and 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, Joey. 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 revolution, 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, from 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 full set of 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 DUX, 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 a screen, but we're actually sat next to each other. So Steve, why don't, 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 dataset. So, the END-DM1, which is a very contemporary dataset, 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. And myotonia, of course, is a very important symptom of this disease. 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-Activ. 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 FDA, for the HARBOR Study. 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 dataset. Importantly, the DM1 natural history dataset now has got a few hundred people in it that are 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 full END-DM1 cohort that we were comparing them to. So really, we de-risked the phase III study, both from the- Yeah -efficacy side, where we've seen great improvements and are 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- Yeah -long-term safety and tolerability for over 61 patient years of 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 2 years, which really speaks well to the tolerability of del-desiran. As you said, you announced the Phase 3 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 1/2 trial will translate into Phase 3? 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. So, 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, I think, you know, maybe just, just to build on Steve's points. Yeah, it's really a pretty simple study from that aspect, and we think also design-wise, pretty elegant. That allows us, you know, from a primary, from the functional endpoints, to do that data cut at 30 weeks, so allows us to move quickly. There's no muscle biopsies in the study. There's no MRIs in the study. So from a patient perspective, it's also one that, that is really amenable from a patient perspective. And, you know, the sites and the patient community are incredibly excited as are 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. And 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. So we really designed the HARBOR study with this in mind. If you remember, the design of the study- Yeah -includes about 1 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. So that's all baked into the study, and also we've got approval from multiple regulators on the study design that is suitable for registration purposes. So is that when they are doing their assessment of the study, it's very clear that it's a registrational pivotal trial, and that's factored into their assessment when they give the approval to move forward. Yeah, and 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. You know, from the partial hold, there's that very narrow aspect around it, which is in relation to first dose being 4 milligrams, which we largely view now as being, you know, an administrative technicality, that as we've guided to, we'll look 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 in on FSHD as an indication. What's the prevalence, disease progression, standard of care, et cetera? Yeah. So FSHD, there's actually a lot of similarities with the, to myotonic dystrophy. It is a rare disease, but a large one, you know, 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, where we're really pioneering 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. You know, 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, you know, to sharing, you know, our 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, "Are we still in March?" But no, we're in April. So I have to say this quarter. And in terms of the diagnosis of FSHD, how are the patients diagnosed, and what type of specialists are seeing these patients? Yeah, you know, I think one of the very tragic aspects around FSHD is a lot of the time people are diagnosed in their prime, prime of life. So, it, you know, in their twenties- Yeah -early thirties. Obviously, there's variability either side of that, but that's what we hear a lot. So it's that time of life when you, you know, you want to be invincible. And, 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. Mm. 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 9 or 10 years before a diagnosis is actually made. And we hear this from the patients that we talk to, that- Yeah -you know, 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. But there's a whole bunch of other people that they need to see: orthopedic specialists, rehabilitation specialists, et cetera, just to manage the progressive nature of the disease. And 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. 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+, which is, an expansion of the registry, looking more at, reachable workspace. As part of our collaboration, with the MOVE and MOVE+ study group, we have access to, 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. You know, from that aspect, that's incredibly important in rare diseases, and 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+. What differentiates your approach, Avidity's approach, relative to, say, competitive clinical programs in FSHD? Just name 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, you know, 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, you know, 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. Very different - completely different mechanism of action. Got it. Makes sense. The FORTITUDE trial, can you give us an outline of the trial design there? And we'll have a couple 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 3 dose escalation cohorts. The first one, patients receive a first dose at 1 mg per kg, and then all subsequent doses at 2 mg per kg. The second cohort is a 4 mg per kg, and the third cohort is an 8 mg per kg cohort. 12 patients in each of the cohorts with 2:1 randomization, so 8 patients on active drug, 4 patients on placebo in each of the cohorts, and then we pool the placebos together so that we have similar size 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 6-week interval, so that we load the patients with the siRNA to get very rapidly to steady state tissue levels, and then it's every 3-month dosing, and the placebo-controlled follow-up period is a year, and then patients roll over into the open-label extension study. And then, of course, we have the expansion cohort, where we'll expand at 1 or 2 doses to get additional experience at those doses, and 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 top-line 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 4 months into the study. So for this disease, 4 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 4-month time point is really focused on delivery to the muscle. Now, we know we can deliver to muscle. Yeah. 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, with our animal studies, et cetera, 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. Yeah. So not turned on all of the time. When it does turn on, it turns on in one in a thousand 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, we'll be looking at the biomarker signature of DUX4 expression, where we would expect to see that we, we see a reduction in that gene signature, over time. And then, of course, we'll 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, et cetera. 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 biopsies. So DUX4 is sporadically expressed. Yeah. 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 on what we see on the baseline, the baseline MRI scan. To some extent, it's not precise science, so 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. 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. Yeah. But 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, you know, 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, but it 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. Yeah. That's something that's pioneered by, by Fulcrum. So that's in there in the mix, but I, we wouldn't prioritize one of those endpoints over another at this stage. Yeah, I'd say, Joe, you know, it's similar to doing a very similar type of approach as we did with myotonic dystrophy. You know, in the phase I/2, well, we go broad. You know, we're looking at a broad range of functional measures- Yeah -with a goal to ultimately be able to narrow that down in, to something much simpler and much more straightforward from, from a registrational study perspective. Yeah. Do you like reachable workspace? You know, we think it, 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, you know, Fulcrum had the reachable workspace- Yeah -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. You know, and I mean, you know, 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 FSHD, actually. But- Yeah. approach-wise, go broad, look to narrow down. Steve- Yeah. Yeah? Yeah, that's exactly right. It's important not to focus too early on any one measure because, you know, we're looking at all things that are being captured in the natural history studies as well, and, and so, but these natural history studies capture things that are relevant to the patients. Yeah. Yeah. Yeah. And again, this is the, you know, this is the first time anyone's doing this. You know, this is all pioneering, leading the space again by directly targeting the aberrant expression of DUX4. So we'll kind of learn a lot. Okay, great. Well, we have a few minutes left. Wanna- Yeah. Ask a couple 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 DMD, from a skipping perspective. The challenge around PMOs has been delivery and getting them into muscle cells, and obviously, we cracked that. We showed healthy volunteer data last year that was really unsurpassed delivery of PMO to muscle cells. You know, it's a pretty straightforward approach. You know, we're targeting, you know, we have a PMO that targets exon 44, and looking forward to sharing our first look at 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 per kg and above. And then we bridged across last year into the patient cohorts at 5 mg per kg. So testing five different dose levels in the healthy volunteers, and then bridging across our patients at 5 mg per kg, and then the patient cohorts, we had at 5, 10, and 20 mg per 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 has been seen with the PPMO constructs. We also saw exon skipping in the healthy volunteers, and 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, and exon skipping up to 1.5% at the 10 mg per kg dose level, and not far behind that, actually, at the 5 mg per kg dose. So really encouraging data on the, on the- Mm-hmm. -exon skipping side. Of course, you can't look at dystrophin in healthy volunteers. Yeah. That's, that's something that you look at in, in the patients, and also very favorable safety as well, as we've seen with our other programs, 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 gonna be in the first patient cohort, so the 5 mg per 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 at after three doses. Got it. And you mentioned the dystrophin levels. What would you consider a 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 and diseases where there's few or no treatments. So the changes in dystrophin that we're gonna be excited about are really stepwise improvements over the current generation of- Yeah -of PMO drugs. What we've seen from the tissue concentration levels in the healthy volunteer studies is that at both the 5 and the 10 mg per 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 a 5% exon skip, 5% dystrophin levels. So we're really gonna be looking at dystrophin levels that are well above that level. Great. Well, last question from us, it's on cash- Yeah -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, you know, it's, 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, Joey. Thanks. Thanks, everyone, for joining us on the webcast. Everyone, have a good day and a good rest of the conference.