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

Good morning, and thank you for joining us today for Volume 11 of our Investor and Analyst Event Series as we take a first look at our precision cardiology pipeline as well as first look at Avidity's next-generation technology innovations. Before we get started today, I would like to note 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 recent reports filed with the SEC. And now without further delay, I will hand over to our President and CEO, Sarah Boyce.

Thank you, Di. As you know, our vision at Avidity is to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. This morning, we're going to share with you the expansion of that vision to now encompass precision cardiology. Moving to the next slide, please. So today, we're going to share with you a couple of things. Firstly, the strategy that we have been building in the precision cardiology space where once again we're looking to lead a field. Utilizing our AOC technology, we are able to tackle and target the root cause of genetic cardiac disease. We're going to present to you data from our first 2 wholly-owned precision cardiology programs where once again you're going to see us tackling underlying genetic -- directly underlying genetic causes of disease and doing something that has never been done before. We'll also share with you a first look at the innovations in our next-generation technology. So in terms of moving forward to -- next slide, please -- in terms of moving forward and looking beyond our late-stage skeletal muscle pipeline that we all know well. So we're going to talk about 2 drugs. First one is AOC 1086 to treat PLN cardiomyopathy. And then the second is AOC 1072 to treat PRKAG2 syndrome. We'll also, as you know, have several other genetic targets that we're working on, and we'll share those with you in due course. But today, we're focusing on 1086 and 1072. We'll share with you data from our preclinical work for both of these programs. And what we're going to show you is how we're ideally suited with our technology to address the root cause of genetic heart diseases. What you'll see is consistent and robust siRNA delivery heart muscle. You'll see potential knockdown of our target of approximately 80% in cardiac-specific genes as well as a consistent favorable tolerability profile as observed in non-human primates. As a reminder, this is the same antibody and the same linker as we use in our skeletal muscle programs. The siRNAs for both 1086 and 1072 do benefit from some of our next-generation innovations around the RNA technology. With that focus with our technology, we're able to get greater durability, increased potency and hopefully ultimately increase patient convenience, enabling things like subcutaneous dosing. Joining me today on the call is Mike Flanagan, our Chief Scientific and Technical Officer; Steve Hughes, our Chief Medical Officer; a new member of our team for you, Georgios Karamanlidis, who is our Cardiology Team Leader; and then Mike Flanagan -- Mike MacLean, sorry, too many Mikes. Mike MacLean, our Chief Financial and Chief Business Officer, will be joining us for Q&A. Without further ado, I'm going to pass over to Mike Flanagan. Mike, over to you.

Thank you, Sarah, and good morning, everyone. Today, we're proud to present 2 areas of our research engine: precision cardiology and our next-generation innovations. Next slide, Di. Heart disease is the #1 cause of death globally and in the U.S. In the U.S., there's more than 30 million adults living with some form of heart disease. Many of you on this call have family members who are limited in their daily lives due to some form of heart disease. I know it has touched my family. Today, we treat most heart patients with the same approach and the same medicines, a one-size-fits most approach. But now we're beginning to see a one side -- but now we're beginning to see this one-size-fits most approach change from general heart care to precision cardiology care where the underlying cause of heart disease is due to a specific disease-causing genetic mutation that can be identified and precisely treated. And this is where our AOC technology is perfectly paired: to deliver to the heart and to specifically target the underlying genetic cause of heart disease. Now heart disease is a broad term that encompasses millions of people. And you might be thinking, Avidity is a rare disease company. How are they going to do this? How are they going to be able to tackle this unmet medical need? Our focus is on cardiomyopathies. Next slide. Our focus is on cardiomyopathies that have a strong genetic drivers. These cardiomyopathies strike people in the prime of their lives and are often undetected until the young person has dizziness, fainting spells, racing of the heart or arrhythmias, extreme tiredness. Currently, these cardiomyopathies are classified based on descriptions of the heart. First, you have hypertrophic cardiomyopathy, or HCM, where there's a thickening and stiffening of the heart preventing it from effectively pumping blood. You have arrhythmogenic cardiomyopathies, or ACM, identified by rhythm changes along with scarring and replacement of the heart muscle with fat. You also have dilated cardiomyopathies, or DCM, where the left ventricle becomes thin and enlarge leading to a reduced ability to squeeze blood to the rest of your body. We believe that our AOC technology is uniquely positioned to address these serious cardiomyopathies that have limited treatment options. And this is because we can effectively deliver siRNAs to the heart and show robust target inhibition. We have a favorable platform safety and tolerability, as you've seen in our 3 ongoing clinical trials. We can target the underlying genetic cause of disease. And there's a defined path to the clinic with known biomarkers of disease. Our ability to deliver siRNAs to the heart and specifically target the underlying cause of disease has a potential to expand to broader genetic-driven cardiac disorders. And now it's my pleasure to introduce Georgios Karamanlidis, who is leading our cardio effort. Georgios joined Avidity in 2021 with over a decade of drug discovery and development experience from both Amgen and Pfizer. Georgios has led drug discovery projects using small molecules, antibodies, oligonucleotide conjugates in both cardiac and metabolic diseases. He holds a PhD in adipocyte biology and energy metabolism. Georgios has conducted postdoctoral research at Harvard Medical School and the University of Washington. Over to you, Georgios.

Thank you, Mike, and good morning from me as well. Today, we will share some exciting data from our lead development candidates in precision cardiology. Next slide. So those are the AOC 1086 and AOC 1072, as Sarah mentioned earlier, which are targeted RNA therapeutics. AOC 1086 is designed to address PLN cardiomyopathy by targeting the phospholamban gene also abbreviated as PLN here. AOC 1072 is designed to address PRKAG2 syndrome, a genetic disorder caused by mutations on the PRKAG2 gene. Both candidates leverage our AOC platform and the data in the subsequent slides intend to demonstrate siRNA delivery to the heart muscle, target engagement in the heart, and that the treatment was well tolerated after a single dose in non-human primates. By the way, all the data shown today are from experiments in non-human primates only. Now let's start with PLN cardiomyopathy. This is a progressive autosomal dominant cardiac disease, meaning that having a single copy of the disease-causing variant is enough to trigger the condition. Patients with this condition develop dilated and arrhythmogenic cardiomyopathy, which can lead to sudden cardiac arrest and often requires a heart transplant at a young age, making early intervention crucial. As the name implies, PLN cardiomyopathy is linked to mutations in the PLN gene with the most common disease variant being the R14 condition, which causes a buildup of toxic protein aggregates that trigger cardiomyocyte death and accelerate disease progression. Our lead candidate here, AOC 1086, is a precision RNA therapeutic that targets and degrades the PLN mRNA, which is the root cause of the disease in this case. While the exact prevalence is unknown, we estimate there are currently between 2,000 and 4,000 patients in the U.S. and Canada. It is also important to highlight here that there are no FDA-approved disease-modifying therapies for PLN cardiomyopathy. In this slide, we illustrate the mechanism of PLN cardiomyopathy and the proposed therapy. Patients with R14 deletion mutation are at a high risk of developing toxic protein aggregates, which accumulate in the myocardium as shown in the green in the image here. And these aggregates disrupt normal cellular function, leading to cardiomyocyte death. And over time, the loss of heart cells contributes to cardiac arrhythmias and progression of heart failure. In the bottom row, we show the therapeutic mechanism of AOC 1086. This candidate delivers siRNA to the heart, targeting and degrading PLN mRNA, which aims to stop the production of the defective PLN protein. This can prevent the buildup of these toxic protein aggregates in the myocardium, which should slow or prevent disease progression. In the next few slides, we'll share data demonstrating that AOC 1086 delivers siRNA to the heart and reduces the PLN expression. So the bar graph here shows a substantial delivery of siRNA to the heart tissue of non-human primates using our lead candidate AOC 1086. Note that this is 28 days after a single dose at 3 mgs per kilogram. This data confirmed delivery and sustained siRNA presence within the heart tissue in non-human primates. The downstream effect of the siRNA delivery to the heart is shown in this slide, which demonstrates the efficacy of AOC 1086 on reducing PLN expression. The graph on the left shows an impressive reduction of approximately 80% in the PLN mRNA levels compared to control after a single dose with AOC 1086. On the right, the image illustrates the reduction in PLN protein. PLN exists as both pentamers and monomers and a decrease in both of these forms aligns well with mRNA reduction. In summary, AOC 1086 demonstrates a robust reduction of PLN expression at both mRNA and protein levels in non-human primate hearts. To assess the potential risk of arrhythmia or other cardiac issues in non-human primates treated with AOC 1086, we've conducted ECGs to monitor 2 critical cardiac conduction parameters, QTc and PR interval. As you can see in the graph shown in the slide, there are no changes in these ECG parameters in non-human primates 28 days after a single dose at 3 mgs per kilogram. These initial observations indicate a favorable tolerability profile for our molecule. Taken together, AOC 1086 showed substantial siRNA delivery in the heart, resulting in about 80% target mRNA reduction and had no negative effects on key ECG parameters. These findings are encouraging for advancing AOC 1086 into IND-enabling studies for developing a potentially disease-modifying therapy for PLN cardiomyopathy. We will now switch gears to discuss our program targeting PRKAG2. PRKAG2 syndrome is also progressive autosomal dominant cardiac disease that is caused by mutations in the PRKAG2 gene. These mutations lead to increased AMPK activity, resulting in the accumulation of glycogen in the heart, which is one of the key features and drivers of the disease. Patients with PRKAG2 syndrome are at the high risk of developing hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome that can lead to arrhythmia or sudden cardiac death. These patients are also at high risk of developing heart failure, which often requires heart transplant, stressing the need for early intervention. Our lead candidate, AOC 1072, is a precision RNA therapeutic designed to target and degrade PRKAG2 mRNA and stop the production of the defective PRKAG2 protein. While the exact patient population is unknown, we estimate there are between 1,000 and 2,000 patients in the U.S. and Canada. The development of AOC 1072 has a potential to offer a first-of-its-kind therapy for a disease that currently has very limited treatment option and does not respond well to standard therapies. As shown before as well, this slide illustrates the mechanism of PRKAG2 syndrome and the proposed therapy. Mutations in the PRKAG2 lead to abnormally high AMPK activity, resulting in excessive glycogen storage in cardiac tissue. Over time, this glycogen accumulation disrupts normal electrical conduction in the heart, leading to progressive damage of the heart muscle. The bottom row shows the therapeutic mechanism of AOC 1072, which targets and degrades PRKAG2 mRNA, preventing AMPK overactivation. By restoring normal AMPK activity, we anticipate a significant reduction in cardiac glycogen accumulation. Reducing cardiac glycogen is expected to slow or prevent disease progression, offering a disease-modifying therapy for patients suffering from PRKAG2 syndrome. We started before by demonstrating delivery. This graph in this slide shows that treatment with our candidate AOC 1072 achieved substantial delivery of siRNA to heart tissue in non-human primates, and this is again 28 days after a single dose at 3 mgs per kilogram. This data demonstrates both effective delivery and sustained siRNA presence within the heart tissue with this AOC as well. More importantly, the data in this slide shows the efficacy of AOC 1072 on reducing PRKAG2 expression in non-human primate hearts. The graph on the left shows that a single dose of our candidate at 3 mgs per kilogram led to a significant reduction in PRKAG2 mRNA by about 80% compared to control group, and this is again 28 days post treatment. On the right, the protein analysis confirms a substantial reduction in PRKNG2 protein in heart tissue from non-human primates treated with our lead molecule. The data here suggests that the tissue siRNA concentrations delivered with AOC 1072 were able to achieve significant target mRNA reduction and protein by about 80%. As also shown with the previous candidate to assess the potential risk of arrhythmias or other cardiac issues in non-human primates treated with our lead candidate, we conducted ECGs to monitor 2 critical cardiac conduction parameters: QTc and PR intervals. The graph here shows no changes on ECG parameters in non-human primates 28 days after a single dose at 3 mgs per kilogram, indicating a favorable profile, at least in this initial study for AOC 1072 as well. As with the previous candidate, the strong target knockdown and the absence of negative effects on ECG parameters increased our confidence in advancing AOC 1072 into IND-enabling studies for developing a potentially disease-modifying therapy for PRKAG2 syndrome. In summary, today we have presented compelling data demonstrating that both of our candidates, AOC 1086 and AOC 1072, have achieved several key milestones such as successful drug delivery, effective target engagement and that all or both of them were well tolerated in non-human primates. Both clinical candidates represent novel precision therapeutic strategies in the cardiomyopathy disease landscape. And with that, I will now hand it back to Mike.

All right. Thank you, Georgios. I hope you can see how our AOC technology and our wholly owned PLN and PRKAG2 cardio targets are perfectly matched to address life-threatening cardiomyopathies that have limited therapeutic options. And now what I'd like to do is just provide a small glimpse of our research engine that continuously innovates on our industry-leading AOC technology. And like Sarah said, some of these innovations have already been integrated into our cardiology -- our precision cardiology programs. So this table represents over a decade of deep insights, determination and dedication by our research group. And we're proud to be the first to show AOC-directed delivery to muscle. That's shown on the left-hand panel, our leading RNA delivery technology currently. We've defined a whole new therapeutic field, and now we're going into cardiomyopathies. Despite this unprecedented siRNA and PMO delivery that we've seen in the clinic, we continue to improve on delivery, whether it's antibody engineering or completely new delivery methods like cyclic peptides or lipids. In addition, we continue to innovate on siRNA chemistries through novel modifications and conjugations. These technology innovations lead to improved delivery, activity and increased durability that allows for new ways to administer our AOC technology, including subQ delivery. On the next slide, we'll illustrate how our AOC technology is continuously evolving. Like all innovative companies, we've never stopped innovating. The left-hand panel shows you our current industry-leading AOC technology. The middle panel illustrates our tomorrow innovations where we've kept the anti-transferrin antibody the same -- the same linker. And what we've done is made novel modifications to the siRNA. Now these tomorrow innovations are actually today because we've included them into PLN and PRKAG2. The right-hand panel shows our future AOC innovations that combine both siRNA modifications and antibody engineering. And you'll see that they demonstrate -- this combination demonstrates a 30-fold improvement in delivery in non-human primates. So in the next few slides, we'll show you the modifications that we made on the left-hand panel and the accompanying data. So here again, we show those modifications on the left-hand panel and then with that, where we've modified the siRNA shown in green. On the right-hand panel, we see a fourfold improvement in siRNA tissue concentrations 28 days after dosing in mice. You can see that this is a 0.75 mgs per kg dose that we've delivered in mice. Again, these siRNA modifications like these that improve delivery stability have now been incorporated into our precision cardiology programs. And of course, with the fourfold increase in muscle tissue concentrations, we would expect to see increased durability, and that's shown next. Here, we show sustained target inhibition for 3 months in mice that has the potential for convenient, less frequent dosing in people living with rare genetic diseases. The left-hand panel shows the siRNA modification again. The right-hand panel shows the sustained target inhibition. On the Y-axis is a percent target or mRNA expression. And you can see at a dose, again, of less than 1 mg per kg, we see nearly a 75% target inhibition. And on the Y-axis shows after a single dose of our AOC technology shown in blue and our next generation shown in green. Again, both show -- well, our new next-generation target again shows 75% knockdown all the way out to 3 months, shows continuous sustained target inhibition. Not only have we improved our siRNA, but we've also discovered antibody innovations that enhance delivery. Combining both the siRNA modifications shown in green and the antibody modifications also shown in green, we see a remarkable 30-fold improvement in delivery in non-human primates. So we've combined both modifications together, that is our siRNA and our anti-transferrin antibody innovations, into one next-generation AOC. The right-hand panel shows the improved delivery in non-human primates. The X-axis shows fold improvement -- or the Y-axis shows fold improvement. The X-axis shows our current AOC shown in blue that's shown unprecedented delivery in the clinic and our next-generation AOC shown in green that now shows a 30-fold improvement of delivery. We anticipate that this dramatic improvement in delivery will lead to increased durability and open up new opportunities for administering our AOC technologies. These studies are ongoing. So in summary, we've provided just a small glimpse of our research engine that continues to innovate on our industry-leading AOC technology. We believe that these -- that our innovations will lead to improved delivery, durability and patient convenience, and improve lives of people living with rare disease. And now I'll hand it back to Sarah for closing remarks.

Thank you, Mike. What you see now is an updated pipeline where we have now included the start of our precision cardiology franchise with our first 2 programs, 1086 and 1070, that are now in the pre-IND phase. This is, of course, in addition to our late-stage skeletal muscle pipeline as well as our other research programs in skeletal muscle. In terms of closing out for today, if we move to the next slide please, we'll close out on our vision. Our vision as a company is to profoundly improve people's lives by revolutionizing the delivery of RNA therapeutics. What you've seen today is the next part of that journey now moving to precision cardiology as well as the advancements that we have made in our next-generation technology to continue to innovate and lead this field. I would now ask my colleagues to join me back on screen, and we'll open for question and answers, and that will be facilitated by Mike MacLean. Mike, over to you.

Great job, guys. Good morning. We have a lot of questions that have been coming in as you guys have been talking. There is one that several questions seem to be aimed toward. This one is for you, Sarah, which is, why go into precision cardiology now? And why start with these 2 programs?

Yes. Great question. So in terms of really precision cardiology is a very natural evolution from our skeletal muscle work. Obviously, the heart is a muscle. And we have known from our skeletal muscle programs and actually our early research work that we can deliver extremely well to the heart. So this is really taking the advancements and the discoveries we made in the skeletal muscle space and now applying them to the heart. From an aspect, it's also a very efficient way to do it because we're using the same antibody and we're using the same linker. From an aspect then also as to why the heart and when we looked at being consistent with our vision around directing our technology to where we can make a profound impact in people's lives, precision cardiology is a whole new space. There's a rich field of targets that have previously been unaddressable. That's where we go with our technology around being able to really make an impact on people's lives by ultimately developing and commercializing drugs that directly target the underlying cause of the disease. And by doing that, we can open up whole new spaces. In terms of starting with these 2 targets, we have many targets we're working on. We also have a collaboration with BMS, where we have 5 targets with BMS. And then we have our wholly-owned programs, of which there are 5 today. And what we shared with you is the first 2. And both PRKAG2 and PLN were very natural places to take our technology where we understand the root cause of the disease well. There's very good data from studying natural history and then also where we can develop really good sequences to be able to target these diseases.

Thank you. And there's a question that came from Eric Schmidt and Josh Schimmer from Cantor that's along these lines too, a little bit more specific, Sarah, which is PLN and PRKAG2 seem like reasonable opportunities, yet Avidity's programs addressing skeletal muscles surpass populations that are 10x larger in size. How do you think about allocating resources to cardiomyopathy versus next-gen skeletal programs?

Yes. Great question. Thank you, Eric and Josh. As always, super thoughtful. So in terms of one of the aspects as we look to move into space, you see from skeletal muscle, there's an aspect of an enormous amount of efficiency when you have more than one program in space. So that's the same for precision cardiology where we can get real efficiency within our research organization, ultimately into our development organization and then also into our commercial organization. So there's an aspect of building one program on top of the other, which is also around the driver to move into the precision cardiology space. Maybe if I have Mike -- I think it would be interesting to hear from Mike Flanagan as to talk about how we organize our research organization around the 3 pillars that we have there. And then from there, we can come back to me if needed. So Mike?

Yes. So just to kind of outline our research strategy, really we have 3 pillars like Sarah said. First pillar is to accelerate our rare muscle disease. So we're hyper focused on accelerating that muscle programs that is DM1, FSHD and DMD. And I think you've seen throughout the year how we've used our innovation and our research capabilities internally, not only to look at RNA splicing, but also to identify a new circulating biomarker for FSHD and most recently, looking at dystrophin production in our DMD program. So you can see that our research capabilities are quite great for accelerating our pipeline. The next part is going beyond skeletal muscle. And what you're seeing today is that effort to go beyond skeletal muscle in precision cardiology. And it fits really well with our strategy, our overall strategy of being able to treat the underlying genetic cause of disease in rare diseases. So in cardiology, there are a number of gain-of-function targets in cardiology. We've started with PRKAG2 and PLN because we think those are really important underlying mechanisms in cardiology. We understand the human genetics. It will provide a really -- a great opportunity for proving our technology in precision cardiology. And then as you know, we have a number of additional targets that will expand those capabilities. In addition, like Sarah said, we have from BMS. So those are the 2 of our pillars, one being accelerate our internal skeletal muscle programs. 2 is to go beyond skeletal muscle, and now you've seen the precision cardiology. And our third pillar of our research strategy is to innovate, to continuously innovate. And you're starting to see some of those innovations, just a small glimpse of what we can do also to innovate to continue to improve our industry-leading AOC technology. So that's how kind of precision cardiology fits in the overall research strategy.

And maybe just to add to round out I think that the final point of the question, we will also be looking to apply the innovations that we have made in delivery, which I mean a 30-fold improvement in delivery is quite significant. And we will be looking to apply those to next-generation drugs for those that we already have in the clinic.

Okay. Thank you, Sarah. Thank you, Mike. The next couple of questions are coming from Joe Schwartz from Leerink. Steve, the first one is to you, a little bit more specific. Is there any collateral damage such as physical or electrical remodeling in either of these indications, which could complicate first order therapeutic interventions focused on removing toxic substrates if patients aren't treated early enough?

Thanks. It's a great question. So in both of these indications, there's likely some cardiac remodeling that's going on in response to the underlying stress, perhaps more so in the dilated cardiomyopathy where remodeling occurs as part of the dilatation process. In terms of that being an impairment to improvement in the disease, of course there are no treatments for these diseases. So we're really pioneering new ground here. But certainly, in other indications or other causes of heart damage such as in ischemic heart damage where some remodeling does occur to the heart, some reversibility of that is possible with the right treatment. So we're certainly looking by reducing the toxic RNAs in both of these diseases to profoundly impact both the symptoms that the patient is having at this point in time and also the cause of disease over time with our ultimate goal being reversal of the underlying cause of disease.

Thank you, Steve. The next question from Joe is about next-gen technology. So Mike, I'm going to give this one to you. A 30-fold improvement in delivery sounds very impressive for your next-generation technology. Can you talk about the modifications which could enable this and estimate when development candidates incorporating these attributes might be ready for study in humans?

Yes. So what I can tell you in general terms is that we've made antibody modifications to the CDR, so looking at different affinity levels. We've made antibody engineering to different conjugation handles and a number of different improvements for the antibody. So just like any great antibody engineering group, we've really looked at all the different aspects of it. First, we have a crystal structure of our antibody bound to transferrin receptor. So we know the contacts. That's also allowed us to look at cyclic peptides and other types of modifications that will continue to aid our delivery and go beyond AOCs. As for the siRNA, we've made a number of different modifications from not only base modifications as well as backbone modifications, applying handles that improve both delivery as well as durability, so once you get in the cell to improve the stability of our siRNAs. So there's no one modification that's the aha, but it's all these different small changes that we make that altogether add up to a really great next-generation AOC. So those are kind of the modifications that I can tell you. Is there a second part to it, Mike, of the question?

The timing of being ready for study in humans.

Yes. So you can see that a number of our modifications have already entered into our siRNA modifications for precision cardiology. Those programs we expect to enter the clinic in '26 and '27 -- 2026 and 2027. So they're really not that far away from entering in the clinic.

Thank you, Mike. And last question from Joe is, I think, Sarah, maybe you can talk to this one. Can you talk about how you arrive at your estimates for the prevalent patient populations?

Yes, it's a good question. And it's always a challenge actually when you're in a new space where you're looking to target underlying causes of genetic diseases, and these are things that have not been done before. So the way we look at our prevalence estimates is we typically start conservative. We look at what is the best available data in the literature, and we use that. So I think they very well be underestimated at this point. We just don't know yet. One of the things that I would say, and this is an element where precision cardiology really is a whole new space. And it's the aspect that people are not routinely genetically tested in the cardiologist's office. Both PRKAG2 and PLN do sit on the standard genetic testing for cardiomyopathies, but most people today are not tested outside of your tertiary referral centers. So that's where -- and it's part of the reason why we're talking about these programs now because we're getting some runway and looking to get momentum as we go into clinic in terms of starting to get more and more people tested for the potential that they have an underlying genetic cause of the cardiomyopathy. So in terms of that work, there's work to do. And as we understand that -- and I think, Joe, as you know as well, we go super, super deep when we go into a space. And as we understand the epidemiology more and more, obviously we'll provide more information on that. But it's one of these areas when you're opening up whole new fields, which is what we do, that we're in spaces where there have been previously no treatments. So there was no need to test for an underlying cause of a genetic cardiomyopathy because you can't target it. That changes now.

Okay. A couple of questions from Ritu at Cowen. I think this first one comes to you and maybe Georgios or Mike. Is the PLN pentamer and monomer more toxic? Is there a PLN threshold knockdown required as suggested by preclinical biomarkers, protein or mRNA?

Yes. So maybe I'll just -- I'll start it and then hand it over to Georgios, who's the true expert. So maybe we'll start with the first one. What I can say is that what we've learned from neuromuscular targets like DM1 that gain of function targets really, it doesn't take very much change or inhibition of that target. For instance, PLN in this case, for instance, the R14del. If you just change in small amounts, you should be able to see an effect, at least that's what we've seen for gain of function. Now for PLN specifically, being that we're still the first ones into the -- will be the first ones into the clinic, the answer is that we don't know for sure. But given our experience in DM1, we think that small changes will have a dramatic effect. Now I'll turn it over to Georgios, who can talk about the monomers, pentamers. Those are normally found. You can see that in the non-human primates. That's a normal way that PLN exists. But Georgios, maybe you can talk more about that.

Yes. Thank you, Mike. So the monomer and the pentamer are natural stage for phospholamban. So basically, it can exist in one or the other. When we talk about protein aggregates, that's beyond the pentamer. So those are multiple components. And actually, they're even not localized in the right place and it's localized and we see those kind of aggregates [indiscernible] across cardiomyopathy. So the monomer and pentamer, in short, they are not the toxic form.

Thank you, guys. Next question from Ritu. Could EEG findings improvement in QT or PR be a potential approval endpoint? Steve?

Yes, that's a very good question. So what we've looked at in terms of the QTc and the PR interval is from the safety side where we saw no impact at all in the monkeys across both of these targets, which is reassuring. Improvements in QT and PR could potentially be approval endpoints. The extent in these diseases to which patients have prolonged QTc, I'm not sure that's been well mapped out at this point in time. So more tractable endpoints for us are going to be some of the novel endpoints potentially that we've seen already being used such as left ventricular mass, oxygen utility, et cetera.

Okay. Thank you, Steve. And now Yanan from Wells Fargo has some questions. And Steve, I'm going to stay with you on this one. On the safety side, what is the evidence that the wild-type genes are dispensable?

So there are a few lines of evidence there. So in both of these diseases, there are animal models where there's knockouts and those don't have a phenotype. We've also knocked down these proteins, the RNA of these proteins, which obviously leads to knockdown of the protein by quite some way, as you saw; 80% in mouse models of disease and in healthy mice over more than 5 months in duration, and we haven't seen any phenotype in the heart that's been associated with that. So we really don't have any concerns about knocking down these 2 proteins. And we have to remember these gain-of-function mutations with a toxic RNA. So the goal here is to dramatically reduce the RNA and thereby dramatically improve the phenotype of the disease.

Thank you, Steve. Mike, the next question is, is there a human or animal genetic evidence?

For the diseases?

Yes.

So the human genetics is really strong. Patients that have these mutations especially for PRKAG2, which is oftentimes an [ R3 or 2 to Q ], those mutations are 90% penetrant. So those -- it's very clear that these mutations are gain-of-function mutations for PRKAG2 and likewise for PLN. So you see that these are gain of function. So the human genetics is super strong. And that's one of the reasons that we picked these 2 targets initially, one there -- the human genetics is strong; 2, the gain of function. So those are really the reason that we did that. In addition, there's animal models that try as best as animal models can do to recapitulate the human disease. And some of these animal models do have some of the characteristics of glycogen increases, especially for PRKAG2. But maybe, Georgios, if you want to elaborate on some of the animal models?

Yes. So starting with PRKAG2, there are several animal models that overexpress this variant causes the disease that is limiting to human condition. And there's also evidence that you can reverse this process if you genetically delete those genes or silence those genes. The same for PLN. Expression of the disease variant was shown to recapitulate features of the human disease. And also there's some evidence as well that silence the gene in reverse or prevent the disease at least in preclinical models.

Okay. Thank you. Now I'm going to move on to Steve Seedhouse from Ray J. I think I can answer this question. Just to clarify, both are wholly-owned programs and not part of the BMS collaboration? You are absolutely correct, Steve. These are wholly-owned programs. We have 5 targets of our own, and we have this collaboration with BMS where there are 5 targets as well, but they do not overlap. Next question. So Steve also has a question, Steve, to you. Any additional comments you can provide on the path to clinical approval? Clinic -- I'm sorry, clinic/approval?

Yes, sure. So as we said already, both of these are toxic gain-of-function diseases. We've got a lot of experience, as you know, in tackling these toxic gain-of-function diseases from the neuromuscular side. And so we're going to apply those learnings to the development path on the cardiac side. And so we'll look for very early biomarkers that we can exploit to get clinical proof of concept. We'll discuss with the regulators, specifically the FDA pathways for potential accelerated approval, and we'll be looking for novel endpoints for full approval where we don't need large numbers of patients. So really, the neuromuscular pathways and learnings that we have, we can exploit to inform our cardiac about.

Yes. Just to add to Steve's point, again, I think this is an area where we have a well-exercised and developing muscle, excuse the pun, in terms of going into new therapeutic areas, developing the biomarkers, then also working with the regulators to negotiate novel approval pathways. And we'll be looking to apply those learnings and apply them to precision cardiac.

Great. Thank you. The next question comes from Gena Wang of Barclays. And this is actually a question that has some common themes as well. And I think this might be Mike and Steve. For PLN and PRKAG2, healthy NHP data showed 80% knockdown. What is the range of knockdown within the therapeutic window? And what is the optimal knockdown level you're looking for?

Yes. So like we had indicated earlier is that from our experience in gain-of-function DM1, again, gain of function mutations in humans, you don't need very much of a change on either toxic protein or toxic RNA to see pretty dramatic effects in patients. And the body really reaches a new homeostasis when you start decreasing these toxic proteins. So while we don't know exactly yet since we'll be the first ones in the clinic to really understand how this disease manifests itself, our expectations is that we're not going to need 98% knockdown. We're just going to need to decrease -- turn it down some and then the body will accommodate that change and re-equilibrate with hope that, that will be sufficient to have to allow stopping of progression would be great and then a reversal of disease would be amazing. But again, we don't think it's going to require very much change in these gain-of-function proteins. But I don't know, Steve, your thoughts on this.

Yes. So as you said, Mike, small changes in these diseases can lead to large effects, and that really talks to where the therapeutic window starts. As we said already in terms of the top end of the therapeutic window for knockdown, we're not anticipating any problems at all from knocking down either of these 2 targets from multiple lines of evidence. So we anticipate being able to go high if we need to. But as Mike said, probably you don't need to have a high degrees of knockdown here to have a very large impact on the disease.

And I think -- and also, you can see from our preclinical data in non-human primates that Georgios showed, a single dose at a relatively low dose gives us greater than 80% knockdown of the target of the mRNA, and that translates into the targets from both PLN and PRKAG2. So you can see we have really robust and potent siRNAs that are highly durable for over a month. So we believe that we're -- we have great siRNAs. We have great delivery. We have really good durability, and we think we have an opportunity to have an effect in patients.

Great. Thank you, guys. Sarah, next question is from Jeremiah Lorentz at Bank of America. Will your next-generation assets be for the indications you are currently looking at: DM1, FSHD, DMD, cardio, et cetera? What is the current time line for these next-generation assets?

Yes. I would say in terms of for the next-generation technology that you saw where we have a 30-fold improvement in delivery, obviously we were sharing non-human primate data. So that gives you a sense that we're pretty far along with regards to bringing that next-generation technology into the clinic. So it's something that you can expect to see in the next probably 2 to 3 years.

Great. And along the same lines, I think maybe Sarah and Mike, you can address this. And this is from Corinne at Goldman Sachs. How do you anticipate leveraging the next-generation AOCs? Are there indications that now become more attractive, improve upon first-generation approaches within key indications where you are already active?

Yes. So maybe I'll start and then Sarah maybe you can think about how we're managing our first generation. So I think you can see from our AOC technology improvements that it really opens up opportunity to deliver first to have really good potency, great durability and patient convenience. So you can imagine in the future where we could dose less frequently that we have an opportunity to do subcutaneous formulations that allow home delivery, delivery within your home subQ delivery. So we think that these opportunities and then these new improvements will not only allow us to have dosing that we currently have, but extend it -- but also have the convenience for patients for subQ dosing in the future. So that's how we think about some of these for patient convenience. But I think more importantly is that these technologies, again, have tremendous activity, potency, durability and improved delivery. And as we know for this opening up these fields first in skeletal muscle and now on precision cardiology, it's all about delivery. It's delivery, delivery, delivery. We've seen this for DM1. We've seen it for FSHD, DMD with PMOs we've seen it, and now we're seeing it for cardiology. And with that improved delivery, we have lots of opportunities for patient convenience.

And just to add, I would say, clearly we'll be looking to apply these innovations to our research pipeline, both for where we have undisclosed targets as well as also working on next-generation drugs for our programs that are already in the clinic.

Okay. Keeping with the next-gen theme, a question from Gena Wang at Barclays. Regarding next-gen, very impressive. Could you -- and this is a common question among what we're getting. Could you elaborate what kind of modifications you have made to both the antibody and siRNA? And then I'm going to follow up with, could this result in subQ administration?

So firstly, for the latter part, we would say yes, in relation to subQ for those modifications. Hey, there's some secret sauce going on here. So we may not necessarily be that specific. But maybe, Mike, if you want to sort of talk about some of that without, obviously…

Without disclosing everything?

Exactly.

Yes. It's great that people are excited about these, and we're excited about them, just the ability to deliver so much more with the modifications that we're making. What I can tell you without telling you too much is that we've made changes across the board with the antibody. Like I had indicated, we have crystal structures of our antibody bound to the transferrin receptor. We know where and the hydrogen bonding, how that works. So we have a very good understanding of how to affect affinity at Avidity. So we're quite aware of that. So that's part of it. Other parts are improving conjugations. So you can make site-directed immunogenesis and improve conjugation that then leads to increased durability. That's been seen in antibody drug conjugates also. So we've now discovered some of the same similar types of modifications for AOCs. As for the siRNA, we've been working on siRNA modifications for well over a decade now. And we have a really good understanding of what's required on our siRNAs. And you've seen in our precision cardiology, we've made changes from our first generation that improves delivery to the heart. So those siRNA modifications are base changes, our backbone modifications, the ability to conjugate different moieties to the siRNA that allows it to traffic through the cell and allows this improved delivery and durability and potency. So what I can say is that we haven't left any part of our AOC technology untouched, that we continue to innovate on all the different aspects of it and really to take it to the next level. You've seen our current AOC technology. It's amazing, right? We're the first ones to demonstrate delivery to muscle. That was in late 2021. And now what you're seeing now is that we've gone beyond skeletal muscle to heart. And it's these innovations that continuously progress our technology and our ability to treat patients with rare diseases.

Thank you, Sarah. Thank you, Mike. I'm going to ask the final question. Thank you for all the great questions. And it comes from Steve at Raymond James. Can you comment on the distribution to the heart for 1072 and 1086 compared to the first-gen programs like del-desiran?

Yes. So when we -- I can answer it. I guess what I can tell you is that the changes that we made have really driven cardio delivery. So we still see great delivery to muscle, and I think that's important because these mutations are in skeletal muscle. But at the same time, we've driven delivery to the heart and some of the modifications we've done improve that delivery to heart. Now the first-generation AOCs, you've seen that, is that delivers well to muscle. We've shown delivery to the heart there. But now with these new modifications, I hesitate to say how much because there are different siRNAs, there are a little bit of differences. But what I can say is that we're really confident in our delivery. You've seen that where we have around, what is it, 90 nanomolar -- what was the 90 nanomolar, right? So you're seeing delivery in non-human primates after 28 days of 90 nanomolars in the heart. So that's a lot. And it's due to some of the changes that we've made. So I hope that answers your question, Steve.

Thank you, Mike, and thank you to the team. And with that, I'm going to turn it back over to Sarah.

All right. Thanks so much, Mike. In closing out, I think one of the things that I hope that you've seen today is both the innovation that we're driving here at Avidity, the commitment to revolutionize the RNA space, the advances that we've made in our technology and more importantly, also opening up a whole new space for people with cardiomyopathies where there is an underlying genetic cause where there previously hasn't been any mechanism to deliver an siRNA to the heart. And this is where, once again, we're leading a whole new field. So thanks very much for joining us this morning, and we'll talk soon. Take care.