Avidity Biosciences, Inc. (RNAM) Earnings Call Transcript & Summary

Good morning, everyone. Thank you for joining us today. My name is Geoffrey 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. And 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 that time with visits to centers to the investigations and to all of the team of the centers for the commitments and the support during the FORTITUDE study and the continued commitment to the study as it continues. What we're looking at now is the 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 can expect from our platform, given our previous experiences. You'll also see Del-desiran delivery to Muscle. We can deliver more [indiscernible] 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 show where we see signs of functional improvement across multiple measures. So in terms of the data we're going to share today is the data of Del-brax 2 milligrams at 4 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 showing 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 2 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. So on a high level around data, we're seeing unprecedented and consistent reductions in the DUX4 regulated genes. We see a greater than 50 -- so 5-0 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 2 years of work. And you'll also see how that correlates with changes in creatine kinase. From our 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 and moderate, no serious AEs, no severe SAEs and no discontinuations. And if I'm [indiscernible] with anything from today, it is our goal of accelerating Del-brax now towards approval. One of my colleagues who are joining me today, we're also delighted that Dr. Statland who's been gracious enough to join us today as well. He is one of the leading experts in FSHD and is an investigator in the FORTITUDE study. So 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 to devastating disease characterized by a 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 in a genetic disease with mainly autism 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. And 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 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 pleae. So I'd just like to continue orienting you now. This is a high-level schematic showing the details of the FORTITUDE study, which we'll be presenting the data today. So starting from the left and moving to the right. It's a randomized, double-blind, placebo-controlled study, is 12 months in duration. So we'll be following the efficacy endpoints and the safety end points over a 12-month period of time, but muscle biopsies for the -- muscle biopsy biomarkers performed at baseline and month 4 and no subsequent biopsies are performed after that. As you will recall, it's a dose escalation study. So we have 2 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-milligram per kilogram cohort, but all patients received 1 milligram per kilogram as their first dose and then all subsequent doses at 2 milligrams per kilogram. The reason we're not showing 4-milligram per kilogram biomarker and efficacy data today is because that hasn't read out yet. It's going to 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, the secondary endpoint. And then our exploratory end points 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. 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 you 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 3 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-milligram per kilogram 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 were made in the study. We 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 2 or more participants is exactly as we would expect. And we have seen some adverse events relating to hemoglobin changes, as you would expect from targeting the transfer sector. As with our Del-desiran program, these hemoglobin related adverse events will be mild to moderate. No patients have had to discontinue dosing. The event -- 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. And 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 going to be sharing some absolutely remarkable data with you today, both on the biomarker side and on the clinical efficacy side showing that we really join 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 for 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 have a follow-up. The follow-up is a 1-year period. Cohort C was actually our expansion cohort in this kind of 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 milligram per kilogram 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-milligram per kilogram cohort isn't there anymore. As we've been saying for a long time now, we really think that our doses at the 2 or 4-milligram per kilogram dose levels similar to the Del-desiran program. And the data that we're going to share with you today at just 2 milligrams per kilogram really reinforces that, that is the correct dose range. And so we've deleted out the 8-milligram per kilogram cohort because that actually allows us to accelerate going into the Phase III cohort much more quickly. And 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 of 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 going to walk you through our very exciting biomarker data.

Thank you, Steven. Good morning, everyone. Thanks for joining. Thanks everyone, and good morning. So, 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 regulated gene panel and a greater than 50% decrease in DUX4 regulated genes across multiple gene panels. Not only does Del-brax lock DUX4 regulated genes, but we show a broad impact on the underlying FSHD disease biology. As Sarah indicated, in a moon shot, 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. This consistent data from Muscle delivery to target engagement, the broader effects on FSHD disease and circulating biomarkers are then linked to transit and functional improvement that Dr. Statland will discuss next. FSHD is a relentless progressive disease striking people in the prime of their lives. As shown on the left-hand panel, FSHD is caused by the aberrant expression of DUX4, 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 sporadically expressed, our siRNA targets and destroys the DUX4 messenger RNA and prevents the poison in the 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 a muscle delivery that's shown on the next slide. And here, we show unsurpassed siRNA delivery to Muscle. This is how 1 month following 3 doses of Del-brax, the first dose being 1 mg per kg followed by 2 doses at 2 mgs per kg. Biopsies are taken 1 month following the third dose -- and as Steve indicated, 7 out of 8 participants in the Del-brax group at both baseline and post-dose biopsies. One participant received a baseline biopsy, but missed the post-dose biopsy. So all DUX4 regulated gene expression will be based on 7 participants that received both at baseline and the post-dose biopsies. So with delivery to muscle, we are interested in determining the effects of the DUX4 -- the effects on DUX4 regulated gene signature. But let me first introduce our gene analysis, which is on the next slide. Our 4G panel was selected for dynamic range, robustness and reproducibility. You can see the genes are listed here on the right-hand panel. We use RNASeq data, patient drive cells the scientific literature, and we validate it using acute PCR assay for the 4Gs. Interestingly, despite having different data sets, different filtering criteria, assay conditions, multiple groups have consolidated on a very similar gene panel. We might recognize these genes, 2 out of the 4 genes overlap the ReDUX and 41-Gene panel that was [indiscernible] last month [indiscernible] and 3 out of the 4 genes overlap with [indiscernible] paper, that was discussed in 2014. 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're interested to see we've delivered [indiscernible]. levels of siRNA. Now what happens to the gene signature, that's shown on the next slide. Here, Del-brax shows unprecedented 53% reduction in DUX4 regulated genes. On the Y-axis as a percent change in DUX4 store from baseline. On the x-axis is the placebo group shown in black and the Del-brax participant shown in orange. All Del-brax participants showed a greater than 20% reduction in DUX4 regulated genes. In addition, all muscle biopsies have the 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 target steps for the underlying cause of FSHD. Now having seen this 53% reduction in gene panel, we are interested to see how Del-brax performed across other gene panels, and that's shown on the next slide. And 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. And 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 2 PCR, but for both the ReDUX4 and the 41 gene panel, we used RNASeq data to quantify the reduction in DUX4 regulated genes. So, independent about how you would 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. So having shown that Del-brax decreases the expression of DUX4 regulated genes, we're interested in understanding the broader biological effects of Del-brax. And 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 the blue or in the lower panel blue changing the red from Del-brax treatment. Some of these changes are linked to Immunofiltration, muscle regeneration. And as we look at this data and mind this 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 of Avidity is that when we go into a disease area, we want to deeply understand that disease. So for the last few years, we pursued a moon shot, the discovery of a novel circulating biomarker, a DUX4 regulated biomarker. And I show on the next slide. Just to introduce you, circulating [indiscernible] really are an excellent way of understanding early detection, understanding the whole value 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 is patient friendly. We began 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 -- multiyear discovery process, where we've used biopsy data [indiscernible] we use plasma from both FSHD patients and healthy volunteers. We've talked to advisers, our own internal disease experts and we now we validated in asset, 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 in our circulating biomarker. The Y-axis shifts change from baseline. The x-axis shows study months and the black arrows indicate dosing of Del-brax. The great color represents the placebo cohort and the orange represents the Del-brax treated cohort. In this case, we have all 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 circling 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 of Del-brax. So I have 2 circling biomarkers. I think really because they're telling us different things. 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. So this morning, hopefully, what I've convinced you that we connected the dots, the dots from delivery to function, to a 53% reduction in DUX4 regulated gene signature to a broad impact on the underlying biology, as demonstrated by RNA-C. We've discovered a new DUX4 regulated circulating biomarker that has a potential to accelerate approval, and now what you'll see is that this connection of the dots from delivery and now the 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 is a leading expert in the field of neuromuscular diseases including FSHD, Duchenne's muscular dystrophy and myotonic dystrophy. His research interests are focused on developing new [indiscernible] relevant outcome measures to assess patient-reported disease burden, functional impairment and physiologic changes in muscle. Dr. Statland's also the co-PI for the FSHD clinical trial research network, a global network of clinical sites that are advancing the understanding and treatment of neuromuscular diseases. So, please join me and welcoming Dr. Statland.

I want to thank a bit 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 spatial weakness, I've asked this individual to purse their lips. You can see they're unable to do that. And as you can imagine, that can have a large impact on your social interaction. In FSHD, in the middle photo, you can see there's loss of the scapular stabilizers that 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 of 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 to the tibialis anterior weakness. He's throwing his leg 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 that are presenting symptom is inability to reach above shoulder height, but another very common presentation in adults is foot drop. And as it has been mentioned earlier, about 20% of individuals will lose the ability to walk or maintain their job by the age of 50. Moving to 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 and 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. And then as the patients think forward about their future, this leads to concerns about the ability to maintain independent in their lives, 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. So 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. So, now we're going to turn to the data from the FORTITUDE clinical trial. Next slide. And we're going to start with measures of motor strength. This is measured by [indiscernible] health dynamometry, which uses a digital force transducer in standardized physicians to really isolate the different muscle function, the muscles chosen for this clinical trial are key muscles [indiscernible] 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 4 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. And 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% to 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 a 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 [indiscernible] game console that came with the 3-dimensional cameras so you could interact with the game, they took that 3-dimensional camera, created a set up where they can then show people videos of standard movement that represents 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, and then in the bottom right of the screen, you can see the reconstruction of those movements, which ultimately creates a volume of base, your reachable workspace and the surface area of that volume is what's captured by the instrument. If we think about the functional impact of our reachable workspace, these are activities like getting dressed, washing your hair, brushing your teeth, to really daily activity. Can we go to the next slide. In the FORTITUDE clinical trial, now you can see improvement 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 are just looking at the dominant arm, on the bottom panel [indiscernible] 1 plus 3 is that space above shoulder height [indiscernible] 1 to 4 or 1 to 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 to 2 years in the natural history. Can we go to the next slide. As it has 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 EU. The goal of this study was to really validate our clinical outcome assessment in a multi-center setting to prepare for clinical trials. The reachable workspace was 1 of the outcomes that was included 237 people entered the study. The visits occurred split over 2 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 intra-class correlation coefficient around 0.95 and then we collected longitudinal data at 3, 12, 18 and 24 months. Can we go out to the next slide. This is comparing the Del-brax treated patients here to a max sample from our RESOLVE study matched by age, gender, a clinical severity score and their baseline reachable workspace performance and here, you can see the natural history cohort is really showing no change or just a slight reduction in the reachable workspace at 3 months and in our Del-brax treated patients we're seeing improvement. Can we go to the next slide. And this equates to both the patient and physician report of benefit in the study. This is usually a global impression of change, is the C you see there or severity is the F, 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 in severity, which has been reflected in an overall quality of life metrics, the EQ 5. 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 4 months and it's worth pointing out the patient, the clinician and the evaluators in the study were all blinded to treatment. Can we go to the next slide. So, in summary, I think we've got a drug that is being targeted. We're showing effective delivery to the muscle with knockdown of the intended target, we're 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 is the field, if we had a gene targeted therapy, 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 I just want to end on one last note, the company did collect quote from the different sites of the patient experience of being in the trial and there was a participant on the [indiscernible] told their investigator that the thing that they noted the most was they were able to purse their lip 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 here more stories like this as the trial continues. I'd like to turn it back over to Sarah for the concluding statements.

Thank you, Dr. Statland. So in terms of what we've seen and what we shared this morning, really, it's an example of how you connect the dots around getting our target, getting a greater than 50% reduction across multiple DUX4 gene panels, seeing the signs of functional improvement, also coupled with the patient [indiscernible] 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 lot more of pipeline now looks like. So in terms of a couple of things to point out here. Firstly, you'll see, obviously, the [indiscernible] study, we're now in Phase III with Del-desiran, and I'm delighted to show that the [indiscernible] study has now been initiated, and you can see on clinical [indiscernible] that are now accruing participants to the static. The [indiscernible] now in the Phase I, II portion, and I'm looking forward to sharing data from the patient cohort later this year. You'll see the program [indiscernible] 45 has moved through IND enabling, and also, I'm delighted to be able to share that [indiscernible] guidance around sharing the very first look on our precision cardiology program. So this will be with our first program, we're planning on sharing additional [indiscernible] in the second part of this year. What you're seeing across the pipeline is what we're leaning in. This is our time to really look at how can we accelerate across all 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 the [indiscernible] study has now been initiated for Del-brax, next [indiscernible] how we accelerate towards approval. First step of that is initiation of the Phase III cohorts. You've heard us talk about 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 a 5-milligram cohort, which we're now anticipating the history 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 just 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 a retail 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 swing, 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.

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-milligram per kilogram to knock down the DUX4 gene signature? And is 4 months expected to be the maximum effect? Or would you expect it to continue past this point?

Yes. So I think it's a great question, just trying to understand. I think looking at the data, and it's really going to be on the biomarker data. So remember, our biopsies are at 4 months. And we don't have any further biopsies. So this time to understand how that's going to 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 our prevention model? What I mean is that we have some siRNA that blocks DUX4, that destroys DUX4, any time that DUX4 is expressed, we're going to 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 Cmax effect, this is really going to be having a durable potent siRNA on board. So looking forward, we think that, again, the dose is going to be somewhere between 2 -- see there going to 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.

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?

This is a moonshot. Honestly, I didn't think that we were going to find a circling biomarker. Thankfully, the researchers didn't listen to me and just kept powering on. So 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 seen effect of Del-brax. So right now, we're filing the IT. What I can tell you is, of course, we know what the gene is. We know where the protein is. We set up a standard curve for using the protein. We know that there's DUX4 binding sites in the promoter enhancer region. We've measured it [indiscernible]. So we know that the data correlate quite nicely. What our job 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 -- 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 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 the 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 who rigorous we are with regards to exploring and making sure that when we have a program, we're looking to understand 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.

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?

It's -- we're leading the field -- maybe honest answer is, I don't know if we're going to see a major dose response to this. We've seen that 2 mgs per kg, really unprecedented decrease in DUX4 regulated genes. When we look at those gene panel, some of the genes are completely knock down as we're looking at that composite score. So looking forward, it will be interesting to see what those data are. And maybe that DUX4 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 high dose, you just need it on board. So it may be a dose scheduled rather than the dose concentration or how much you dose initially. So 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 circling biomarkers that will really help us because we'll be able to understand kind of the schedule, we'll be able to understand the return of kinetics and really be able to dial on that dose. So we're looking forward to those statements.

Dr. Statland, we would 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.

Yes. I mean that's a question we've been grappling with in the field. I think for now many years. I think the things that I can say with certainty, there's consensus around DUX4 being the molecular cause for the disease, clearly shows damage when you look in families with FSHD, there's 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 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 in the measures of strength on cross-sectional data.

Our next couple of questions are from Ritu Baral at 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?

Yes, it's directly related to DUX4. So we know that it's a DUX4 regulated protein. Again, we know that DUX4 [indiscernible] 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 [indiscernible] level. So it's independent. And that's what makes us such a great biomarker, right? It looks at specifically DUX4 regulation, where as a CK issue this general indication of muscle health.

And a follow-up on the dose response. Does the Cohort B data, either functional or biomarker to date suggests you are at or near the top of the dose response curve?

Yes. So based on what we know from our nonclinical data, based on where we dosed our [indiscernible] mouse model, we're probably close to the top of the curve even at 2 mg per kg. We're looking at somewhere around those concentrations in the muscle that are probably at close to EC90 kind of thing. So it will 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 nonhuman primate data. So obviously, across our portfolio of projects, we've dosed well over 100 nonhuman primates. So we have a pretty good sense of how our siRNA to work and what the doses are. So we're probably closing -- even at 2, we're probably pretty close.

Next question is from Yanan Zhu at Wells Fargo. The regulatory strategy, I 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?

So maybe I saw and Steve, I'm sure you'll add as well. So in terms of one of the key [indiscernible] 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 in the muscle biopsies from the circulating biomarker and looking at CK that makes a really compelling package. And I think Dr. Statland's insights around what we know from the disease and all of that understanding helps build that [indiscernible] package. So 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 want to add anything?

Yes, I think just as Sarah said, the consistency of the data and also being able to see 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's just not nice taking multiple biopsies on 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 enough. A follow-up for Dr. Statland. How would you compare Avidity's dataset today with Fulcrum's Phase II data, especially in terms of functional data?

I mean that's a great question. I'm always a little hesitant in compare one to the other to be honest. Because as a field, we're excited about those, and wanting to see treatment come forward. I think that there's differences. The Fulcrum data was over a longer time period. So it was over 48 weeks, and while there was, I think, exciting data looking at sort of muscle quality on MRI, the reachable workspace and the patient reports have changed, 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, but I think it's just too early to tell for sure.

Our next question is from Steve Seedhouse of 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?

Yes. So as you know, CK isn't as elevated as, for instance, CMP patients. So in Duchenne muscular dystrophy, because of the kind of muscle damage that's broadly found, that CK levels are elevated. Whereas in FSHD patients, it's more kind of maybe 5x the upper limit than 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, global improvement in reduction in CK, which indicates that you're having less muscle damage, but it's not as great as what has been observed in Duchenne's 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?

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 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 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 section or snapshot at how these correlations play out over time.

And 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 nondominant arm?

There's quite a few questions there, rolled into one. But I think that, one, I mean, I like strength as an outcome in FSHD. When you talk to patients, so much of what is affecting their lives is due to the loss of that strength. And so, I think it's 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. They're having problems reaching and doing tests with their arms. So I mean, the reachable workspace is a very nice option. It's conceptually nice. It really gets up this idea of what's the functional space you can work in with your arm, and so I do think improvements there would be significant. We're working out now the breakdown of 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 patient-reported impact. I mean ideally, what you really like to see is the concordance across these different levels. In theory, 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.

Our next question is from Geoff Meacham of Bank of America. Again, thank you for the congratulations Geoff. A question on biomarkers. And how do we think these DUX4 related biomarkers can be used in practice as well as from a regulatory perspective?

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 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. So I think we're 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.

And a follow-up. This is for you, Sarah. What does this mean for the broader platform and pipeline?

Thanks Geoff and 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 sales and from a -- what 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 gas? And how can we accelerate some of our earlier programs and really like to move that [indiscernible] as quickly as possible, given both the reproducibility and the consistency that we're seeing now across multiple different diseases that's incredibly exciting.

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?

Yes. I think what I would be hopeful for, this is a fairly early time point as a field and as a researcher, what I'd like to think is this would be the initial sign that we're getting a benefit. I think that we likely could see continued separation. 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 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.

Our next question is from Joey Stringer at Needham. Would you suggest accelerated approval based solely on the biomarker? Or would it be some type of composite end point?

So maybe I'll take that one. So we're targeting accelerated approval directly on biomarker. But remember, we do have more than 1 biomarker. So we have multiple gene panels on the muscle biopsies. We got RNA-C 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. And of course, any accelerated approval submission will also have the clinical response data when 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.

And we have time for one last question and 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 is 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 presubmission meeting. And we're really confident that there are early signs that we're seeing from the study are going to 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. Thank you for the questions. As always, we really enjoy the Q&A and really getting into the data. I would just call out again thanking all the participants in the FORTITUDE study, the investigations 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 lives. With that, I wish you a good morning.