Hello everyone. I'm Kath Gallagher, Senior Vice President of Communications and Investor Relations at Avidity. Thank you so much for joining us today. Before we get started, we want to remind everyone that we will be making forward-looking statements based on the current expectations that are subject to and covered by the safe harbor protections provided under the Private Securities Litigation Reform Act of 1995, based on current expectations, including statements about the initiation of clinical trials. These forward-looking statements are not a guarantee of performance, and Avidity's actual results may differ materially from these forward-looking statements as a result of various important factors, including the risks and uncertainties related to the company's business. As discussed in the Risk Factor sections of Avidity's SEC filings, including our recently filed 10-Q and 10-K. These statements are time sensitive and represent Avidity's views as of today's date. We disclaim any obligation to update these forward-looking statements following this presentation, except as required by law. This is the first in a series of investor and analyst events that we plan to hold this year. Welcome to volume one, where we'll be focusing on engineering AOCs. There will be a Q&A session at the end of the call today. Please feel free to submit questions to us at any time throughout the presentation by entering your question in the white box under the video screen. I'm going to hand the call over to Sarah Boyce, Avidity's President and CEO. Thank you so much, Kath. Good morning, afternoon to everyone who's joining us on this call, which as Kath said, is the first of a series of webcasts focusing on our whole journey as a company. One of the things just to remind everyone, our vision and our goal is to be able to profoundly impact people's lives by what we believe is going to be a revolution in the delivery of RNA therapeutics through our technology, the Antibody Oligonucleotide Conjugates. One aspect in terms of looking at delivering on that vision, there's a couple of elements. Firstly, if we look at platform, one of the things that we have done and developed entirely in-house with our lead and his team is develop what we believe is a new class of therapeutics, the antibody oligonucleotide conjugates, and we've demonstrated preclinical proof of mechanism in multiple different tissue types. We're looking to broaden through other tissues and cell types as well through partnership and discovery. One of the first places we directed our technology was looking at muscle. We have a large pipeline targeting a range of different muscle diseases. The first of those, AOC1001, is set to enter the clinic in the second half of this year, which is hugely exciting for us as a company and also for the myotonic dystrophy patient community. We're also planning to initiate two clinical programs next year, AOC1044 in DMD and our FSHD program as well. We're doing a lot of company building, as you would expect. We firmly believe that people build companies. We're very much focused on bringing in people with real deep experience in a broad range of areas, but in particular, rare disease and RNA therapeutics. Taking a little bit of a broader look at our pipeline. One of the things that I did talk about this morning, and hopefully those of you who are paying close attention, was that we actually now have selected our lead candidate. We now have a candidate that we're entering into IND-enabling tox, so DMD, and that is targeting exon 44, so it's aptly and hopefully somewhat appropriately named AOC1044. We're looking forward to entering the clinic there next year along with FSHD. Also, we'll spend time today talking about AOC 1001, where we plan to initiate the phase I/II study in the second half of this year. In terms of moving from pipeline, I started broad, moving on to pipeline. Let's focus specifically on the goals for today. Firstly, this is an opportunity to really provide a deep dive for the first time of the years of engineering that have been completed here at Avidity to support our AOC platform. We're also looking at how that platform then pulls through in relation to our pipeline, and we're also really looking forward to the panel discussion, where we're getting into also offering a broader perspective on the history as well as the future of RNA therapeutics. For those of you who know us well, you know that we love engaging in discussion. We love talking about our science, our company, our technology. Very much looking forward to taking your questions as well as we go through today. In terms of specifically looking at the highlights and what's new. The first aspect is a deep dive on the AOC platform. We actually haven't done this to the depth that we're doing today before. It does two things. One, really demonstrate that data-driven approach and that aspect of following the data that took us through to the engineering of the technology, as well as showing some previously unseen data that we've also used in specifically to choose the use of the monoclonal antibody. We're also going to look at AOC 1001 and the safety profile as we enter into the clinic. First, to sharing additional non-GLP tox data, as well as really excitingly presenting the outcomes and data from our GLP tox studies as well. Then the third area around what's new is really announcing that movement and progress with our pipeline, in particular, the naming of AOC 1044, which is now entering into IND-enabling tox. Looking towards the agenda for today, I'm going to be handing over to Art in a minute or so, who's going to go through the engineering and really looking towards the future of RNA therapeutics as well. We then have a panel looking at translating RNA research actually into medicines, where we're delighted to be joined by two esteemed guests, Doctors Stephen Dowdy and Phil Zamore, who are both experts with deep experience in the RNA space. We'll also do a Q&A session as well as part of that panel, and then also I'll wrap up at the end with closing remarks. Moving to introducing our speakers. First off is Mike Flanagan. Mike Flanagan is going to be facilitating the panel discussion. Mike joined us at the beginning of the year. He brings with him both deep expertise in the RNA space, in the antibody space, as well as in the ADC space as well. We're thrilled to have Mike join our company. The next key speaker, who I think needs no introduction, is Art Levin. Art is one of the leading experts in the RNA space and has really dedicated his career to bringing RNA medicines to patients. With that, I'm going to hand over to Art, and we'll start to dive into the presentation. Art? Thank you very much. Thank you for the kind introduction. I would like to, first of all, thank the panelists for joining us today. More importantly, I'd like to thank the folks in the audience who I wish I could see but can't. Unfortunately, that's not how this presentation works. It's absolutely overwhelming, the interest that we have today, and it's a great day when we can talk in depth about the science. Earlier this week, we were talking about, am I excited about Science Day, and I had to laugh because in my world, every day is Science Day, I think. This is just a great opportunity to demonstrate where we came from and where we're going. My talk is going to be broken up into three bits. The first will be a bit of a concentration on how we got to where we are, a little bit of our history, some of the fundamental experiments that we did as we engineered this technology. I'll show you how that engineering has been applied to our first clinical program, AOC 1001, for the treatment of myotonic dystrophy, a disease for which there are no currently approved therapies. Finally, we'll talk a little bit more about the pipeline and then where we're moving from there to actually broaden out the platform, where AOC technology is broader than just skeletal muscle programs, and I'd like to talk a little bit about that going forward. The company started years ago, and we were founded to use monoclonal antibodies to deliver oligonucleotides because the key issue in oligotherapeutics, of course, is delivery. At that point in time, we were using a nanoparticle formulation, and in the process of engineering that nanoparticle formulation, we actually realized that, and we were using a nanoparticle preparation that was decorated with monoclonal antibodies in order to target our nanoparticles. As we engineered those particles, we realized that we're actually getting more effective delivery with the Antibody Oligonucleotide Conjugate alone rather than the nanoparticle. The company pivoted, again, based on data, to really become focused on using these direct Conjugates. We reasoned at the time that taking advantage of the information that was available to us from the oligonucleotide conjugates that were being used in the liver, we realized that there were professional transporters that could be exploited to deliver oligonucleotides into cells. We began a search, came up with the transferrin receptor, which was an obvious choice because the transferrin receptor is highly expressed and is quite active as a professional transporter, and we began to develop a technology around that particular antibody. Note that this is pretty much different than the way other companies have developed oligonucleotides in the past. In the past, people have fallen in love with a particular molecular target, and they said, "Well, we can modulate that molecular target easily with an oligonucleotide therapeutic or with CRISPR or Cas," and not realizing that mechanisms are great, but you really have to get the oligonucleotide into the cell. We started from the opposite end of the spectrum. We said we can deliver oligonucleotides, and we found that we can deliver oligonucleotides throughout the muscle, and then we built a pipeline on that. Similarly, we're now exploring other monoclonal antibody cell surface pairs, each one of which may have the potential to build kind of a vertical platform, vertical pipeline, as we identify new receptors that we can use. The problem, and I'm lightly paraphrasing Steve Dowdy, one of our panelists today, the problem is that there are eons of evolutionary progress which have made cells impermeable to external genetic material. Cells have evolved to actually keep out external genetic material, and when that goes awry, that's pretty disastrous, as we have learned in the past 15 months, and that's why we're all on Zoom today and not in a posh hotel ballroom somewhere in Boston or New York. Moving the genetic material, the genomic material for a virus, in this case COVID-19, has led to a worldwide pandemic. When those barriers break down, when the barriers to keeping genetic material out of cells break down, there's considerable trouble. Cells, we've had to figure a way to get around that. Again, looking at nature has used receptor-mediated uptake in order to facilitate the movement of various entities into cells. Again, using receptor-mediated uptake here, we are taking advantage of the fact that cells can internalize our monoclonal antibody oligo conjugate. That oligo conjugate then binds, is then degraded, the antibody is degraded, and the oligonucleotide can be released. With monoclonal antibodies specifically, we can take advantage of their specificity, we can take advantage of their high affinity, and we can actually direct them to cells. Avidity didn't start out necessarily focused on monoclonal antibodies. In fact, we tried small molecule ligands in some of our programs. We tried peptide fragments in some of our early collaborations. Ultimately, we found that monoclonal antibodies performed the best and they have the greatest safety profile and the least technologic risk. Here's an example of a study that we did in non-human primates where we compared an siRNA that was loaded onto a Fab fragment, and we're looking at our plasma pharmacokinetics versus an siRNA that is loaded onto a full-length monoclonal antibody. You can see quite clearly that the full-length monoclonal antibody has superior pharmacokinetics. We've optimized each of the components of our antibody. We started components of our AOC, starting with the antibody. Selection of the antibody was the first thing. We also selected the epitopes for this particular transferrin receptor that we built our muscle pipeline on, so it doesn't compete with endogenous transferrin. We've also made that, in particular, taking advantage of 30 years of monoclonal antibody engineering, we've been able to make that monoclonal antibody effector function null, so we're not going to induce ADCC. We've also engineered where the monoclonal antibody is conjugated with the oligonucleotide. Each of these concepts was brought in for the initial step of, okay, let's select our targeting ligand. In this case, we selected on the basis of data, letting data drive us to the monoclonal antibody, not small molecules, not peptides, not fragments. We've also engineered the linker. One of the things that I didn't make clear when I was talking about the fact that the company started out with nanoparticles is that we brought in a number of bioengineers. You know that bioengineers, of course, like to push systems. This is an example where we pushed the system. We took a long-lived monoclonal antibody, injected it into the mouse, to which we conjugated using three different linkers an siRNA. What you can see here, there is remarkable differences in, again, the plasma circulation times of these oligonucleotides, depending upon which linker was used. This is when you're going to design a car and you want to test that car, you don't drive it around on suburban streets. You take it out onto the race course, or you move it to the desert, or you go to the Arctic to test it. This is kind of a worst-case scenario here. We took a very long-lived monoclonal antibody, to which we then conjugated using different linkers, and we chose the one with the greatest selectivity. We engineered this specifically, maybe not for the transferrin receptor, which is actually relatively short monoclonal antibody of the transferrin receptor, which is actually relatively short-lived, one-day half-life in certain species. For the future, when we want to have a monoclonal antibody oligonucleotide conjugate pair circulating for longer periods of time. We're using a non-cleavable linker that is conjugated to our monoclonal antibody at the interchain disulfide bridges. Again, as we're moving through the AOC complex itself, I talked about the optimization of the antibody. I talked a little bit about the optimization of the linker. One of the key pieces, people have tried making oligo-antibody conjugates in the past. One of the key pieces that we really concentrated on was finding the right modification patterns. What you're looking at here is an experiment that we did in the mouse, where we took different versions of a siRNA, in this case against myostatin. We made different chemical modifications to that particular siRNA. What you can see here is depending upon the modification pattern, you can get very different behavior of this. Again, here we're looking at relative myostatin knockdown. You can see that in blue we have a particular molecule that is long-lived, highly potent, and long-lived. That modification patterns or modification patterns like those that we ultimately selected. Each one of these components was then, as I told you, was optimized individually and then ultimately how the molecules were arranged in space. Using our technology, we're taking advantage of decades' worth of safety experience with the engineering of monoclonal antibodies, and the fact that monoclonal antibodies provide very little technologic risk. Dozens of companies around the world know how to make monoclonal antibodies. Our linker is a linker that's been known and used before. It is highly stable so that there's not going to be dose dumping when the drug is administered. We also know that that linker ultimately is irrelevant because the antibody is ultimately going to be degraded in the endosome-lysosomal complex. Finally, we modified the siRNA so that it can withstand lysosomal enzymes. This is actually a key point because you'll see later on in my talk that our monoclonal antibody oligonucleotide conjugates have quite extraordinarily long-lived activity, which is great news for patients because it means that they can be dosed relatively. We foresee them being dosed relatively infrequently in clinical usage. To get to the place where we had all of these engineering bits aligned, we did a lot of studies. We spent a lot of time doing studies in non-human primates. We used non-human primates specifically because they were going to have more direct readout to clinical trials. You can see that very early on, we were looking at our delivery moiety. Should we be using a Fab fragment, should we be using a full-length monoclonal antibody? Ultimately, for the reasons that I showed you and for reasons of the known safety profile of the full-length monoclonal antibodies, we landed there. We did studies that allowed us to select the lead monoclonal antibody. We did studies in non-human primates that allowed us to actually select the lead siRNA and its modification pattern. We did an extraordinary study, what we're calling NHP Study Six, where we did an extensive pharmacokinetic analysis of the pharmacokinetic/pharmacodynamic interactions, and I'll show you those data in a few slides from now. Finally, of course, the news for the day is that we've recently completed our GLP tox studies, and we're now presenting the data from the primate studies. Spoiler alert, we're talking about the data. The data are extraordinarily favorable to moving forward in the clinic. While we're talking about moving forward to the clinic, our first drug, AOC 1001, really embodies a number of the key characteristics that I've tried to outline for you in the past few minutes. Talking about myotonic dystrophy, of course, this is an irreversible disease at this point in time. There are no currently available therapies for these patients. These patients suffer from a mutation in a gene called DMPK. The mutation, in this case, causes an expansion of a triple nucleotide, CUGs. Unlike other triple nucleotide repeat diseases, this does not ultimately result in the expansion of CUGs, and the DMPK gene does not result in a toxic protein. It's the RNA itself that's toxic. The manifestations of this disease are there are a number of changes in skeletal muscle, cardiac muscle, respiration, and in the GI tract, each of which can be explained on the basis of the following mechanism. The myotonic dystrophy DMPK gene has these excess CUGs in them. Those excess CUGs in normal patients or normal people have 30 or less CUG repeats in their DMPK gene. Patients with the disease or people with the disease can have thousands of copies of CUG. Those CUGs form a hairpin loop. They're self-complementary, so Cs will bind to Gs on the other side of that hairpin. These high concentrations of CUGs that are associated with this messenger RNA attract a CUG- binding protein called Muscleblind-like protein, here abbreviated MBNL. If MBNL is inappropriately sequestered binding to these CUG repeats, it can't perform its downstream function. The downstream function of MBNL is to be a splice factor for other genes. If all the MBNL is being sequestered in these large hairpin loops, the Muscleblind-like protein is not going to be performing its normal function, and the downstream genes that are normally processed by Muscleblind-like protein are misprocessed. It is actually the misprocessing of those messenger RNAs associated with other gene products that are responsible for the characteristics of the disease, the electrophysiologic changes that are associated with the characteristic myotonia, where patients can't relax a muscle, and that's related to the fact that there's a chloride channel mis-spliced. There are cardiac conduction defects, which are probably related to either the chloride channel or the fact that there's also a calcium channel that's mis-spliced. Patients with myotonic dystrophy have an inappropriately spliced insulin receptor. Each of the manifestations of the disease can actually be explained by the missplicing of a number of proteins that have been missplicing a number of RNAs and ultimately misprocessing of proteins. Of course, those can serve ultimately as biomarkers since we know what the downstream effects are of Muscleblind sequestration. The key here is that if you can reduce the number of CUGs in the nucleus, you can then reduce that sequestration of Muscleblind-like protein, and you'll get normalization of the splicing patterns. Data to that effect have already been generated in a clinical trial that unfortunately for the patients was stopped because they were reaching, with an oligonucleotide, levels of the drug which were potentially toxic. In order to produce the pharmacologic effect that we're interested in here, you need to knock down the expression of DMPK. We were interested in the concept of because DMPK is normally localized 50% in the cytoplasm and 50% in the nucleus. In the disease state where there are all the extra CUGs, there's a significant fraction of the DMPK messenger RNA, which is trapped in the nucleus. What I'm showing you here are data that demonstrate that our lead siRNA can knock down both the cytoplasmic fraction of DMPK as well as in the nuclear fraction. These are data that were collected from a DM1 patient, a patient with thousands of CUG repeats, and here you can see quite clearly we can knock down the expression of DMPK in the nucleus. If you knock down DMPK in the nucleus, you're going to see a reduction in nuclear foci, and the next slide shows that quite nicely. What you're looking at here in the top panel on the left-hand side is encircled are muscle cells in which you can clearly see that the nuclear foci are present. When treated, you can see that the nuclear foci are missing. On the right-hand side, what you can see, in fact, is that we've essentially saturated the pharmacology here. Even one nanomolar concentration of our siRNA is producing greater than a 50% reduction in the number of nuclear foci, all of which is very encouraging. I would also point out the fact that these are drugs that are active at the nanomolar range, which I'll emphasize more coming up in the next few slides. Reducing foci are important. It's clearly something that you can visualize under a microscope, that's nice. The real goal here is to change the ways that cells are splicing key genes. In this particular experiment, I want you to compare the untreated cells shown as the black diamonds on the right-hand side with cells that have been treated with, sorry, myotubes which have been treated with our lead siRNA. Here you can see that there's a 56% increase in the splicing index. This is an unbiased selection of 100 different splicing events. You can see that we've moved the splicing pattern up about 56% more towards the normal pattern, which is shown in either the blue circles or the black filled diamonds. Again, the key component here is the fact that when we are producing a reduction in the gene expression of DMPK, we're reducing the number of nuclear foci. We're getting the kinds of splicing changes that you want in order to produce pharmacologic activity. This is all important, but now let's see what happens in vivo. In vivo, these are some data in normal non-human primates. These non-human primates have been treated with a single dose of 2 mg per kg, gave this by the intravenous administration. The dose is two milligrams per kilogram of the active siRNA, or about 20 milligrams per kilogram of the total dose. What you can see here is that there's greater than a 75% knockdown that lasts through 12 weeks. Single dose, 12 weeks at least worth of activity. Now, there's no magic here. We understand quite well why we get such long-lived activity. Again, recall that I've mentioned that we've stabilized our siRNA preparations so that they are stable within the endosomal-lysosomal complex. The endosome actually works in our favor here. It works as a controlled release depot, allowing our oligonucleotide to pay out over time and continually loading the RNA-induced silencing complex. By loading RISC, we're going to maintain activity for long periods of time. On the next slide, I'll show you a dose-response curve that we get, again, in non-human primates. Single dose of 1 mg, 2.5 mg, or 5 mg per kg produces greater than a 50% reduction in the expression of the key target gene here, DMPK. Again, it lasts for a long time. More importantly, note that our ED50 here is less than 1 mg per kg. These are data that were taken at week six. Again, long-lived activity. We're getting activity in the tissue types and cell types that are required in order to help these patients. We know their cardiac conduction defects. The previous slide showed you knockdown in skeletal muscle. Here we also show the change in gene expression in the diaphragm. These are key areas for the patients with this disease and areas where we want to make sure that we have great activity. On the right-hand side, you can see again, much like the skeletal muscle data that I showed you on the previous slide, we have long-lived activity. A single dose of 2 mg per kg still produces greater than 50% knockdown in the heart and almost 70% knockdown in the diaphragm. We think, although there are no strong data to actually create a firm threshold, we believe that knocking down the toxic mRNA, DMPK, of greater than 50% is probably going to be required for activity. We will be attempting to knock down gene expression to that degree in future clinical trials. The next slide shows that we get knockdown of gene expression in multiple muscle biopsies from multiple cell types. Here, a single dose of 6 mg per kg four weeks after administration, you can see that there's greater than 80% knockdown of DMPK. Below each of the bars, what you can see is the tissue concentration in nanomolar. When compared to data that had been generated previously, and published or presented using an antisense construct, they were attempting to achieve micromolar concentrations, and these are data from a clinical trial that has been reported by others. The tissue concentrations where we're getting activity are in the nanomolar range. Clearly there is extraordinary activity of an siRNA therapeutic to knock down gene expression across a broad range of muscles that are shown here, including organs or tissues which are potentially enriched in smooth muscle. As is shown by the data from the jejunum and the ileum on the far right-hand side of the slide. As we were studying AOC 1001, we did a pharmacokinetic pharmacodynamic study, which also served as our non-GLP tox study. As you can see here, we did extensive plasma pharmacokinetic analyses. What's interesting about this particular slide is that with repeated administration of our AOC 1001, you get similar peak concentrations over time, you get similar trough concentrations from injection one to injection two, and the slopes of the lines are similar for each of the dose groups going from injection one to injection two and injection three. This indicates that there are no neutralizing antibodies to our AOC 1001 in the non-human primate. Why is that good news? It's good news because we're actually giving a human protein to a monkey and not seeing a large immune response, which is indicative of the fact that we've done a good job at designing our monoclonal antibody and designing our AOC so that it's not inducing a significant immune response, which is going to change either the pharmacokinetics or the pharmacodynamics. Note that the plasma half-life for this particular construct is about one day in non-human primates. It is slightly dose-related. We might expect that this half-life will be a little bit longer in humans, but not significantly so. That's at this point in time, of course, speculation since we have yet to do the studies. The key point here is that even though we're giving a human protein to a monkey, we're not seeing neutralizing antibodies, which was really something that allowed us to rest easier because, of course, this was one of the unknowns we had moving forward. Is this construct going to have some sort of new immunogenic potential? So far, and again, that's what you have to do before you get to a clinical trial. So far, the data suggests that that's not the case. The pharmacokinetics as you saw, the plasma pharmacokinetics as you saw on the last slide were almost textbook. Beautiful first order kinetics. What you can see on the left-hand side is that we also have beautiful tissue kinetics. What you're looking at on the left-hand side of this particular graph is that we have a concentration versus dose plot, and you can see that we have linear accumulation in skeletal muscle, depending upon dose. The right-hand side really is a nice demonstration of the fact of just how good these kinetics are and just how thorough our analyses have been and the kinds of data that we're giving to our clinicians as they're designing the first clinical trial. What you can see on the far right are the number of different dose groups that are represented in this particular study. You can see again, a broad range of doses that we're using here. What you're seeing on the right-hand side of this slide is the reduction in DMPK expression versus tissue concentration. If you look at day 21 or day 28 post-dosing, the effective concentration that produces 50% knockdown is less than a tenth of a nanomolar. Again, we have a highly active siRNA that we can deliver effectively across a broad range of skeletal muscles, as I showed you a couple of slides ago. These are the kinds of concentrations that are easily achievable in clinical trials with doses below which we've already presented here. The big reveal for the day are the GLP tox studies. Of course, the GLP tox studies are a key component of any investigation on new drug application or any CTA, and we're really quite proud of the data that have been generated, and I think you'll be impressed by the data as well. We saw no dose-limiting toxicities that were observed in the monkeys at the highest dose tested. We saw no changes in platelets or renal toxicity that have been associated with other oligonucleotide therapeutics in the past. There were no treatment-related changes in histopathology. No other changes in hematology, adverse effects in hematology or serum biochemistry. We also looked at safety parameters, such as cardiac, respiratory, and neurologic changes. All of those were uniformly negative. The NOAELs, the no adverse effect levels, were the highest doses tested in the monkey, and as I'll show you on the next slide, the pharmacology was essentially saturated. We had similar results in the mouse. First, we think that the non-human primate is the most relevant, and that's what we'll concentrate on today. This slide shows the reduction in gene expression of DMPK in our GLP tox studies. What you can see here is that across a broad range of skeletal muscles, gastrocnemius, latissimus dorsi, vastus lateralis, diaphragm, intercostal muscles, left ventricle, in skeletal muscles, we're seeing almost 80% or 90% knockdown of gene expression that was essentially saturated across the doses that we used in this study. You see significant knockdown, greater than 75% knockdown in the left ventricle. Again, the key point on this slide, the point that I want you to take home with respect to our GLP tox studies, excuse me, is that there were no effects, no adverse effects associated with the reduction of DMPK, and no adverse effects associated with the administration of the transferrin-based AOC, AOC1001. Again, outstanding pharmacology, essentially saturated pharmacology in most tissues, and yet no adverse effects associated with these high dose exposures. These exposures are manyfold higher than the doses that are intended to be used in the clinic. We're ready to move into clinical trials. Our planned phase I, phase II study is to initiate in the second half of this year. That's based upon the fact that we can deliver this particular RNA therapeutic in a highly effective way. We get reductions in the key gene that we're interested in. Our EC50s are in the nanomolar or sub-nanomolar range. We have activity weeks after administration of, or even months after administration of a single dose. We have a favorable safety profile, and we have a safety profile which also includes the fact that reductions in gene expression are primarily localized to the key target tissues of interest. Finally, we recently received a patent for the AOC 1001. We're moving towards clinical trials with significant wind at our backs, and we're highly encouraged by the characteristics of this particular AOC, and we think this particular AOC bodes well and serves as a model for other AOCs that we're putting into the clinical trials soon, and that brings up the concept of our pipeline. We're building upon our experience with AOC 1001. Of course, AOC 1001 is now completed IND-enabling studies. We're getting ready to move, or we're moving our next clinical program, each building on the same transferrin monoclonal antibody, into clinical trials or into IND-enabling and then ultimately clinical trials. Two programs that are moving forward in near parallel at this point in time are FSHD program, which is targeting a gene called DUX4, which is inappropriately expressed in patients with FSHD. We have got a program in exon skipping where we can take advantage of our AOC technology to deliver a single-stranded morpholino oligonucleotide that's designed to skip particular exons in the dystrophin gene, in this case, exon 44, suitable boys or treatable boys, and that compound is moving into GLP tox at this point in time. We also build on a number of other programs in Duchenne muscular dystrophy. Of course, this is a disease that is currently underserved. We think that our program offers significant advantages over some of the existing programs out there, and the ability to use our monoclonal antibody platform to build a whole armamentarium in muscular dystrophy alone is extraordinarily useful. In addition, we've got programs in muscle atrophy and in Pompe disease, all of which are building upon the knowledge that we gained from AOC 1001. The FSHD program is a really good example of how we could actually accelerate a program once we had the appropriate experience developing AOC 1001. It was relatively, I don't want to make it sound too easy because the team worked all summer long and under pandemic conditions, but it was relatively easy to identify an active molecule and then create not just the active siRNA, but then create the active AOC, the complete conjugate. Again, we are incredibly enthusiastic about the ability of us to build this pipeline based upon our existing experience with AOC 1001, allowing us to continue to move compounds into formal development and then ultimately clinical development. In addition, the technology for antibody-oligoconjugates is more broadly applicable. We know that there are other targets in the liver besides hepatic parenchymal cells, and you can find other monoclonal antibody receptor pairs that can perhaps target other cell types in the liver. We are looking currently with a collaboration with Bristol Myers and MyoKardia at delivery of oligonucleotides to the heart. I've already shown you data today that demonstrates that we have activity of our oligonucleotide therapeutics in cardiac muscle. We have data that support activity of our AOC technology in immunology and in collaboration with Eli Lilly. That's where Lilly has a defined number of targets in the immunology space and other diseases that are in fact allowing us to broaden our technology into immunology as well as having access to a library of monoclonal antibodies for particular targets that Lilly is interested in. What we've done strategically is we're getting a lot of experience by interacting with these companies who are area experts in the particular areas that they're working in. Finally, we have programs in-house, both in immunology and in immuno-oncology, that are, again, taking advantage of our ability to find cell surface receptors and monoclonal antibodies to those cell surface receptors that can effectively deliver oligonucleotide therapeutics in order to get the appropriate activity of an oligo therapeutic. The dream of oligonucleotide therapeutics has always been to be able to take advantage of Watson-Crick base pairing in order to rationally design therapeutic agents based upon genomic information. The problem has always been that we were unable to deliver on that dream because we couldn't get the oligonucleotide therapeutic to the cell or tissue of interest. With our AOC technologies, we're taking advantage of, in this case, monoclonal antibodies to find new cell surface receptors or take advantage of cell surface receptors that are internalized that will bring our oligonucleotide therapeutic into the cell. It's the result of years of engineering that we've performed on this platform, and it's really taking advantage of the safety profile of full-length monoclonal antibodies and the safety profile of siRNAs that's really allowing us to build not just the muscle pipeline, but potentially other pipelines in other therapeutic areas. That's really the goal for the company. We want to treat patients with rare skeletal muscle diseases, but we also want to make sure that we can offer treatments to other patients with other diseases and other cell types where oligonucleotide therapeutics have an appropriate role, but where we've been unable to deliver them. Again, we've shown you data from in the general case, and we've also shown you data in the specific case of AOC 1001. We're poised to begin our phase I, phase II studies in the second half of this year. We have an expanding pipeline, as you said, and as you've seen, and we certainly have the potential to administer AOCs for a number of different disease indications that are outside of liver, outside of skeletal muscle, and in other tissues. For today, we're focused on our newly declared candidate for exon skipping for exon 44 and the acceleration of our FSHD program into IND-enabling studies. We have our focus on rare diseases, and moving forward from that, of course, we have the potential to deliver oligonucleotide therapeutics from across a broad range of indications. The technology has both a really nice vertical component with respect to our ability to develop a pipeline of rare muscle diseases, but we also have the ability to develop other vertical pipelines in other therapeutic areas. I think that's really where we would like to go with this technology in the future. With that, I'm going to turn it over to Mike Flanagan, and Mike can introduce the panel speakers. Thank you, Art, for sharing how we've followed the data to deliver RNAs to rare muscle diseases and beyond. I'm really happy to have our panel discussion today, delighted to have two accomplished RNA experts to continue the discussion of translating RNA research into medicines. Let me first introduce Doctors Phil Zamore and Steve Dowdy. Dr. Phil Zamore is the Gretchen Stone Cook Professor of Biomedical Sciences and Professor of Biochemistry and Molecular Pharmacology at UMass. Dr. Zamore is a Howard Hughes Medical Institute investigator and chair of the RNA Therapeutics Institute at UMass. Dr. Zamore is a leading expert in RNA-targeted therapeutics and has been associated with leading companies in the field. Phil received his AB and PhD in biochemistry and molecular biology from Harvard and then pursued postdoctoral studies at MIT and the Whitehead Institute. Thank you for joining us, Phil. Dr. Steve Dowdy is a professor in the Department of Cellular and Molecular Medicine at UC San Diego School of Medicine. Dr. Dowdy's research focuses on the delivery of novel therapeutics, especially RNAi, into cells and tissues. Dr. Dowdy's been involved in multiple RNA biotech startups and currently sits on five scientific advisory boards. Steve received his PhD in molecular genetics from the University of California, Irvine, go Anteaters, and performed his postdoctoral fellowship at MIT and Whitehead. Welcome, Steve. Let's get started. You like the go Anteaters, huh, Steve? Inside joke. We've had enormous advances around RNA therapeutics in the last decade. Both of you have played key roles in these advances. Let's start with Phil first. Phil, what do you think has been the single most important development in delivering RNA therapeutics beyond the liver? Beyond the liver, I would say delivery to the CNS by redesigning what we think of as siRNAs to have either different conjugates or to be dimers. Steve, thoughts? Yeah, I think the ability to go beyond the liver is really because of the chemistry that was developed with the GalNAc that conjugates to the liver to understand what we needed to do in order to get conjugates to work and the metabolic stability. It's really the chemistry that's been applied to the siRNA for that incredible up to six months stability inside of the endosome of the target tissues. Yeah, I totally agree with that stabilizing chemistry has turned what people thought was a huge weakness into an unexpected strength that makes these among the most durable oligonucleotides to date. Yeah. I think you can see that demonstrated in the data that we presented today where a single dose of an oligonucleotide, in this case, in a skeletal muscle that previously, a tissue that previously was untargetable or undruggable with oligonucleotide therapeutics, where we have at least 12 weeks of activity after a single administration. I think that really speaks well to the fact that you can take advantage of the fact that there are internal depots of drug that are going to slowly pay out the drug over time, and whether that's in the CNS where, of course, there's long-lived activity or whether that's in muscle or potentially other tissues. I know Steve Dowdy used that as a weakness. That's not true. You're paraphrasing. On the other hand, yeah, we can actually take advantage of those long lived depots, and that's how you get such remarkable activity like I showed earlier, where a single dose produces activity for 12 weeks or even longer as we saw. The depot effect where the drug, the RNA stays inside of the endosome is clearly a huge advantage, but again, because of the metabolic stability, the enzymes just aren't available in a lysosome or late endosome to chew these up and degrade them. That gives the opportunity for this very slow continuous release. We can just work in the future to enhance that so we can tackle things like oncology, which is really untackable today because of the rapid turnover of the cells and trying to get it delivered to all of those cells, for instance, too. I think when you look at the RNA therapeutic chemistry today versus 10 years ago, it's black and white. It's absolutely night and day. You can't pull any of the data that we learned 10 years ago about these types of drugs, none of that is relevant. Anything that you, the audience may have heard five, 10 years ago, these are unstable, they can't be delivered, all these sort of things, yeah, that is simply not true today. It's proven in human clinical trials, approved RNA drugs of ASOs and siRNAs. This is a brave new world of an amazing molecule. Can you imagine a drug you take once every three months or once every six months, and perhaps in the future, as we continue to optimize the chemistry and the knowledge of delivery, maybe once a year? It's amazing. It's absolutely amazing. Yeah, if you look at the first lipid nanoparticle siRNA drug, ONPATTRO, that's three-week dosing. Here we are looking toward widespread use, hopefully, of drugs that have semi-yearly dosing. It really totally changes the landscape of compliance issues. Patients will be taking their drugs without fail. You're doing just an effort to get the drug twice a year. An add-on to that too is it doesn't stop at three months. Art's, knockdown doesn't stop or Avidity's knockdown doesn't stop at three months. It keeps going on and on, so the patient doesn't have to show up at three months plus one day, otherwise, all the therapeutic benefit is going to be thrown out. It can drag on longer than that, and so the patient has some flexibility to come in this week or next week to get their next dosing. It's not an absolute got to take it this morning, every morning kind of a thing in order for it to work. Just an amazing, broad new world of medicine. Yeah. It is one of those things that is just, even a few years ago, just you couldn't imagine just being able to dose so infrequently, especially for diseases in children where you really want to take them out of soccer practice and go to the doctor and those kind of things, right? We've all been there where you're doing sports and you're traveling and all those kind of things where you may not be close to your doctor. It's really beneficial for patients, I think. One other thing is that, kind of thinking about this brave new world, we're constantly learning about new roles of RNA in biology, and we could argue about it, but it really truly is an RNA world. I think one of the things, and maybe, Steve, I'll have you start on this, is that what role do you think oligonucleotides in general and maybe conjugates and AOCs in particular could play in modulating these newly identified RNA functions? Yeah. Just to go back a little bit, like 3 billion years, it really was a primordial RNA world that then became encapsulated in the first lipid bilayer that essentially was the first living cell. RNA then allowed the development or drove the development of DNA for a more stable storage of genetic information, that we have to go back to the world and all the defenses that the cell has is based on RNA. We exude RNases from our fingers. Our cell phones are covered in RNases. Everything we touch is covered in RNases because it was an RNA-centric world. Unfortunately, when we all went through graduate school, we were taught the standard central dogma of DNA to RNA to protein, and then RNA can be converted back into DNA with reverse transcriptase. It really is this RNA-centric world. When you look at the regulatory mechanisms of RNA interference, piRNAs, other regulatory RNAs, lincRNAs, it's just amazing how much RNA is central to life on this planet. As we discover more and more of these RNA pathways, what better drug than an RNA that can base pair to that specific RNA? That's the beauty of these precision genetic medicines, is they're going after the root cause of the disorder, which is the RNA. Other small molecules just don't have the size of information embedded in them to specifically go after an RNA like we can get due to base pairing. This RNA therapeutic world is really set up as the next level of regulatory RNAs become discovered and shown to be involved in human disease, we can rapidly jump onto those with these RNA therapeutics. I think the other thing that makes RNA drugs special is that the delivery modality and the targeting modality are discrete modules that can be shuffled. If you have an siRNA that you know works against a target in liver with a GalNAc conjugate, that same siRNA can be delivered as an AOC to a muscle disease. You can take the same delivery method that's been demonstrated in non-human primates at Avidity and swap out the siRNA for a different target. These have truly become modular informational platforms where we're finally taking advantage of all of this genomic sequence and transcriptome profiling to design both the targeting moiety and to design the drug itself. Yep. Mike, just to go even sort of further on the development of RNA therapeutics, not only can we go after every individual RNA because of the base pairing, but cGMP manufacturing, the line that produces these is the same line for every molecule. Just as Phil said, all we're doing is changing the sequence of the RNAs and the targeting domain, in this case, the active site of the antibody. The rest of the processes are all the same. We don't have to set up an entirely new line of manufacturing in these facilities. We just plug in our particular sequence, plug in whatever the targeting domain is, the antibody, and then bam, the linkers and everything else is the same. This modular approach really improves the overall efficiency of manufacturing and the consistency as well too. Yeah, those are great points. I guess what I'm hearing from my point of view, though, I'm hearing you guys are describing it as a platform where it's kind of you can plug different pieces and put different pieces together depending on the disease and tissue type. Art, what are your thoughts about that? I think you're seeing the example of that here because we're going to move a lot faster on the second program, third program, and fourth program than we did with the first. We did the engineering around the targeting moiety, in this case, the transferrin receptor. We understood that, and then obviously it becomes, I don't want to say plug and play, but it's a lot more plug and play than developing a new small molecule every time. It allows us to take advantage of a delivery mechanism and then put on the appropriate therapeutic entity. Yes, it is extremely useful, and you can even see that the fact that we could accelerate FSHD, our FSHD program faster than we thought because once we found an active moiety, an active siRNA, we then know how to perform the rest. It is a little bit, fortunately, like Tinkert oys. I don't want to denigrate all the hard work that our chemists are doing and that our biologists have to do to make sure that we have the Tinkert oy effect. In reality, we are getting significant synergies from one program to the next, which of course has always been the dream, the concept. Yeah. It's really impressive, Art, that for those of you in the audience, Avidity is head and shoulders above any other group or company for making antibody-oligo conjugates. The ability then to just plug and play, I don't think you're being excessive in saying that, Art, because I think it's really on the verge of being really straightforward in that sense. Thank you. Right? I can tell you the team thanks you. Hopefully, the team's going to hear this, but they've been working hard to make it look plug and play. If you think about the way small molecule drugs are discovered, that's high-throughput screening to identify a lead, and then medicinal chemistry to make the lead a real drug. Whereas you have the ability to spend all of that energy that you no longer have to spend on h igh-throughput screening on bringing a chain of incremental improvements to a great technology to make it better each pass, whereas you're not going back to the exact beginning again and searching for a new drug. Yeah. Great points. I think, as we're talking about this and trying to think about how RNA therapeutics fit into the broader landscape, we've had recent advances in technology. We talked a little about delivery, being able to deliver it to different tissues. We have gene editing on the horizon, we have gene therapies on the horizon that promise a single treatment for a lifelong effect. I think, Phil, maybe you can take this one. How do you see RNA therapies and siRNA in particular fitting into this future landscape of RNA therapeutics overall? Well, the advantage of drugs over permanently modifying people's genomes is that you can alter dose, you can change the target, you can change the drug modality as people age, as their condition develops, as their diet or exercise changes. You have the ability to respond to the way the patient changes with time. With gene editing is premised on the idea that the defect is immutable relative to the person. Of course, we know that the interaction between environment and genetics plays a huge role in the outcome of diseases. I think drugs will always have the advantage that you can stop them and change drugs. You can change doses. You can go to an improved therapeutic modality in a way that isn't possible with gene editing. Yeah. I think there's the notion of a hit-and-run approach with an RNA therapeutic, which is similar to small molecules and biologics as well too. It's there when you want it to be there, and it's not there when you don't want it to be there, should there be any adverse effects or change in your overall physiology. I think that the non-viral DNA therapeutics, the viral therapeutics, the editing, I think all of these will have places. I think that depending on what the disease is, the severity of the disease, and the delivery of all of these agents to the specific disease cells, that it's going to dictate which modality you would use. We're not going to do away with small molecules, for instance, either. RNA therapeutics is not going to 100% displace small molecules or biologics, and likewise, permanent single-dose modalities are also not going to replace RNAs or small molecules. I think there's plenty of unsolved human disease out there, unfortunately, and there's room for all of these modalities, and that both the patients will decide what the risk they're willing to do and what they would like to take, whether they stick with statins or take an RNAi or be edited to solve hypercholesterolemia, for instance. There's 7 billion of us out here that need therapeutics for various diseases. I think there's room for everybody. We're not even close to having things competitive against each other because there's so many untreatable diseases currently today. Art, your thoughts? I think just building on top what Steve was saying, with a multitude of untreatable diseases and now the ability of RNA therapeutics to come in and actually use rational drug design drugs based upon genomic information. Then being able to deliver to those tissues, that really will ultimately allow us to deliver on the promise of oligonucleotide therapeutics. We have all the genomic information. We know it. It's essentially digital. It's not binary information, it's quaternary information. We have that information, and then with a little bit of empirical work, we all know that we have to do a gene walk at this point in time in order to find the right sequence. With a little bit of work, you can find an active sequence relatively fast. I think the evidence for that is in our FSHD program. It can actually accelerate in the midst of a pandemic. Using that digital format that nature has given us, we can rationally design drugs. Now if we can deliver them to a broad range of tissues, that really becomes a game changer for the way we think about disease. That's always been the dream. Phil's got the institute at UMass related to the dream. Yeah, of course, most diseases are not genetic diseases. They're complex interactions among the level of mRNA expression in the patient. One can know the therapeutic target even without understanding the underlying cause of the disease. If you have high cholesterol, we know what to do, even if we don't really understand the complex genetic interactions that led you to have high cholesterol. For most diseases, it isn't even clear how you would use these more permanent non-drug approaches, the editing approaches, because there isn't an obvious target. The ability to target a disease gene without having to know its function or its structure, which is the case that you absolutely need to know those for small molecules, is just really a paradigm-shifting approach. It allows the power of genetics and DNA sequencing and RNA-Seq to identify targets that RNA therapeutics can very rapidly jump onto. Yeah, going after FSHD, I have an MD-PhD student in my lab who has this disorder, and she's like, "I can't believe it." There's a company up the road that's going to start a clinical trial on this. It's been hereditary in her father, her grandfather. It's really a brave new world. It's really a fantastic time in medicine to see these kind of things coming into clinical trials to help these patients that otherwise have absolutely no help with the prior modalities. Yeah. It is remarkable. One of the things, we're thinking about this brave new world and helping patients in a broad number of different diseases. Just wanted to think about, and this question might take a little bit of time because it's a big future-looking question, but it took us 30 years to deliver oligos beyond the liver. We were in the liver. If you had to pick an organ, liver is not bad, but going beyond it took us 30 years. What is the next big dream, and how could it take us five years rather than 30 years to reach that next big dream for RNA therapeutics? Art, I don't want to leave you out, so Art, why don't you take a shot at the big dream picture first? The dream, and I think we've already gotten to the dream to some extent, but the dream that I have and a dream that I really look forward to seeing come to fruition is that we may have, at some point in the very near future, the ability to deliver oligonucleotide therapeutics to multiple cell and tissue types. Perhaps have a library of monoclonal antibodies or a library of bispecific antibodies that's going to allow us the specificity that we can use and the selectivity of targeting specific cells that we can use to deliver oligonucleotide therapeutics to a broad range of cell and tissue types. That we really do fulfill the promise that we've been talking about in the oligos space, in my 25 years in the oligos space, about this being another leg of the therapeutic stool, and that so that we can really begin to utilize oligonucleotide therapeutics appropriately. Now with oligonucleotide therapeutics having such long pharmacologic activity, we really are talking about potential revolutions in a number of different areas. My dream is having the ability, having a library of delivery agents that's going to allow me to go to tissue X, Y, or Z, target gene X, Y, Z. Again, this kind of the Tinker toy approach where we have our targeting ligand, we have our linker chemistry worked out, we then have our therapeutic. Pick your cell, pick your therapeutic target, link them together, off you go. It's my dream. I'd love to see it happen. I think we're very close. We're closer than we ever have been. I think using the understanding that we're getting from this technology and perhaps developing other technologies like bispecifics for these kinds of approaches will really potentially revolutionize the way that we even think about oligonucleotide therapeutics, which is already a revolution. Yeah. I think for me, the prospect of siRNA drugs for CNS disorders will be fulfilled in five years. We began working on Huntington's within a few years of founding Alnylam. To date, I think we're finally close enough that we'll see this in the clinic. However, the holy grail is to be able to deliver siRNAs intravenously to treat CNS disorders. I think that is still a major challenge. Obviously, one is not going to deliver siRNAs to treat diseases where there are existing drugs if you have to have direct administration to the CNS. That really raises the bar in terms of severity of disease and lack of options. I'd love to see that developed. For me, before we started, we were talking about baseball. I'm going to swing for the fences here. I'm a cancer biologist. I would love in my lifetime to have patients go to the clinic, get biopsied, have their DNA of the tumor sequenced by mass spectrometry, which is instantly. Then the doctor says, "Oh, yeah, you have KRAS 12, G12V mutation." Why don't you sit here, read a magazine. I just ordered your drug. It's sitting in a warehouse downtown. It'll be here shortly by drone. I'll inject it into you. You're going to come back in three months. We're going to do it all over again, see if any new tumors have any mutations arise. If they have, we have all of these sitting on the shelf. The model for this is when we order an siRNA today in a basic science laboratory from a reagent company, they don't make these siRNAs for us. They're already sitting on the shelf against KRAS, MYC, every oncogene, every important regulatory gene, there's libraries of vetted, validated siRNAs sitting in freezers on the shelf in reagent companies. They show up the next day or two days later. I hope that model can be applied to not only oncology, but to every or most human diseases. The one rate-limiting little, tiny, humongous problem is what's called endosomal escape. This is part of the delivery problem. These endosomes are like little vesicles, like a stomach. It's like your stomach in your body, and your food is sitting in there. If the food can't get out of the stomach into your blood, it doesn't count. For a cell, the stomach is this endosome, and the siRNA stay in there, as we talked about earlier, as a depot, which is fantastic because it drips in, the siRNA slowly escape out of there. We just need to figure a way to enhance that, maybe five, 10-fold would be fantastic, and have control of it. Then we can really hit diseases like cancer, which because of the cellular division and the metabolics of the diseases, are really difficult to treat. If we can enhance that escape into the cytoplasm of the cell, this idea of being able to deliver to any tissue, any cell in the body with targeting domains, just like Avidity has here, yeah, that's realizable in our lifetimes. It probably will happen sooner rather than later, the way this is really accelerating now. Because we're standing on the shoulder of the chemists that for 50 years solved every problem you're concerned about as an investor, the chemists have already solved that in the prior 50 years. I love the dream and the swinging for the fence. I love that. Specifically the drones dropping off the silencing RNA to clinic. I just thought that on the spot as I was thinking, right, you wouldn't use a messenger. By the time we can do this, you're not going to have a messenger on a bicycle doing this for you. It's going to be a drone. Yeah. That was awesome. Any last things, Art, before we wrap up the panel on the dream? I can't top Steve's dream with the drones and the whole works. No, I think that there is consensus that the dream is to have delivery systems that are reliable, that are cell-specific, and that can get the oligonucleotide therapeutics to where they need to get, whether that be the CNS, whether that be to tumor cells or tumor cells in a particular state or various cell and tissue types in other disease states. I think that the dream is clear and similar amongst us, and I think, yeah, it's a great place, and it really is a great place for us to open the questions up more broadly to the audience. Some of them will be directed at Avidity, and some of them will be directed at the experts that we have. It really has been a pleasure to be part of this discussion, and I love the dreams, and yeah, for those of us, Phil and Steve and I, who've all really lived through the evolution of oligonucleotide therapeutics, it is nice to see when you make a jump to yet another system that works. We made a jump from naked oligos or lipid particle oligos to conjugates, and now we've got specific conjugates. It is gratifying and really fun to be really fun and important in the field because we can now address more patients, and that's the key. Yeah. I'd like to just join Art in really thanking Steve and Phil for joining us on the panel. I think some of your dreams are the same dreams that why I recently joined Avidity, right? The opportunity to create that broad delivery platform, discover RNA therapeutics really quickly and turn them into medicines, and the opportunity to improve patients' lives. Those are my dreams also and the reason why I recently joined. Thanks to everyone, and I think, Art, you're going to be moderating questions from the audience. I will be. Thanks, Mike, and thanks. Let's realize some of these dreams. Yeah. Clearly, the audience hasn't held back with tough questions. The first one is. Phil has a lot of answers. Fortunately, Phil has all the answers. This one is from Ritu at Cowen. Ritu's asking about the physiologic distribution of the. Sorry, let me welcome Sarah to the panel as well. Thank you, Sarah. Ritu's asking a question about the physiologic distribution of the transferrin receptor across organs and tissues. I think I will take that one. We do know that the transferrin receptor is ubiquitously distributed across a number of cell and tissue types. Interestingly, the liver has its own transferrin receptor, transferrin receptor 2, but the transferrin receptor 1 is ubiquitously localized or not localized. What we found in our studies, however, is that if you deliver an oligonucleotide as an siRNA to a housekeeping gene that's conjugated to the transferrin receptor monoclonal antibody, that the primary activity that we see is in striated muscle and to a lesser extent, smooth muscle. We will see knockdown of our housekeeping gene primarily only in cardiac, skeletal, and to a lesser extent in smooth muscle. The data that we recently generated at toxicologically significant doses demonstrates that there is a little bit more activity there than perhaps we had expected. In general, the activity is not proportional to the expression of the transferrin receptor. It may be actually differences in tissue sensitivity are related to the way the transferrin receptor traffics after it's been internalized. Although we had expected, and really, we talked about this frequently in the past, we had expected that our AOCs built upon the transferrin receptor would have much broader activity than they did. We were given a gift here, much like the gift that the GalNAc had for the liver, where you only address hepatic parenchymal cells with our transferrin monoclonal antibody, at least the one we're using. We're seeing activity primarily in striated muscle and to a lesser extent, smooth, as I said, and very slight activity in a few other tissues. The distribution of the receptor itself does not necessarily predict the activity in that particular tissue. Ritu also asked another question related to did we see any effects on the kidney, and the answer is we did not see any effects on the kidney in our tox studies. Again, the data that we have is highly supportive of the fact that we're getting great activity, saturated pharmacologic activity, in the absence of adverse effects, using the classical toxicology endpoints, which have been thoroughly analyzed in that study. The next question comes from Joe Schwartz at Leerink. Joe is asking, and I'll let you have this one be a toss-up for folks, we can go around the table. He's asking about nuclear siRNA, is there any evidence that siRNA works in the nucleus more effectively in rapidly dividing tissues or in slowly dividing tissues? To date, I don't know whether I've seen publications that relate to that specifically. What we do know is that all the components for siRNA are present in the nucleus, I think Joe has recently done a review in that area. I have not seen data that suggests that there are differences between rapidly and slowly dividing cells, but it's certainly an area. I don't know whether Steve or Phil have any ideas on this. I've not heard that before. I've not read that or seen that presented at a meeting. No, I don't think we know the answer to that yet. Yeah. Clearly the data that we demonstrated today, and I think the data that have been demonstrated by labs like David Corey's lab and others, have demonstrated that there is nuclear activity of siRNA. I think some of the data that I showed today demonstrates that we can take advantage of the nuclear localization of the siRNA machinery to actually knock down nuclear targets. That's obviously key to our first program, where the toxic messenger RNA is trapped in the nucleus. I think I'll take this one, and Steve, you can have a crack at it as well. We have a question from Credit Suisse, from Judah from Credit Suisse, who's asking, can you walk through the process of endosomal escape for the construct? I'll take a crack at it, and then I'll let Steve have it. Steve, of course, has been spending the past seven, eight, I probably lost track of time, looking at endosomal escape. What I think is going on, hopefully Steve will concur, is that once an oligonucleotide that has been stabilized or modified in order to withstand lysosomal enzymes, once it's in the lysosome, ultimately the lysosomal membrane is being replaced and turning over time, or there are faults in it which can be detected using immunohistochemistry. If you look at some of the fluorescent proteins, like if you look at a fluorescent LAMP antibody, you can see that the LAMP flare will change over time. These are proteins that are associated with the lysosomal membrane. We know that the lysosome is essentially breathing, and it's at least my hypothesis that as the endosome breathes, the oligonucleotide can escape. No. Art froze. What he was going to say is the antibody's been degraded long prior to this, and it's kind of like going to the moon, where you jettison the main rocket once you leave Earth. That's kind of the equivalent of the antibody. Once it's in the lysosome, then because of the chemistry of the siRNA, it's metabolically stable, and it's trapped inside this lipid bilayer of the lysosome that is very similar to the lipid bilayer of the cell membrane. The direct answer to the question is, we do not know how you escape from in here to get out here into the cytoplasm. What we do know is it happens because we have all these controls and activity, et cetera. As Art was starting to discuss, lysosomes are not just this static vesicle type of an endosome. They're constantly fusing with other endosomes, with other vesicles as well too, and they're spitting out MVBs and all these different biology is happening. Every time you fuse or you pinch off a vesicle, there's a breach of the lipid bilayer. It may very well be that there is a modicum of escape that happens right as those vesicles get pinched off. It could be that there is actually a breach of the lipid bilayer of the lysosome, and that this happens when you look at the clinical trials in liver, it looks like maybe five siRNAs escape every hour for up to six months. It may very well be that plus this combination of the lysosomal vesicles that are fusing and pinching off that would lead to this amount of escape. You only need about five or 10 to escape every hour to continue to fill up Argonaute so that you're above this maximal number of siRNAs in the cytoplasm, which is only about 2,000, whereas a small molecule, it's about 100,000 to 500,000 molecules of that small molecule have to be in the cytoplasm in order for it to be active above its threshold concentration. Art, you got cut off and I sort of jumped in right near the end. Thank you for picking up the baton. Thank you. We went through 80 testing the water talks and on a whole roadshow. I'd never been cut off before. I'm joining by tethering my cell phone at the moment. My apologies for getting cut off. You're the lucky guy. In fact, I'm glad you're here to pick up the baton. You went right with it. The thing that I would add about the endosomal escape is while we don't know the mechanism, and it may just be sort of an artifact of evolution where for these really small RNA molecules, siRNAs, there wasn't this protection for having them invaded because prior to RNA interference, they didn't have any genetic information that could alter the nascent cell back in the primordial world. While we don't understand these mechanisms, we do know that they happen, and they happen at very low doses. You're looking at single doses of three mg per kg on average that give you a three-month PD response. Once we know what these mechanisms are in academic laboratories like mine and many others around the world are investigating this, they present an opportunity for us to design the siRNA or the whole delivery molecule in a way that takes advantage of whatever this mechanism is so that we could further enhance the endosomal escape. We'd still have this depot effect of 80%-90% of the molecule in the endosome, in the lysosome that could slowly come out over three to six months, but we could enhance that escape if we understood these mechanisms. It's a new area of research that there was many problems to solve prior to this. This is now the rate-limiting problem is endosomal escape, and there's, as I said, labs around the world at universities and institutions that are investigating this, as well as biotech companies. A solution will be identified that will be viable for the clinics at some time in the relatively near future. Thanks, Steve. It's great to have the endosomal escape guy on the panel today because I think that is a key question. We all know that there's orders of magnitude more potency that we can get out. The question is whether you can do it safely. We have another question from Josh Schimmer from Evercore. He says, "Great overview. Thanks for hosting." More importantly, he's asking, we see a lot of promising preclinical data, and do we have thoughts on why there's been a translational gap? Why have we not been able to translate so well from preclinical data to the clinic? Steve, Phil, I don't know whether you want to take this one. I know it sort of- Yeah. I'm not sure that's true anymore, right? I think the most established siRNA platforms can go from target identification to IND in less than 18 months. You can't achieve that if the majority of your preclinical trials are failing. I think they're having tremendous success at translating into viable clinical strategies. Thus far, there are three plus approved siRNA drugs on the market. I think we're going to see an acceleration of successful clinical programs. I would just add to that, I think that thinking is sort of in the black and white century, and now we're in the color century. The molecules today, if they work in a non-human primate, an NHP, then that's almost a one-to-one dose carryover and safety profile into humans. If you work in a mouse, you would say, well, okay, maybe it's going to work, maybe it's not going to work. In all likelihood, it will. If it works in NHP and all the RNA biotechs, including Avidity, I mean, NHPs is the go-to model here because it tells us so much information of what the clinical trials, the protocol will be set up as and what they'll look like. Yeah, I think that's kind of a pre-conjugate question, whereas we're in the AOC world now that's entirely different, much higher odds of success. Pulling out my toxicology card since I'm a card-carrying toxicologist, I think many of the drugs that have failed where you didn't get the translation is you ran into toxicity before you get pharmacologic activity. With modern oligonucleotide therapeutics, and particularly siRNAs and, of course, the relatively non-toxic PMOs, we're not running into those problems anymore. We have the ability to more effectively deliver. We have therapeutic agents which have lower levels of inherent toxicity. When you combine lower levels of inherent toxicity with lower levels, because you now have targeted delivery, you're going to increase the probability you're going to achieve pharmacologic action at levels which are therapeutically attractive and which are well within the therapeutic index of a particular compound. I think. Go ahead, Zamore. I was just going to say, I think that is just a reflection of the fact that siRNAs work catalytically, that very small amounts of siRNAs are needed to have a very significant impact on the expression of a target gene. The big difference now is we have a platform where the therapeutic index is huge, and you're delivering a very small dose with most of the siRNA in the endosome. Where the endosome is acting like a depot for us. Yeah. Let's move on. We have to get a lot of questions in. We have another question from Chad Messer from Needham, who's looking at the AOC 1001 IND-enabling studies. I guess I'll take this one as well. He's asking whether the differential in potency between skeletal and cardiac muscle is explainable by transferrin receptor biology. I think the answer to your question, Chad, is that it may be. There are multiple factors that are going on here. I think there may also be greater nonspecific uptake in cardiac muscle so that you may have higher concentrations in cardiac, there's nonspecific uptake of the antibody. We don't know for sure how that receptor biology might be differing between skeletal muscle and cardiac muscle, but clearly, there are differences in the concentration response curves. Clearly and importantly for the patients with myotonic dystrophy, we effectively deliver to the heart, and we get effective reductions in the toxic RNA expression in cardiac muscle. The data suggests that while the potency may not be there at the doses that we're giving, there are effective levels that are being achieved, and we're getting the reductions in the expression of the DMPK in both cardiac as well as in skeletal muscle. Mike Flanagan, there is a question that's specifically directed towards you, lucky guy. Should we expect AOC 1044 to be in the clinic before the FSHD AOC? Yeah, I guess, based on the announcement today, you might expect that AOC 1044 would be first to enter in the clinic. As we talked about, FSHD program has accelerated, and they're really kind of neck and neck. I'm not really sure which one's going to enter the clinic, but what I can tell you is that we're looking forward to both programs being in the clinic in 2022. I hate to put it on the teams, but we'll see how neck and neck, we'll see who wins the race. I think it's a good question on AOC 1044, and we're excited about both programs. I have a question on BD strategy and how we're going to expand the utilities of AOCs. In fact, Sarah, I can address that one to you. Sure. Thanks, Art. From a BD perspective, I think it's first important to note that for rare disease, they're the types of programs that we plan to develop and commercialize ourselves. When we look at BD, there's an element around how can we accelerate the technology, and I think two good examples of that are our collaborations with Lilly and now with MyoKardia. The collaboration with Lilly primarily focused on the immunology space allowed us to be able to accelerate the technology into a new therapeutic area. It also enables us to work with an expert in that field. That collaboration is a set number of targets. There's six targets, so we have the rest of the space to work for our own programs. MyoKardia is a similar type of structure, a research collaboration, single target in this case, that allowed us to be able to work with experts in targeting the heart and to learn with them, to also then, in turn, be able to develop our own programs. As you see an approach with regards to expanding the technology, it's very much my plan to very much be a blend of both our own efforts internally as well as also partnering with respective leaders in certain therapeutic areas or certain aspects. Great. I have a question from Yanan at Wells Fargo, and he's asking in our first-in-human study, I guess this one is directed to the Avidity team. In our first-in-human study, would it be possible to achieve doses that enable the tissue concentration above the 10th nanomolar concentration that we showed for our EC50 for our non-human primate studies? For example, the high potency of AOC 1001 would it be possible to achieve an EC90 in clinical trials? I guess I will take that one as well. The answer is, of course, as we negotiate with regulatory authorities for our starting doses and ultimately the full dose range that we're going to be using in our clinical trials, we would certainly hope to be able to achieve the 10th nanomolar concentrations that were associated with the EC50 in our non-human primate studies. As to whether we could achieve an EC90, I think certainly the data suggests that the concentrations that are required there are relatively modest and may be achievable. It really ultimately will depend upon some variables that we can't address today, and that is where we start our clinical trials and also how well the data translate from the non-human primate to the human. In particular, we will expect some differences in the disease subjects versus the non- human primates that we've been assaying up to this point. However, I think that those differences are certainly addressable with the high potency siRNAs that we're administering as part of our AOCs. There are a couple more questions. Art if I could just add one comment to that. For the audience, when we talk about 3 mg per kg, because these are much larger molecules than small molecules, an siRNA is about 25x the size of an average small molecule, that the 3 mgs per kg, the number of molecules the patient's being exposed to is 25x less than a small molecule drug exposure. The safety profiles are much better. We're talking milligrams. We really should be talking about nanomoles that are administered to the patient, but traditionally, because of small molecules in the pharmaceutical world, we're talking about amounts, milligrams per kilogram instead of nanomoles per kilogram, which would be an apples-to-apples comparison of the actual numbers of molecules, and that the number of molecules a patient's exposed to is directly related to safety and toxicity profile. There are a couple more questions, then we'll wrap up. There's a question from Joe Schwartz at Leerink. He's asking, if we have positive results in our DM1 study, how much does that read through to other diseases? Mike, Sarah? Well, for me, I think first proof of concept and just understanding the dose and response in patients is huge, right? You're building on a platform. You have the same transferrin receptor with different siRNAs. I think that will tremendously help speed and accelerate our internal research to deliver new medicines faster. Yeah. I think, Mike, to build on your point, the aspects, looking back at our goals when the company was founded, around tackling what has been one of the real challenges in the RNA therapeutic space, which is around delivering. We're really looking forward to the aspect of starting a program where being able to deliver RNA therapeutics to muscle. Of course, there's an element of platform in there, as Mike talked about. Also each program in our pipeline for different diseases. One of the things that we know from rare diseases is that each development program is unique. Part of our strategy also builds very much where we built things like patient advocacy and medical affairs early from an aspect of really understanding each disease, both from a patient caregiver and a physician experience, to help us better design our clinical programs. Each clinical program is unique because each disease is unique as well. Of course, there is an element, very much a platform in here as well, which we're pretty excited about. I think we've seen this already in the siRNA arena, that, of course, the first conjugated siRNA. We got the second, we got the third, we got the fourth, again, you begin to pick up momentum. I think getting some good momentum going with our DM1 program, where it really is a program where we're talking about a toxic RNA, knocking down the expression of a toxic RNA, really will provide us with a significant amount of momentum moving forward. It will allow us to really get to an even faster cadence of drug discovery, getting drugs into the clinic, and getting drugs approved for the patients who need them. There's also a question. Perhaps Mike and I can address this one. Can you elaborate on the translational value of the non-human primate DMPK knockdown? That's the target gene we're talking about in healthy non-human primates compared to the disease state. Art, you want to start first? Sure. Of course. When was I ever shy? We've obviously thought through that, and with existing data that we and others have generated, we are expecting that there will be a slight reduction in the potency of the siRNA in the disease state. I think the data that I showed you demonstrating that there were differences between nuclear and cytoplasmic knockdown, you saw that there was 70% reduction of cytoplasmic fraction. We had slightly less in the nuclear fraction, somewhere around a reduction of 70%. We know there's going to be a little bit of a difference in the translation there. In a worst case scenario, you might think of a fivefold or a 10-fold loss of activity. Because the agents that we're using are so potent, I think that any reduction activity we might have related to the disease state should actually end up translating quite well from the existing non-human primate data. I think that the data that we've collected to date t he data from previous experience with other oligomer-based therapeutics, particularly siRNAs, that suggest that the non-human primate generally underpredicts for man, still all bode well for us, even if we lose a little bit of potency in a disease state. Certainly, there's no surprise that the disease state, even though we've selected the siRNA based upon knockdown of DMPK in cells from a human subject with myotonic dystrophy, we selected our siRNA specifically for that, we still know that there are going to be differences in the way that that messenger RNA conforms in space. It's going to be crowded with Muscleblind-like protein. There's going to be other proteins that bind to it. We're expecting that there will be a slight reduction in the potency in a diseased state, and certainly the data in the nuclear RNA, mRNA. The data that we've collected to date suggests that that should be overcome by the sheer potency of the siRNA that we're using in this particular case. When I look at it, the key things are that, as Steve and Phil had indicated, we have non-human primate data that translates quite well to humans. Second is that we're using siRNAs that have a broad therapeutic window. I think, given that we see activity in non-human primates, we have a broad therapeutic window, I think we can reach those doses that will knock down the mutant DMPK in the clinic. It's always a challenge, right? The clinic is always a challenge because patients come in with a variety of different number of repeats, different kind of clinical manifestations of disease. Trying to understand how that knockdown of mutant relates to clinical benefit is always a challenge when you have a variety of unique patients coming through for clinical trials and then future treatments. Honestly, I did diligence before I started on the company because it's my career. I did that diligence, and the non-human primate data is quite compelling. For such an early company having seven different non-human primate studies and now GLP that looks really clean, I think we have a really good chance. Great. Thanks. I think that's a really great point to close the discussion and turn it over to Sarah for wrap-up remarks. Before that, I want to thank Steve and Phil for joining us today and for their expertise. Sarah? Thanks so much. Thanks also from myself as well as on behalf of the team for Steve and Phil for joining us today. Really been such a pleasure to have you on the panel. In terms of, firstly, we hope you've really enjoyed the discussion, thank you very much for also the questions. One of our goals for today was to provide that deep dive into the engineering that has really underpinned the technology, as well as that aspect of what we have the potential to be able to do with our technology as well, with our different clinical programs, as well as that progress that we've made, both with AOC 1001, with regards to entering the clinic in the second half of this year, also in terms of advancing AOC 1044 into IND-enabling and IND-enabling tox. One of the other aspects as well, very much here for me, I really enjoyed the broader perspective and some of those dreams on the future of the RNA therapeutic space, very much enjoyed your questions. It's one of the things that we probably enjoy the most, is being able to talk about our technology and get into those scientific discussions. In terms of one of the aspects we also spoke about a little on the panel is the aspect of that pre-clinical proof of concept and also looking at additional skeletal muscle and other tissues. Very much AOC 1001 is the beginning, with two other programs entering into the clinic behind it in 2022. We hope in terms of much more to come from an aspect of delivering our goal, to be able to really impact people's lives, and in particular, people living with rare diseases, people like Luke who lives with Duchenne today. With that, I'll close out and thanks very much and enjoy the rest of your day. Take care.