Good morning, everyone. Thank you for joining us today. My name is Geoff Grande. I'm the Vice President of Investor Relations and Corporate Communications for Avidity, and we're very happy to have you with us for volume 9 of our Investor and Analyst Event Series to discuss our unprecedented AOC 1020 data from the FORTITUDE study in FSHD. As always, following our prepared remarks, we'll leave time for Q&A, so please feel free to submit any questions via the box on your screen. Before we get started, just a reminder that this presentation contains forward-looking statements as defined under applicable law. Forward-looking statements involve risks and uncertainties, both known and unknown, which may cause actual results to differ from the forward-looking statements contained in this presentation. You are cautioned to not place undue reliance on these forward-looking statements and to refer to the more detailed cautionary language in this slide and in the Risk Factors section of our most recent reports filed with the SEC. With that, I'll turn the call over to our President and CEO, Sarah Boyce. Thank you, Geoff, and good morning, everybody. We're thrilled that you've been able to join us. Our vision at Avidity is to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. The data we're going to share today shows how we're moving further and further towards the realization of that vision. Before we start, I would like to take a moment to thank all of the participants in the FORTITUDE study who have given their time with visits to centers, to the investigators and to all of their team at the centers, for their commitment and their support during the FORTITUDE study and the continued, the continued commitment to the study as it continues. If we can go to the next slide, please. What we're looking at now is reproducibility and consistency around what we're able to deliver with our technology. What we'll share with you today with del-brax is safety and tolerability data, which is consistent on what you would expect from our platform, given our previous experiences. You'll also see data on delivery to muscle. We can deliver more siRNA to muscle than anybody else. We can also do the same with PMOs. We're going to share with you data on target engagement. We can hit our target, and also, even at a 4-month time point, we're going to share with you data where we see signs of functional improvement across multiple measures. You can go to the next slide, please. In terms of the data we're going to share today, it's the data with del-brax, 2 mg at four months. What we see is unprecedented, consistent reduction in DUX4-regulated genes. We're also seeing signs of functional improvement, and those signs are across measures of muscle strength, reachable workspace, as well as patient and clinician-reported outcomes. We'll also take you through the very favorable safety and tolerability profile. Given the importance of the data that we're sharing with you today, we are now accelerating del-brax as much as possible towards improvement. The phase I, II portion of the study is now fully enrolled, and we're going to be initiating two phase III cohorts. The first of those is a biomarker cohort, which we're planning to initiate in the second half of this year, and then the second of those is a functional cohort, which we're planning to initiate in the first half of next year. We are leaning in and looking at how we can accelerate getting del-brax to the patients who need it so very, very much. We can go to the next slide, please. So at a high level, around the data, we're seeing unprecedented and consistent reductions in the DUX4 regulated genes. We see a greater than 50, so five-zero, reduction across multiple DUX4 gene panels. Every participant who received del-brax had a reduction greater than 20%. We have also been able to identify a DUX4 circulating biomarker. This is a huge breakthrough for the field and is a result of two years of work. And you'll also see how that correlates with changes in creatine kinase. From a functional improvements, we're seeing improvements in muscle strength, reachable workspace when we compare to both placebo and also natural history, along with the patient, the positive patient and clinician-reported outcomes. From a safety and tolerability perspective, it's as expected. All AEs were mild or moderate, no serious AEs, no severe SAEs, and no discontinuations. As I leave you with anything from today, it is our goal of accelerating del-brax now towards approval. If we can move to the next slide, please. You all know my colleagues who are joining me today. We're also delighted that Dr. Statland has been gracious enough to join us today as well. He is one of the leading experts in FSHD and is an investigator in our, in the FORTITUDE study. We'll move to the next slide, please. Without further ado, I'm going to hand over to Steve. Thanks, Sarah. So, some background on FSHD, just to orient and remind folks ahead of getting into the data. So FSHD is actually one of the commonest forms of muscular dystrophy. It affects tens of thousands of people in the United States, and a similar number in Europe. It's a devastating disease characterized by relentless loss of muscle function and progressive disability, and about 20% of people living with FSHD become wheelchair dependent. There are currently no approved therapies. It's also a genetic disease with mainly autosomal dominant inheritance, which means that multiple members of the same family may be affected. The underlying genetic cause is aberrant expression of DUX4, which is a transcription factor that activates hundreds, if not thousands, of downstream genes. Many of these gene products are toxic to muscle and poison the muscle, causing muscle weakness and wasting. Del-brax is the first treatment that's specifically designed to reduce DUX4, so it specifically addresses the root cause of FSHD and thereby has the potential to have a really meaningful impact on this disease. Next slide, please. I'd just like to continue orienting you now. This is a high-level schematic showing the details of the FORTITUDE study, for which we'll be presenting the data today. Starting from the left and moving to the right, it's a randomized, double-blind, placebo-controlled study. It's 12 months in duration, so we'll be following the efficacy endpoints and the safety endpoints over a 12-month period of time. But muscle biopsies for the muscle biopsy biomarkers are performed at baseline and month four, and no subsequent biopsies are performed after that. As you'll recall, it's a dose escalation study, so we have two dose escalation cohorts, Cohort A and Cohort B, and then we have an expansion cohort, which is Cohort C. Today, the data that we'll be presenting is from Cohort A, which is the first cohort in the study. This is our 2 mg per kg cohort, but all patients receive 1 mg per kg as their first dose, and then all subsequent doses at 2 mg per kg. The reason we're not showing 4 mg per kg biomarker and efficacy data today is because that hasn't read out yet. It's gonna read out really shortly. We're just not quite at that point yet. As with first in human clinical trials, safety and tolerability is the primary endpoint, pharmacokinetics is the secondary endpoint, and then our exploratory endpoints look at pharmacodynamics, that's the biomarkers, measures of clinical activity, such as muscle strength and function, and then we also have patient and clinician-reported outcomes. Next slide, please, Ty. With respect to the baseline characteristics for the cohort that we'll be sharing today, at high level, really the placebo and active treated patients, pretty well-balanced on the critical baseline characteristics. If I guide your eyes down towards the bottom of the table, the reachable workspace and the quantitative muscle testing, which is muscle strength measure, the del-brax-treated patients were actually a little bit worse than the placebo patients on this measure. And then just one other point of orientation. The reachable workspace measures here are about 50%, less than you would expect a normal, healthy person to be able to perform, so these patients already quite impaired coming into the study. Can we move to the next slide, please? So, once again, delighted to share with you favorable safety and tolerability data. This has been a consistent theme across the three programs for which we've shared data now, and we're absolutely delighted to have yet another program that's following the same pattern. The safety data, we're sharing data from all patients that are on the study, so for the safety data element, we do include the 4 mg per kg patients, and this safety data cut is up to May of this year, so it's very recent. We've enrolled 39 patients in the clinical trial, and all 39 patients remain in the study. We've had no serious adverse events, no severe adverse events, no patients have discontinued. All adverse events were mild or moderate. The most common related adverse events, which is those occurring in two or more participants, is exactly as we would expect, and we, we have seen some adverse events relating to hemoglobin changes, as you would expect from targeting the transferrin receptor. As with our del-desiran program, these hemoglobin-related adverse events have all been mild or moderate. No patients have had to discontinue dosing. The hemoglobin changes are completely reversible, so they're transient. The hemoglobins tend to go down a little bit in the first couple of weeks after dosing and then come back up again. You'll recall from our del-desiran program, where we recently disclosed long-term data from our open label extension study, as we go out over time, we would anticipate that these events will fade away. If we can now move to the next slide, please. So, as Sarah alluded to, we're gonna be sharing some absolutely remarkable data with you today, both on the biomarker side and on the clinical efficacy side, showing that we've really joined the dots between drug delivery to muscle, in pathway engagement, changing the biology, clinical endpoints, and patient-reported outcomes. And really, that provides an excellent foundation for us to accelerate our pathway to registration. And the most efficient way for us to do this is to actually modify the FORTITUDE study, rather than trying to initiate a new phase III study. And that's exactly what we've done. So on this slide, just to orient you, this shows the current study design and the changes that we're making to the study design. So if we look at the top of the slide, we see Cohorts A and B. These are the dose escalation cohorts. As Sarah said, these are completely enrolled now, and these patients are in follow-up. The follow-up is a one-year period. Cohort C was actually our expansion cohort in this clinical trial. So that cohort was already there, but we're adapting it for a potential accelerated approval, and it becomes our biomarker cohort. So we're increasing the sample size a little bit. This cohort we're planning to initiate in the second half of this year. We're not quite at the point of being able to nail down the dose and the regimen at the moment. We're still waiting for the 4 mg per kg cohort to read out, but we anticipate that we'll be able to make that selection in the third quarter of this year, and we're right on the cusp of the third quarter now, so very close to making that dose selection. One thing that you'll also notice is that our previous 8 mg per kg cohort isn't there anymore. As we've been saying for a long time now, we really think that our dose is at the 2 or 4 mg per kg dose levels, similar to the del- desiran program. And the data that we're gonna share with you today at just 2 mg per kg really reinforces that that is the correct dose range. So we've deleted out the 8 mg per kg cohort because that actually allows us to accelerate going into the phase III cohorts much more quickly. Now if we look towards the bottom of the slide, you'll see Cohort D. This is our functional cohort. We're planning to implement that by protocol amendment. And that cohort, we're planning to start in the first half of next year, and this is targeting full approval. Cohort D will be at the same dose and measurement that we select for Cohort C, and importantly, Cohort D won't have any muscle biopsies. If we can move to the next slide, please. So now I'm delighted to hand you over to Dr. Flanagan, who is gonna walk you through our very exciting biomarker data. Thank you, Steve, and good morning, everyone. Thanks for joining. So today, let's see. Am I on now? Okay, there we go. Thanks, everyone, and good morning. We're on now. Today, what I'd really like you to focus on is the consistency of the data. From the effective delivery to muscle, to a 53% reduction in our DUX4 regulating gene panel, and a greater than 50% decrease in DUX4 regulated genes across multiple gene panels. Not only does del-brax block DUX4 regulated genes, but we show a broad impact on the underlying FSHD disease biology. And as Sarah indicated in a moonshot, we've identified a novel DUX4 regulated biomarker in patient plasma that shows a 25% decrease after dosing, and these results are augmented and extended by a 30% decrease in creatine kinase, a marker of muscle damage. These consistent data from muscle delivery to target engagement to broader effects on FSHD disease and circulating biomarkers are then linked to trends in functional improvement that Dr. Statland will discuss next. So next slide. FSHD is a relentless progressive disease striking people in the prime of their lives. As shown in the left-hand panel, FSHD is caused by the aberrant expression of DUX4, a transcription factor that activates thousands or hundreds to thousands of downstream genes that poison muscle cells. Our AOC technology is perfectly suited for treating people living with FSHD, as shown on the right-hand panel, because we know we can deliver to muscle. We have a potent and durable DUX4-specific siRNA, so that when DUX4 is radically expressed, our siRNA targets and destroys the DUX4 messenger RNA and prevents the poisoning of muscle cells. If we can prevent DUX4 expression and prevent further poisoning of the muscle tissue, we believe that del-brax has the potential to stop FSHD progression. So the first step in doing this is showing that we have muscle delivery. That's shown on the next slide, and here we show unsurpassed siRNA delivery of muscle. This is at one month following three doses of del-brax, the first dose being 1 mg per kg, followed by two doses at 2 mg per kg. Biopsies are taken one month following the third dose, and as Steve indicated, 7 out of the 8 participants in the del-brax treated group had both baseline and post-dose biopsies. One participant received a baseline biopsy but missed their post-dose biopsy, so all DUX4-regulated gene expression will be based on 7 participants that received both the baseline and the post-dose biopsies. So with delivery to muscle, we are interested in determining the effects on DUX4 regulated gene signature. But let me first introduce our gene panel, which is on the next slide. Our four-gene panel was selected for dynamic range, robustness and reproducibility. You can see the genes are listed here on the right-hand panel. We've used RNA-Seq data, patient-derived cells, the scientific literature, and we validated using a qPCR assay for the four genes. Interestingly, despite having different data sets, different filtering criteria, assay conditions, multiple groups have consolidated on a very similar gene panel. You might recognize these genes. Two out of the four genes overlap the ReDUX4 gene panel that was published last month in The Lancet Neurology. Three out of the four genes overlap with the Yao et al., 2014 paper that was discussed, indicating that these sets of genes are well-validated by several groups, that really multiple groups have consolidated on a very similar set of genes. So using this gene panel, of course, we were interested to see if we delivered unsurpassed levels of siRNA. Now what happens to the gene signature? And that's shown on the next slide. Here, del-brax shows unprecedented 53% reduction in DUX4-regulated genes. On the Y-axis is% change in DUX4 score from baseline. On the X-axis is the placebo group shown in black and the del-brax-treated participants shown in orange. All del-brax-treated participants showed a greater than 20% reduction in DUX4-regulated genes. In addition, all muscle biopsies had a DUX4 gene signature, demonstrating that we successfully used MRI informed to inform our muscle biopsies. This 53% reduction in DUX4-regulated gene panel is only possible because del-brax directly targets DUX4, the underlying cause of FSHD. Now, having seen this 53% reduction in gene panel, we were interested to see how del-brax performed across other gene panels, and that's shown on the next slide. Here we show that del-brax shows greater than 50% reduction in DUX4-regulated genes across multiple gene panels. Using the ReDUX4 gene panel, in the middle, we see a 53% reduction. Then looking at a broader 41 gene panel, we see a 60% reduction across DUX4-regulated genes. I should point out that the 53 and the 60% reductions are independent of the assay used to measure. For our Avidity panel on the far left, we've used qPCR, but for both the ReDUX4 and the 41-gene panel, we use RNA-seq data to quantify the reduction in DUX4-regulated genes. Independent of how you assay this gene panel, independent of what genes you select, we see a decrease following del-brax treatment. Again, the consistency, the magnitude of reduction in regulated genes is only possible because del-brax is directly targeting DUX4. Having shown that del-brax decreases the expression of DUX4-regulated genes, we're interested in understanding the broader biological effects of del-brax. Here on the next slide, we show a heat map at baseline on the left-hand panel and after del-brax treatment on the right-hand panel. Each column is an individual participant at baseline and after dosing. Each row is a different gene. We've removed all the DUX4-regulated genes to better understand the underlying secondary and tertiary effects of del-brax. At first glance, I hope you can quickly see that hundreds of transcripts are changing, as shown in the upper panel, in red, changing to blue, or in the lower panel, blue changing to red, following del-brax treatment. Some of these changes are linked to immune infiltration, muscle regeneration, and as we look at this data and mine these data even further, we'll be able to understand better the underlying disease state. So not only is del-brax affecting DUX4-regulated genes specifically, but these changes are also having broader biological effects in the muscle. Now, one of the hallmarks at Avidity is when we go into a disease area, we want to deeply understand that disease. So for the last few years, we've pursued a moonshot, the discovery of a novel circulating biomarker, a DUX4-regulated biomarker, and that's shown on the next slide. Just to introduce you, circulating biomarkers really are an excellent way of understanding early detection, understanding the whole body response to a treatment, in this case, del-brax. And unlike a biopsy, a circulating biomarker really provides a comprehensive assessment. We're able to look at the whole body. It allows continuous monitoring, and it's patient-friendly. We've again been looking at this for several years. Shown on the next slide, kind of indicates how we've gone about this. So it's been a multi-discovery, multi-year discovery process where we've used biopsy data, of course, RNA-seq data. We've used plasma from both FSHD patients and healthy volunteers. We've talked to advisors, our own internal disease expertise, and now we've validated an assay where we can look at this novel DUX4-regulated circulating biomarker. And what we see is that it's significantly upregulated in people living with FSHD and in our FORTITUDE cohort as compared to healthy individuals. Because this biomarker is plasma-based, we can use it for continuous monitoring, and it really allows us to dial in our dose regimen. And most importantly, our DUX4-regulated biomarker has the potential for an accelerated approval endpoint. So let me show you the data on the next slide. And what we see is an early and sustained reduction on our circulating biomarker. The Y-axis shows change from baseline, the X-axis shows study months. And the black arrows indicate dosing of del-brax. The gray color represents the placebo cohort, and the orange represents the del-brax treated cohort. In this case, we have all eight participants because it's a plasma base. And what we see is 25% reduction in our circulating biomarker compared to baseline. Now, to support and extend this, the importance of our circulating biomarker, we also evaluated creatine kinase, a well-known biomarker of muscle damage. And we found that both our novel DUX4 regulated biomarker and creatine kinase showed a 25% and 30% reduction after treatment with del-brax. So why have two circulating biomarkers? I think really because they're telling us different things. The del-brax the DUX4 regulated biomarker is telling us that we're specifically reducing DUX4 regulated proteins, while the CK biomarker is telling us that we're reducing muscle damage following treatment with del-brax. Next slide, Dan. So this morning, hopefully, would have convinced you that we've connected the dots, the dots from delivery to function, to 53% reduction in DUX4 regulated gene signature to a broad impact on the underlying biology as demonstrated by RNA- Seq. We've discovered a new DUX4 regulated circulating biomarker that has the potential to accelerate approval. And now what you'll see is that this connected - connection of the dots from delivery and now to function in Dr. Statland's section. So it's my privilege to introduce Dr. Statland. Next slide. So Dr. Statland is a distinguished professor of neurology at the University of Kansas Medical Center. He's a leading expert in the field of neuromuscular diseases, including FSHD, Duchenne muscular dystrophy, and myotonic dystrophy. His research interests are focused on developing new disease-relevant outcome measures to assess patient-reported disease burden, functional impairment, and physiologic changes in muscle. Dr. Statland is also the co-PI for the FSHD Clinical Trial Network, a global network of clinical sites that are advancing the understanding and treatment of neuromuscular diseases. Please join me in welcoming Dr. Statland. Great. I want to thank Avidity for the opportunity to share the preliminary clinical data on strength, function, and patient-reported disease impact from the FORTITUDE trial. On a personal note, before I get started, over the last 10 years, along with my collaborators and our industry partners, we've really been working to build the infrastructure and tools to support clinical trials in FSHD, all really with our goal of fostering development of molecularly designed gene-targeted therapies. So it's with particular excitement I share this clinical data from FORTITUDE, which I think is worth pointing out, is our first gene-targeted clinical trial in FSHD. On this slide, you can see the clinical hallmarks of FSHD. Starting at the top picture with facial weakness, I've asked this individual to purse their lips. You can see they're unable to do this, and as you can imagine, that can have a large impact on your social interactions. In FSHD, in the middle photo, you can see there's loss of the scapular stabilizers. This can cause your scapula to rotate up and out, but it results in the inability to reach above shoulder height. In the lower photo, you can see a couple hallmarks of the disease, including the asymmetry of muscle involvement, and in her right leg, you can see dramatic wasting of both the tibialis anterior and the medial gastroc. These are common muscles affected in FSHD. And if we can play the video, this is from a motion lab at the University of Kansas Medical Center, and you can see how these different patterns of weakness can come together. This individual has bilateral foot drop due to tibialis anterior weakness. He's throwing his legs forward because of weakness in the thighs, making it difficult to lock the knees, and you can see his core muscle weakness leads to exaggeration of the lumbar lordosis and instability at the pelvis. Next slide. This cartoon illustration shows you some of the common early muscles affected in FSHD in pink, and then some of the later muscles affected in blue. But ultimately, any muscle can become affected in FSHD. In adults, by far the largest percentage of patients, their presenting symptom is inability to reach above shoulder height. But another very common presentation in adults is foot drop. And as had been mentioned earlier, about 20% of individuals will lose the ability to walk or maintain their job by the age of 50. Can we have the next slide? So when we think about then the perspective of the patient living with FSHD, we have the advantage of having several large surveys, both in the U.S. and the European Union, and they have been quite consistent in what patients say. On the right, I'm showing you data from our most recent survey, which was in the European Union and had over 1,000 respondents. In panel A, you can see the most prevalent and impactful symptom categories identified by patients. Notice the top items are almost all related to muscle weakness, difficulty around the shoulders or with gait, or the results of muscle weakness with fatigue or lack of energy or endurance. As the patients think forward about their future, this leads to concerns about the ability to maintain independence in their life, both due to the motor problems, but also having the energy to do the work they want or live the life as they want to live it. As we think about therapies and FSHD, treatments that improve muscle strength or function will be important to patients. Can we go on to the next slide? Now we're going to turn to the data from the FORTITUDE clinical trial. Next slide. We're going to start with measures of motor strength. This is measured by handheld dynamometry, which uses a digital force transducer in standardized positions to really isolate the different muscle functions. The muscles chosen for this clinical trial are key muscles important to FSHD, two around shoulder function, the elbow and knee flexion and extension, and ankle dorsiflexion. These numbers can be standardized to give you a percent predicted of normal. All of the graphs I'm going to show you from here on out have the same format, showing the change in strength or function from baseline to four months. Zero, the dotted line, would be no change. Moving to the left on the graph would be declining or worsening performance. Moving to the right would be improving performance. The orange color will be the del-brax-treated patients, and the gray will be placebo. Here you can see a separation occurring in the total body composite strength. And you can see this reflected in trends and improvements in strength in the upper extremity around the shoulder girdle and in the lower extremity at ankle dorsiflexion. To put the size of this difference into some sort of perspective, the size of this difference is about what we would see over a year of natural history in FSHD, a loss of somewhere around 2%-5% of their quantitative strength. Can we have the next slide? When we think about function, the outcome that was chosen for this study is the reachable workspace, originally developed by Jay Han and his group. This was a novel repurposing of an existing technology. Many of you may remember the Xbox game console that came with a three-dimensional camera, so you could interact with the game. They took that three-dimensional camera, created a setup where they can then show people videos of standard movements that represent the Reachable Workspace that someone has around their body. Can we show the video? You can see this individual seated, looking straight ahead at a screen that shows instructions on what movements to make. Then in the bottom right of the screen, you can see the reconstruction of those movements, which ultimately creates a volume of space, your Reachable Workspace, and the surface area of that volume is what's captured by this instrument. If we think about the functional impact of our Reachable Workspace, these are activities like getting dressed, washing your hair, brushing your teeth, so really daily activities. Can we go to the next slide? In the FORTITUDE clinical trial, now you can see improvements in the reachable workspace, actual gains from baseline, whether you're looking at the average of the right and left side on the top panels, or just looking at the dominant arm on the bottom panel. 2, 1 + 3 is that space above shoulder height. 2, 1-4 or 1-5 is the full reachable workspace, with quadrant 5 being able to reach back behind you. Again, the separation that we're seeing here would be around the size of the difference that might be seen over 1-2 years in the natural history. Can we go to the next slide? As had been mentioned, I helped run a clinical trial research network. We've had a trial preparedness study that we call ReSolve, that's been running on 11 of our centers in the U.S. and E.U. The goal of this study was to really validate our clinical outcome assessments in a multicenter setting to prepare for clinical trials. The Reachable Workspace was one of the outcomes that was included. Two hundred and thirty-seven people entered the study. The visits occurred split over two days at baseline. This allowed us to calculate the test, retest reliability of the instruments, which for the Reachable Workspace, is quite high, with an intraclass correlation coefficient around 0.95, and then we collected longitudinal data at 3, 12, 18, and 24 months. Can we go to the next slide? This is comparing the del-brax treated patients here to a matched sample from our ReSolve study, matched by age, gender, a clinical severity score, and their baseline Reachable Workspace performance. Here you can see the natural history cohort is really showing no change or just a slight reduction in their Reachable Workspace at three months. In our del-brax -treated patients, we're seeing improvements. Can we go to the next slide? This equates to both the patient and physician reports of benefit in the study. This is using a Global Impression of Change, is the C you see there, or Severity is the S. The patient report is on the left. The clinician report is on the right, and if we start on the left, we can see that patients, there are trends towards improvement in their Global Impression of Change and Severity, which is then reflected in an overall quality of life metric, the EQ-5D. When we look at the clinician impression of that change, you can see there's a slightly larger benefit being seen in either the change or the severity at four months. It's worth pointing out the patients, the clinicians, and the evaluators in the study were all blinded to treatment. Can we go to the next slide? In summary, I think we've got a drug that's being targeted. We're showing effective delivery to the muscle with knockdown of the intended target. With looking at DUX4 targets, we then see some evidence of the systemic response with the novel DUX4-related biomarker, but also with the reduction in a general measure of muscle damage, the serum CK, and then this is supported so far by this preliminary data showing improvement in strength or function. I think one question we have as a field, if we had a gene-targeted therapy, would all we really see is a halt of what would be the natural history, or would we actually see patients start to get better? And I'm optimistic that this early data at least sets the stage for a scenario where we might start to see people improve with continued treatment. And so I'm definitely looking forward to continuation of the trial and just want to end on one last note. The company did collect quotes from the different sites of the patient experience of being in the trial, and there was a participant on the East Coast who told their investigator that the thing that they noticed the most was they were able to purse their lips and make a fish face, which is something they had never been able to do in their lives before. And so I'm hopeful that we'll continue to see, hear more stories like this as the trial continues. All right. I'd like to turn it back over to Sarah for the concluding statements. Thank you, Dr. Statland. Thank you. So in terms of what we've seen and what we shared this morning, really, it's an example of how do we connect the dots around hitting our target, getting a greater than 50% reduction across multiple DUX4 gene panels, seeing the signs of functional improvement, also coupled with the patient-reported outcomes and a very favorable safety and tolerability profile. Our job now is how do we accelerate del-brax towards approval? And Steve shared with you those plans. What I'd like to do now is take a look at what our pipeline now looks like. So in terms of a couple of things to point, point out here. Firstly, you'll see obviously the HARBOR study. We're now in phase III with del-desiran, and I'm delighted to share that the HARBOR study has now been initiated. And you can see on clinicaltrials.gov, the centers that are now recruiting participants to the study. The AOC 1044, we're, you know, now in the phase I, II portion, and we're looking forward to sharing data from the patient cohort later this year. You'll see our program targeting exon 45 has moved through IND enabling. Also, I'm delighted to be able to share that we're now updating our guidance around sharing the very first look at our precision cardiology program. This will be with our first program, but we're planning on sharing data on that program in the second half of this year. What you're seeing across the pipeline is where we're leaning in. This is our time to really look at how can we accelerate across all of our programs, given the consistency and the reproducibility that we've seen with regards to what our technology can deliver. So now just looking, focusing in on this year. So if we can go to the next slide, please. So firstly, I'm delighted to be able to share that the HARBOR study has now been initiated for del-brax. Our next task is around how do we accelerate towards approval. First step of that is initiation of the phase III cohorts. You've heard us talk around the timing of those. And then for AOC 1044, we're actually able to put forward our guidance around when we can look forward to seeing our first set of patient data from that program with the 5 mg cohort, which we're now anticipating for Q3 of this year. In terms of going back to look at our vision and to close out on that. Our vision as a company is to profoundly improve people's lives. I hope what you have also seen in that aspect of revolutionizing the delivery is the consistency and the reproducibility that we can achieve, and with our platform technology. And of course, we're incredibly excited about del-brax and the data that we shared with you today. I would now like to pause and invite my colleagues back to the screen, and we'll start our Q&A portion of the webcast, which will be facilitated by Geoff. So Geoff, over to you to facilitate our Q&A. Great. Thank you, Sarah. We're compiling our questions here. Wait for everyone. I believe we have everyone on screen. Great. So our first question is from Joe Schwartz at Leerink. And Joe, thank you for the congratulations on the data. Mike, I think this question is for you. How much do you expect the 4 mg per kg to knock down the DUX4 gene signature? And is four months expected to be the maximum effect, or would you expect it to continue past this point? Yeah. So I think it's a great question to try to understand. I think, you know, looking at the data, and it's really gonna be on the, on the biomarker data. So remember, our, our biopsies are at four months, and we don't have any further biopsies, so it's hard to understand how that's gonna translate further on. But I think looking at the way that we're treating patients, you have to think about it as a prevention model. And what do I mean by a prevention model? What I mean is that if we have a silencing RNA that blocks DUX4, that destroys DUX4, anytime that DUX4 is expressed, we're gonna knock it down. So it's really this sporadic expression across, muscle cells of DUX4 poisoning muscle, is that you just need a constant level of siRNA on board. So we think that, rather than a C-max effect, this is really going to be having a durable, potent siRNA on board. So looking forward, we think that, you know, again, the dose is gonna be somewhere between 2... You know, it's either gonna be 2 or 4. And as we get more information on our circulating biomarkers, able to look at some of the biopsy data, which we don't have yet, we'll be able to better dial in that dose. Thanks, Mike. And a follow-up on the circulating biomarker. When will we, and perhaps, Sarah, this is for you. When will we learn more about the circulating biomarker? And Mike, for you, how much do changes in it correlate with changes in the DUX4 gene signature or clinical changes when you look across patients? Yeah. I’ll start first, and then- You go. So, you know, this is a moonshot. Honestly, I didn't think that we were gonna find a circulating biomarker. Thankfully, the researchers didn't listen to me and just kept plowing on. So it's a great, it's a really amazing finding, and we just have this data just now. So we didn't know that it actually had any, could measure in plasma and see an effect of del-brax. So right now, we're filing the IP. What I can tell you is, of course, we know what the gene is, we know what the protein is, we set up a standard curve for the using the protein. We know that there's DUX4 binding sites in the promoter enhancer region. We've measured it by RNA-Seq, so we know that the data correlate quite nicely. What our job is to do is to better understand this, and then as the IP files, then we'll be happy to share it with the rest of the community and really to help push the science forward. I think it's one of those things that you just don't like, this doesn't happen that often. People have been looking for this for years. I mean, Dr. Statland, I think, can probably tell you better how hard this is. And you know, we've just been able to do this. And really, the reason why we've been able to do this is that del-brax targets DUX4. And when you have something that targets DUX4, then you can start seeing these broader effects on the overall body, and that's really what's allowed us to be able to validate this biomarker. I don't know, Sarah, if you have anything else to add? I don't think I've got anything to add to that, Mike, other than I think in terms of one of the other things, that this is an example of how deep we go with our science and how rigorous we are with regards to exploring and making sure that when we have a program, we're looking to understand it, you know, as deeply as we possibly can. And this is just an example of the diligence and the commitment and the investment that we put into that scientific understanding. Great. Thank you. Next, we have a couple of questions from Eric Schmidt at Cantor, and again, Eric, thank you for the congratulations. Mike, first one for you, and I think second one for you, Dr. Statland. Mike, based upon PK/PD data or any other available information, would you expect a dose response to be observed in the 4 mg per kg group? Yeah, it's, you know, we're leading the field, but the honest answer is, I don't know if we're gonna see a major dose response for this. We've seen at 2 mgs per kg, really, unprecedented decrease in DUX4-regulated genes. You know, when we look at those gene panel, some of the genes are completely knocked down, you know, as we're looking at that composite score. So, looking forward, it'll be interesting to see what those data are. It may be that four is an optimal dose, but again, I think I'd go back to what we're trying to do is prevent DUX4 from being expressed. You may not need a high dose, you just need it on board, so it may be a dose schedule rather than a dose concentration or how much you dose initially. So you know, that's what Steve and we'll be looking at, trying to really dial in this dose. And I think going back again to the circulating biomarkers, that'll really help us because we'll be able to understand kind of the schedule. We'll be able to understand the return kinetics and really be able to dial in that dose. So we're looking forward to those data. Thanks, Mike. And Dr. Statland, we'd be interested in your view on DUX4 as a surrogate endpoint for accelerated FDA approval, in particular, the strengths or weaknesses around the correlation between DUX4 signaling and disease progression. Yeah. I mean, that's a question we've been grappling with in the field, I think, for, for now, many years. You know, I think the things that I can say with certainty, you know, there's consensus around DUX4 being the molecular cause for the disease. The, you know, clearly shows damage. When you look in families with FSHD, you know, there's a, a pretty high expression of DUX4 in affected individuals. You can see a very low level of expression in unaffected family members, so there's some level that potentially could be tolerated. But up, up to now, we haven't had the data set or the ability to do a lot of correlation in predictive studies because we've had nothing that could knock down DUX4 to see what would happen if we were changing it. But one thing I can say, there are associations between DUX4 and what we see in the muscle pathology, and it does appear on a single muscle level, moderate correlation to the DUX4 and, and the measures of strength on cross-sectional data. Great. Thank you, Dr. Statland. Our next couple of questions are from Ritu Baral at TD Cowen. Mike, I think this is for you, another one on the biomarker. Is your novel biomarker related to plasma CK or other muscle damage markers, or is it more directly related to DUX4? Yeah, it's directly related to DUX4. So we know that it's a DUX4 re-regulated protein. Again, we know that DUX4 binding sites are mapped to the promoter enhancer region of this gene. We know that it's increased in FSHD patients, including our cohort. So we've seen that both at the RNA level as well as at the protein level. So it's independent, and that's what makes it such a great biomarker, right? It looks at specifically DUX4 regulation, whereas the CK gives you this general indication of muscle health. A follow-up on the dose response. Does the Cohort B data, either functional or biomarker to date, suggest you are at or near the top of the dose response curve? Yeah. So based on what we know from our non-clinical data, based on where we dose our FLExDUX4 mouse model, we're probably close to the top of the curve, even at 2 mgs per kg. You know, we're looking at somewhere around those concentrations in the muscle that are probably close to EC90 kind of thing. So it will... It'll be interesting to see how that translates, but we're probably close to the top. And this is consistent actually, with our del-desiran and some of the data that we know from that, as well as non-human primate data. So, you know, obviously across our portfolio of projects, we've dosed over well over a hundred non-human primates. So we have a pretty good sense of how our siRNAs work and what the doses are. So we're probably close. Even at two, we're probably pretty close. Great, thank you. Our next question is from Yanan Zhu at Wells Fargo on the regulatory strategy. I just think this is probably for Sarah, you and Steve. When do you plan to discuss with the FDA the data from FORTITUDE? How confident are you that the FDA is amenable to your phase III strategy, especially the biomarker accelerated approval strategy? Yeah. So maybe if I start and Steve, I'm sure you'll add as well. So in terms of one of the key aspects of our next steps is dose and dose frequency. And it's probably once we've done that selection, sort of getting in and having that discussion around the biomarker approach, it's something that we have not had that discussion yet with the regulators. What I would say, though, is in terms of it's the aspect of the consistency across how you measure it, both from the muscle biopsies, from the circulating biomarker and looking at CK, that makes a really compelling package. And I think, you know, Dr. Statland's insights around what we know from the disease and all of that understanding helps build that case and package. But this is work that we need to do, and it's our goal to be able to get in and do that as quickly and as expeditiously as possible. Steve, I don't know if you would add anything. Yeah, I think just as Sarah said, the consistency of the data and also being able to see these trends in improvement across multiple functional measures as well really bolsters the validity of the biomarkers. And I guess the last thing is that unlike just going in with a muscle biopsy biomarker, where you really are limited in your ability to track that over time, because it, it's just not nice taking multiple biopsies from patients. The circulating biomarker really allows us to track the kinetics of that over time and demonstrate very clearly that the improvements that we're seeing at the early time points also are maintained or improving out to the later time points. And then, of course, CK is well established as a measure of muscle damage, and so seeing changes in the CK really, we believe, validates the changes that we're seeing in the other muscle biomarkers. So really a consistent package. Great. Thank you both. And a follow-up for Dr. Statland. How would you compare Avidity's data set today with Fulcrum's phase II data, especially in terms of functional data? Right. I mean, that's a great question. I'm always a little hesitant to compare one to the other, to be honest, 'cause as a field, we're excited about both, and wanting to see treatments come forward. You know, I think that there's differences. The Fulcrum data was over a longer time period, so it was over 48 weeks. And, you know, while there was, I think exciting data looking at the sort of muscle quality on MRI, the reachable workspace and the patient reports of change, not quite the same consistency across different levels of thinking about the disease. And so some of the changes seen here, I think if you projected them forward and we saw this continue with the patients, would suggest that we might see a more robust effect. I think it's just too early to tell for sure. Great, thank you. Our next question is from Steve Seedhouse at Raymond James. Mike, I think this is for you. How elevated were CK levels at baseline in this cohort of patients? Could you put the 30% reduction into context? Yeah. As you know, CK isn't as elevated as, for instance, DMD patients. So in Duchenne muscular dystrophy, because of the kind of muscle damage that's broadly found, CK levels are elevated. Whereas in FSHD patients, it's more kind of maybe five times the upper limit of normal would be the top, but most of them are kind of in this normal range. So what we're seeing is it still looking at that CK level, you're still seeing this improvement, you know, global improvement in reduction in CK, which indicates that you're having less muscle damage. But it's not as, you know, it's not as great as what has been observed in Duchenne muscular dystrophy, but still meaningful. Our next question is from Gavin Clark-Gartner at Evercore. I believe we touched on this, but a slightly different spin on the regulatory question. Could you lay out your plan for correlating these multiple biomarkers to clinical outcomes and how you will approach the regulatory discussions? So maybe if I take that one. So the regulatory path to correlating biomarkers, correlating, patient-reported outcomes, quality of life measures, et cetera, is pretty well described. There's regulatory guidelines that cover what, what you have to do. Part of it is having a larger data set. Obviously, this is relatively small cohort sizes. As we move out into our registrational cohorts, we'll have more data to work with. It will be easier for us to to form those correlations. And of course, important is correlation of things over time, and now having a circulating biomarker really allows us to look over longer durations rather than taking a cross-sectional snapshot at how these correlations play out over time. Great, thank you. A follow-up for Dr. Statland. In your mind, what is the relative importance of Reachable Workspace versus muscle strength versus the PRO-CRO measures? Would you expect a larger Reachable Workspace benefit in the dominant or non-dominant arm? Yeah, there's quite a few questions there rolled into one. But I think that the, One, I mean, I like strength as an outcome in FSHD. When you talk to patients, you know, so much of what is affecting their lives is due to the loss of that strength, and so I think it's, it's a, a good measure for FSHD. Reachable Workspace is hitting one of the hallmarks of the disease in terms of functional categories. I mean, this is probably the most common thing we hear when people first come to us, you know, they're having problems reaching and doing tasks with their arms. So, I mean, the Reachable Workspace is a very nice, option. It's conceptually nice. It really gets at this idea of what's the functional space you can work in with your arm. And so I do think improvements there would be, you know, significant. We're working out now the breakdown of, you know, how large a change and what a quantitative measure is going to be clinically meaningful. But we'll have that data very, very soon. And then, you know, patient-reported impact. I mean, ideally, what you really like to see is the concordance across these different levels. In theory, you know, we'd expect to see some isolated strength changes first, then function being affected, and then finally, patients telling you they're feeling better. And so in an ideal world, what you'll see is there'll be some concordance across each of these outcomes. Great, thank you. Our next question is from Geoff Meacham at Bank of America. Again, thank you for the congratulations, Geoff. Question on biomarkers, and how do we think these DUX4-related biomarkers can be used in practice as well as from a regulatory perspective? Think I should take that? Yeah. So, obviously, in clinical practice, doing muscle biopsies on your patients is rather invasive. So those really are a clinical trial tool, I think. And, Dr. Statland can maybe speak a little bit more to that in a second. The circulating biomarker, though, is game changing. It really allows us to track response over time, allows us to confirm that we're maximally hitting DUX4, and allows us to really see how the patient is responding over time, and, of course, creatine kinase as well. I think, we've obviously working towards patenting our circulating biomarker because we believe it has potential for monitoring patient response to treatment in more real time than the muscle strength and function and mobility measures that might take a little bit longer to maximally change. A follow-up. This is for you, Sarah. What does this mean for the broader platform and pipeline? Yeah. Thanks, Geoff. I think that's a really great question. It's this aspect on what we're seeing is reproducibility and consistency around what we can do when you can effectively deliver an RNA to your target cells. And we've discussed around what this means for del-brax, but also across our pipeline, this is our time now around how can we turn on the gas, and how can we accelerate some of our earlier programs and really look to move them into the clinic as quickly as possible, given both the reproducibility and the consistency that we're seeing now across multiple different diseases. It's incredibly exciting. Our next question is from Keay Nakae at Chardan. For Dr. Statland, would you expect the benefit, as measured by Reachable Workspace, to further separate with a larger sample size of treated patients? Yeah. So what I mean, I think what I would be hopeful for, you know, this is a fairly early time point. As a field and as a researcher, what I'd like to think is this would be, you know, the initial sign that we're getting a benefit. I think that we likely could see continued separation. You know, there'll be a question about the maximum degree that we'll be able to see because there's fibrosis in some of these muscles. And so while there's muscle, there's still muscles there, and we can expect to see improvements, the ultimate upper limit, I think, isn't known, but we haven't had a treatment to try to push that so far. But I'd be very hopeful that we would continue to see this improve with continued treatment. Great. Thank you. Our next question is from Joey Stringer at Needham, and Joey asks: "Would you suggest accelerated approval based solely on the biomarker, or would it be some type of composite endpoint? Maybe I'll take that one. We're targeting accelerated approval directly on biomarker. But remember, we do have more than one biomarker, so we have multiple different gene panels on the muscle biopsies. We've got RNA-Seq that we can use to show changes in disease biology, and we have the circulating biomarkers that we're able to use to show longitudinally how the patients are responding. Of course, any accelerated approval submission will also have the clinical response data and the patient-reported outcome data, albeit not statistically powered in those accelerated approval cohorts. But that does provide supporting data as well for an accelerated approval. So really, a totality of evidence on the biomarkers across multiple different markers of both target pathway engagement, disease biology, impact on muscle health, and then supported by the clinical data. Great, thank you. And we have time for one last question, a follow-up from Ritu Baral at TD Cowen. "How are you thinking about Europe for FSHD? Do you feel that you need alignment from the FDA and the EMA regarding initiation of the new cohorts? No, not alignment. So, as you know, accelerated approval, at this point in time, isn't a pathway for Europe. So that accelerated approval cohort, while it will provide very useful data to support the subsequent filing in Europe, it won't support an accelerated approval in Europe. So for the global filing activity, that's the functional cohort that we're initiating. And that's why it's super important that we move both of these cohorts as aggressively as possible, so that we can bring the drug to patients around the world as quickly as possible. And at the end of the day, the data will speak for itself in terms of regulatory approval. It's unusual to get exact alignment between the different regulators, and then your next opportunity is at your pre-submission meeting, and we're really confident that these early signs that we're seeing from the study are gonna translate as we move to larger patient populations into a really compelling data set. Great. Well, thank you everyone for the questions. Thanks to our team for being here. I'll turn the call back over to Sarah now for closing remarks. Thanks, Geoff. And thank you for the questions. As always, we really enjoy the Q&A and really getting into the data. I would just close out, again, thanking all of the participants in the FORTITUDE study, the investigators, and all of the teams at the site for their work in getting us to this point. And again, how we're one step closer to really fully realizing our vision of what we're trying to do, which is to make a profound impact on people's lives. With that, I wish you a good morning.