Thank you for standing by, and welcome to REGENXBIO RGX-202 interim data call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. To remove yourself from the queue, you may press star one one again. I would now like to hand the call over to President and CEO, Ken Mills. Please go ahead. Hello, good afternoon, everyone. This is Ken. If you're joining through the webcast, there are slides available and they are self-guided. If you're joining on the phone, the slides are available on the investor section of our website. I'm going to start on slide two. Thanks for joining the call today. I'm very excited, so we'll get right into it. We have two updates today. First, we're reporting an update on patients dosed with RGX-202 from dose level of our AFFINITY DUCHENNE study. This update will be presented at the World Muscle Society conference in Charleston, South Carolina, this week. Compared to our last update in July, this will include additional patient, longer-term follow-up, safety, and first measures of RGX-202 microdystrophin expression from patient biopsies that are collected at three months. Second, we're reporting on updates to our program plans, including recent AFFINITY DUCHENNE trial amendments designed to support the acceleration of the development of RGX-202, to provide a clear path to a goal to submit a BLA using the FDA Accelerated Approval Pathway, with RGX-202 microdystrophin as a surrogate endpoint for clinical benefit. With us today to update are Dr. Steve Pakola, our Chief Medical Officer, who will walk us through the clinical data, as well as Dr. Aravindhan Veerapandiyan, who is a pediatric neuromuscular neurologist at the Arkansas Children's Hospital and also a treating physician from one of our AFFINITY DUCHENNE trial sites. And he will share his observations and impression of the trial with us today. Moving on to slide three. But before I go further, I have to stop here and remind everyone that today's conference call will include forward-looking statements regarding our financial outlook, in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, or other words of similar meaning. Moving on to slide four. In January of 2021, we introduced a program for the development of a potential one-time gene therapy for the treatment of Duchenne, which is based on a novel microdystrophin construct. Since then, our team has worked tirelessly and in meaningful coordination with the Duchenne community. These are some photos of members of the REGENXBIO team sharing their passion and engagement with members of the Duchenne community. I wanted to stop here and thank the families, the advocates, the partners, many of whom have become friends, and all of whom have provided our team inspiration and support over the last several years. You motivate our continued commitment to discover and develop new treatments for Duchenne. Thank you. On slide five, today, we're here to discuss the lead program in our pipeline of AAV therapeutics that are designed to treat Duchenne, a rare disease caused by mutations in the DMD gene, which is responsible for making dystrophin, a protein of central importance for muscle cell structure and function. All of our treatment candidates are intended as a potential one-time gene therapy for the treatment of Duchenne. If you're listening today, you're probably already familiar with the fundamental science at the core of our approach, AAV-mediated microdystrophin or AAV microdystrophin treatment. Data from dystrophic laboratory trials and recent human trials suggest that AAV gene therapies delivering a form of microdystrophin, such as our RGX-202 candidate, may provide new and substantial added muscle function for patients with Duchenne to support a change in the trajectory of the disease. Recently, we've seen the first FDA approval of an AAV-mediated microdystrophin gene therapy. While in principle, all types of DMD gene mutations are addressable with this microdystrophin platform approach, clinical evidence from a number of sponsors of AAV microdystrophin gene therapy trials suggest that certain mutations or clinical backgrounds might need to be excluded from accessing certain treatments. In addition, not all microdystrophin gene therapies are created equal. Today we'll talk about some evidence of important advances in science that present as potential improvements. With over 300,000 boys living with Duchenne worldwide, there continues to be an undeniable and important unmet need for patients in the care and the potential treatments, including investments in novel approaches like RGX-202 for Duchenne. So let's jump to slide six. Depicted in the cartoon on the right is RGX-202, our novel, highly differentiated treatment candidate. The design of RGX-202 is based on innovative science and vector engineering by REGENXBIO scientists, and incorporates learnings from the laboratory of George Dickson, the University of London, pioneering figure in dystrophin research. The features of RGX-202, excuse me, include a transgene for a novel microdystrophin that includes the functional elements of the C-terminal domain or the CT domain, that's found in naturally occurring dystrophin. You're going to hear continued reference to me for the next few slides to the CT domain. You see, the presence of the CT domain, perhaps our most differentiating feature, has been shown to recruit several key proteins to the muscle cell membrane, leading to improved muscle resistance to contraction-induced muscle damage in dystrophic mice, especially when compared with transgenes, for instance, without the CT domain. The data from dystrophic laboratory trials suggests that a gene therapy delivering a microdystrophin, incorporating an extended coding region from the CT domain, such as RGX-202, may provide substantial added muscle function for patients with Duchenne. Another element of RGX-202 is a well-characterized muscle-specific promoter called Spc5-12. This feature further supports the delivery and targeted expression of RGX-202 microdystrophin transgenes throughout the skeletal and the heart muscle. That's where it's needed most. Finally, RGX-202 is designed to use the NAV AAV vector, a vector that's used in numerous clinical trials, both run by REGENXBIO and others, and therefore, with a well-established profile. Moving on to slide seven, and with these elements and features in mind, our RGX-202 program has several distinct potential differences and advantages over alternative microdystrophin gene therapy candidates. Slide seven shows more cartoons, but with RGX-202 features aligned with other familiar products and candidates that represent some of the class of AAV-mediated microdystrophin. With RGX-202, again, we can focus on our AAV capsid design. In addition to being a well-characterized AAV for targeting muscle, this time, the AAV capsid also represents an alternative for boys who may not be eligible for other AAV-mediated microdystrophin with other capsids due to the presence of preexisting neutralizing antibodies. We estimate that they may be anywhere from 15%-30% of boys, emphasizing the need for diversity in capsid features to help address a broad population of Duchenne boys. Again, we look at the transgene. Achieving the same levels of expression as other gene therapies have demonstrated, our CT domain design has the potential to improve outcomes in boys with more biologically potent and stronger microdystrophin. You see, again, the CT domain is involved in recruiting and building a very complex set of proteins around dystrophin naturally. Dystrophin really acts as a hub in the muscle and cardiac cell, attracting other proteins that serve all kinds of important physiological functions for the cell. We believe, and we've actually shown, that adding the CT domain brings back more functionality in terms of getting together more proteins that are essential for more muscle function in animals. CT means more function. I'll circle back on this soon. Lastly, I just wanted to emphasize that we make RGX-202 with a commercial-ready, high-quality process with high yield and purity to support the potential for rapid development and commercialization. We're recently encouraged that the FDA has supported the accelerated approval of the first in the class of microdystrophin AAV gene therapies, providing a much-needed new therapeutic alternative to the Duchenne community and important clarity on the regulatory pathway for this class of treatments. We believe this approval event provides a clear path for us to submit a Biologics License Application or BLA, using the accelerated approval pathway with RGX-202 microdystrophin as a surrogate endpoint for clinical benefit. Now, finally, on to slide eight for some of my remaining points about our journey to support novel treatment for Duchenne. Basically, when you look at history, science has been guided for many years by the nature of mutations found in attenuated forms of Duchenne muscular dystrophy, which is called Becker muscular dystrophy, where patients have very large deletions in the protein, but still have some function left, and this has guided the design and development of gene therapy treatments. We've emphasized that with RGX-202, it's designed to deliver a microdystrophin transgene, which includes the extended coding region of the CT domain that's found in naturally occurring dystrophin. Throughout the literature, it's also reported to be that the CT domain is universally present in dystrophin from the Becker phenotype. This is nature supporting the biological plausibility of the design feature itself. Now, as we saw in the prevous slide, Slide seven, a CT domain can be left out of some microdystrophin constructs, and that's what's been done before, because it's not absolutely required for some essential function. However, presence of the CT domain in nature shows clear evidence of the biological relevance. You can see, as is further indicated on this slide in the cartoon, where those CT binding domains for these necessary and important recruited proteins, which help stabilize muscle function and physiology. Protein like dystrobrevin, has an important role. Syntrophin is a group of proteins that also attract other proteins, and they're important for physiology of muscle. These protein species constitute what is referred to as the dystrophin-associated protein complex, or on this slide, the DAPC. So while RGX-202 microdystrophin is a short version of dystrophin designed to fit into AAV vectors, its design is most similar, compared to others in the class, to the dystrophin that is observed in the Becker Muscular Dystrophy phenotype, specifically because of the overlapping inclusion of elements of the CT domain. So while it's possible to build truncated dystrophins that are still active without the CT domain, it seems useful, if not essential, to include the CT domain if you could do so. It was this thinking that led REGENXBIO scientists on the journey to design RGX-202. We began our design of RGX-202 only a few years ago. Many of the references you're looking at associated with earlier candidates in development were more than 10 or 15 years old. ... So it's a blend of innovation of science, the recent understanding of dystrophin, the design of microdystrophin gene, and AAV vector development that is now well established that allowed us to start this promising journey. I'd really like to turn the call over now to Steve to lead us through the interim update on the AFFINITY DUCHENNE trial. Thank you, Ken. Good afternoon, everyone, and thanks for joining us. We are thrilled to share our interim clinical data from our AFFINITY DUCHENNE clinical trial. Before I turn to the data, you can see on slide 10 the main study design elements and the key interim outcome measures we are presenting today, which include safety and 3-month biomarkers for RGX-202 microdystrophin expression. Importantly, we chose to measure microdystrophin expression by two separate methods. First, by Western blot, using an instrument and method called Jess, which provides an automated and more precise measurement than a traditional Western blot approach. Our team has also developed a proprietary liquid chromatography-mass spec method, or LC-MS, among the most sensitive means to assess expression. To our knowledge, we are the first and only sponsor to assess microdystrophin by these two different methods. Slide 11 shows the age, weight, and duration of post-treatment follow-up of the three boys treated to date. RGX-202 has been well tolerated in all three boys, with no SAEs observed. The first two treated patients have reached the three-month time point and have had muscle biopsies collected. On slide 12 are the results for the four-year-old patient. Change in microdystrophin expression from baseline was 38.8%, as measured by Western blot and reported as a% of normal control, meaning levels of wild type dystrophin in boys without muscular dystrophy. Importantly, we see comparable results on the proprietary LC-MS method. Additionally, a reduction from baseline in serum creatine kinase, CK, of over 40% was observed. On slide 13 are the results for the 10-year-old patient, showing microdystrophin expression of 11.1% compared to control, with comparable results seen on LC-MS. This patient also had a decrease in CK levels of over 40%. On slide 14, we also see assessed microdystrophin expression via immunofluorescence staining at 3 months, where you can see clear microdystrophin expression in a high proportion of muscle fibers, as well as localization to the muscle cell membrane. So in summary, results from the first three patients show RGX-202 was well tolerated, and initial results from the first two patients show robust microdystrophin expression and appropriate localization to the muscle cell membrane. Now, in addition to these new interim clinical results, we also present new preclinical pharmacology results in the mdx mouse model that are shown on slide 17. The same two doses being evaluated in AFFINITY DUCHENNE, 1E14 and 2E14, manufactured by the commercial-ready process, demonstrated highly statistically significant improvements in muscle function, as assessed by grip strength and treadmill exhaustion compared to untreated mdx mice. It was also observed that the 2E14 dose restored both grip strength and treadmill performance to wild-type mouse levels. These strong preclinical results further support our plans to immediately initiate dose escalation to dose level two. We are also excited to announce the approved amendment of the protocol to allow accelerated development by being able to expand the dose level two cohort after dosing of two staggered patients instead of the three previously. We, in addition, expect to initiate pivotal phase development in 2024, with a clear path to submit a BLA using the accelerated approval pathway with microdystrophin expression as a surrogate endpoint for clinical benefit. And with that, I'm glad to have the opportunity to turn to Dr. Veerapandiyan, principal investigator in the AFFINITY DUCHENNE trial. For those of you on the call who don't know this, Dr. Veerapandiyan is affectionately known by patients and families, and his colleagues, and us by the name Dr. Panda. So Dr. Panda, first, thank you for joining us today to discuss the 202 program. You're not only a very experienced Duchenne clinical trialist, but you actually treated two of the boys within the trial that we discussed today. So I think it would be great to start off hearing from your standpoint as not only a clinical trialist, but a clinician who treats a lot of Duchenne boys in your clinic. Can you tell us how do you think of these results, and what are some of the key takeaways for you when you see these results? Yeah. Thank you. Thank you, Steve. Hi, everyone. Steve, like, you know, we always say, I think there is still an unmet need for these boys with Duchenne muscular dystrophy for a treatment that can change the trajectory of the disease. Can you hear me okay? ... Yes. So I think, you know, while these results are early, I am very excited and encouraged what we have seen so far, what we have seen so far, right? So when you talk about the safety, we know with the gene therapy overall, especially the AAV-based gene transfer therapies, there are adverse effects that can be seen within the first two weeks, and then there's a set of adverse events that can be seen around four to eight weeks after the infusion to your immune system. And I think I'm pleased to see that at least two of these patients have passed those thresholds, and we have not seen any serious adverse events on any of them so far. I think that's very encouraging. From an efficacy standpoint, the robust expression of microdystrophin that you have presented, that we have seen in these boys, and also the microdystrophin is actually seen where it should be, seen in on the muscle cell membrane. So I think these are all very encouraging and exciting, and I'm looking forward to continue to follow these boys long term and also to move on to the next dosing phase, which is a dose 2. Excellent. Thanks, Dr. Panda. You, you mentioned not only the safety but also being pleased with the biomarker results that we're seeing. Maybe you can say a little bit more about that and maybe your perspective on what Ken elucidated in terms of the differentiators of RGX-202 vis-a-vis the functional elements of the CT domain. Are those differentiators aspects that are important context when you look at the results here and you think of potential benefit for your boys with Duchenne? Right. You know, I think like Ken had explained about the construct and the importance of the C-Terminal domain. We know from the preclinical studies and data we have, that that's actually that domain is important in maintaining the structural integrity of the muscle membrane and also, you know, to the other proteins to be involved in this whole complex of keeping the muscle membrane intact and the muscle fiber intact. But I think how that translates into a boy with Duchenne and how is that gonna affect the disease trajectory, I think we would know from the study, and I'm excited to see that difference in the construct and see what how that can affect, you know, the microdystrophin levels and especially the functional outcomes related to that. I think, you know, we also touched upon the biomarkers. One other impressive thing that we noted here is the serum creatine kinase level drop around more than 40% of the baseline, which is quite impressive. Now, these boys have high serum creatine or CK levels, you know, from the get-go, from day one, indicating the muscle damage. Reduction of that, it is quite impressive. Now, one could argue that could some of the steroids that are being given and some of the other immunosuppressive agents that were given, you know, proactively, could that play a role in the reduction of CK levels? Again, that's why we can't completely exclude that. I think, still this amount of reduction is impressive, and continue to collect that CK data long term as we continue to follow these boys would be much more helpful. Great. Thanks. Thanks again, Dr. Panda, for sharing your insights. And now we'll turn the call over to the operator so that we can take questions from the audience. Operator? Thank you. As a reminder, to ask a question, you will need to press star one one on your telephone. Again, that's star one one on your telephone to ask a question. To remove yourself from the question queue, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Gena Wang of Barclays. Thank you. I hope you can hear me okay. I don't know if my signal is good enough. We can hear you, Gena. Okay. Okay, perfect. So, first wanted to say congratulations, and I have tons of questions, but I will limit myself to two questions and then leave my colleagues to also ask other questions. I will jump back to the queue. So the two question is: the first, you know, seems like, you know, the protein level is very good, a very for the four- years- old. So the question is whyrotatiro rotat 4-11, when we look at across, you know, all the clinical trials or like, you know, the ongoing clinical trials, usually the 4-7, and we understand the older patient, the muscle, you have more damage, more irreversible damage, so will be a little bit more difficult to improve. So maybe first question, you know, why going after older patient, not limit to the younger patient, that would be easier to show clinical benefit? And then my second question was regarding the regulatory path, and the biomarker for approval. Was that based on the FDA feedback? ... Thanks, Gena, for the good questions. And thanks for limiting it to two. We know everyone's probably got a lot of questions, so we'll keep everyone moving. I think you bring up a good point about, you know, the, the data. We're being as, of course, transparent as we always are about everything that we're generating. You know, we, we don't have access to all of the data from all patients that have been treated with AAV microdystrophin with respect to microdystrophin levels, for instance, in, you know, some patients in trials that have been dosed over age seven. So I think we do, you know, have, have sort of some of the best comparability data between sort of that age range of 4-7 and what we're seeing with respect to the four-year-old. With the 10-year-old, we're excited about these levels. I think, you know, the, there's a lot of discussions going on with respect to the team and the, the physicians about how to think about what can be achieved, in patients of, of those ages and sort of, you know, different backgrounds of disease. And the fact that we're seeing strong signals of expression on both Western Blot and, LC-MS, gives us confidence that this can, as Dr. Panda alluded to, have the potential to change the projectory, trajectory rather, of, of patients in that age range as well. Even, you know, maybe sort of let him speak to how he views the difference between, you know, the opportunity to preserve function in a, in a four-year-old versus a 10-year-old. But on the biomarker point, Gena, look, we, the accelerated approval of the first AAV gene therapy product on the basis of microdystrophin, I think, is a strong, you know, regulatory and legal precedent. We have been, you know, lobbying for that and emphasizing it with our colleagues for years. We formed the Pathway Development Consortium with Solid Biosciences and teamed with them on making arguments for the use of biomarkers to support accelerated approval in Duchenne. I know that a lot of industry participants support that, and we believe that FDA has made it clear to industry sponsors with respect to the class of microdystrophins, that this is an acceptable endpoint. So we rely on that. We rely on the historical conversations, discussions, and that action. Dr. Panda, any thoughts about four-year-olds and 10-year-olds and the opportunities in both cases to, you know, affect disease and preserve or improve function? Sure. Yeah, that's a, that's a great question, Gena. I think, one of the things is there is, one, there's not a lot of, possibilities or options available for those late, ambulatory boys. Number one, I think it's, it's, there's, there's a greater unmet need for that group. And that way, I'm, I'm so happy to see that we're including boys that are older than seven. But, to your point, I think from a, from a safety perspective, right? I think the, the age, really is not key. It's, it's, it's how much they, they weigh. I think the more vector load that you give, that potentially increases risk of adverse effects. So I think the age factor doesn't play into role in that, in that perspective. But obviously, when they're older, their disease is more progressive. So, if their muscle there, I think, you know, it may be hard to show a functional improvement within a short period of time in those boys. But, from a microdystrophin expression perspective, I think it's important to know that these older boys who have more severe disease, have more muscle gone, also showing expression and where it's supposed to be is critically important, if you're looking at, you know, long-term approvals, for these boys. Thank you. Operator? Thank you. Please stand by for our next question. Our next question comes from the line of Dane Leone of Raymond James. Hi, thanks for taking the questions. Congratulations on the first data set here. Very exciting. I'll follow Gena's example and limit myself to two questions here. So two related questions. I guess the first one being the microdystrophin expression from both boys, I think, came in at the higher end of expectations, which is great. Could you opine a little bit on one, what you would expect in terms of a potential dose response when you're doubling the dose into dose level two, and what that could be reasonably expect to affect on microdystrophin expression levels? And then secondly, focusing on the older patient, patient two, who's over ten years old. The 11% microdystrophin expression does seem like you could potentially get into a clinically relevant range with the higher dose level. What would be the expectation of what you would need to hit on microdystrophin expression to feel good about seeing real clinical effect on, you know, different functional assessments like the North Star Ambulatory Assessment? Thank you. Yeah, thanks, Dane, and thanks for your continued leadership on keeping it to two questions as well. So, look, I think we're incredibly enthusiastic about the results that we're seeing early here with respect to microdystrophin expression. And we're, you know, eager to start to build the case for the relationship with functional assessments. I think, you know, we had a set of, you know, preclinical experiments that we had done to sort of, you know, design the study. And that was relying on the fact that, you know, we had a dose curve that sort of signaled that 1E14 was going to be, you know, starting to be a minimally effective dose. I think it has, you know, presented so far as having met or exceeded the expectation. But with respect to 2E14, and I think we've brought this forward, we were running this preclinical study recently to really dig into a head-to-head comparison between 1E14 and 2E14. And we started to see functional benefit differentiation, not just from wild type and near normalization of wild type function with 2E14, but, you know, separation even between 1E14 and 2E14, that got us similarly excited. And that really, between that, the safety data that Dr. Panda has been emphasizing, and the levels of microdystrophin, you know, we think we can get more. Can we get, you know, two times the levels of what we're seeing at 1E14? I think it's within the realm of possibility, but we need to see. I think functionally, though, we think we can achieve more at the higher dose, and we, you know, want to start dosing that dose as soon as possible, certainly before the end of the year, and be able to make a dose decision as efficiently as possible, and as early as possible in 2024 to be in pivotal phase. So I think we'll be relying on safety and the other measures that we presented today to be able to affect that decision. Again, you know, reflecting on, you know, I think the 10-year-old, you know, we have been, you know, aware of and familiar enough with kind of, you know, the points that Dr. Panda made, that, look, there's less muscle. More muscle, more functional muscle has eroded in older children, and there's a higher unmet need, and there's on a weight-based dosing, you know, there's more virus that needs to get to these kids, which, you know, in some ways, presents questions about, you know, are we presenting with something that can continue to show safety, which we so far have been really comfortable with and happy with? And on the other case, we really wanna help these boys. You know, I mean, there's clearly still a significant unmet need here. I think there needs to be more data, more community engagement. I go back to that slide four that I showed. I think the number of people in the community, number of, you know, families, the number of physicians that have expressed significant interest in that unmet need. We're gonna be really efficient about the execution of the development in the 4-7 age range. I mean, there's a playbook there now that I think has been, you know, carefully curated and managed by a lot of stakeholders, and I think we wanna follow that. You know, I think in the 8-11 range, we wanna continue to generate more data and have, I think, the advantages of things like the science of the CT domain, potentially address more of the unmet need there as well. Dr. Panda, I feel like this question is gonna keep coming up. Yeah. I'm gonna bring it back to you again. Yeah. I mean, anything else from your clinic that you see about, you know, that dystrophin level and microdystrophin level in a 10-year-old that you can comment on? Yeah, I think... Yeah, thank you, Ken. I think, you know, can the, the double, double dosing, you know, going up to the higher dose, double the dystrophin levels? I agree with Ken. We don't know. It's still, it may be possible, but doubling it, right? But, one thing we need to, you know, we need to, when we talk about the functional improvements and other things, we need to, we need to keep in mind is, we have seen, we have seen change in the, the course of the disease, instability in treatments, in dystrophin-restoring treatments that make much lower level of dystrophin than what we are talking about. So I think that's. So I think we need to keep that in mind. And also, we are not. We are going... The dystrophin microdystrophin expression we're gonna see is gonna be a range. I don't think every you know we're gonna because every single boy is different. The same having same genetic change can you know can look different in these boys. So every single one is individual boy. So there's not gonna be one magic number that we're gonna skip to, "Hey, all of these boys are gonna have 50%, 60% dystrophin production." It is gonna be a range, and we know overall, over a long period of time, you will find a difference in those boys who are treated versus non-treated. If that helps you get a you know get a picture. Yeah. Good, good context, additionally. Thanks, team. Great. Thank you. Uh, operator? Thank you. Our next question comes from the line of Alec Stranahan. Again, that's Alec Stranahan of Bank of America. Hey, guys. Thanks for taking our questions, and just wanted to offer my congrats on the data as well. Just a couple from us. Just to put a finer point on the baseline characteristics, could you maybe speak to the commonalities or differences in enrollment criteria for RGX-202 compared to the study for Sarepta's drug, as I imagine many people will be using this study as a benchmark for activity. And second question, just going back to the point on regulatory setup with the FDA, do you think that now there's an approved therapy for DMD, that non-inferiority will be required to be shown, even if a surrogate endpoint such as microdystrophin expression remains the bar for approval? Thanks. Sure. No, I don't think non-inferiority will be something that will be requisite. I think we're looking at. You know, and there's evidence of this even in the existing exon-skipping treatments where, you know, NS Pharma came in with sort of a follow-on, relying on the same sort of biomarker evidence, if you will, of, you know, near full-length dystrophin from the exon-skipping products for an accelerated approval in the same mutation as the preexisting Sarepta product. So, you know, I think we're, we're pretty familiar and comfortable with what the regulatory pathway is here to navigate right now. And I think that that remains the plan for how we execute efficiently as possible over the next several years. With respect to the enrollment criteria, you know, in this trial, I mean, I'm not sure precisely which additional trial or set of trials you're comparing it to, or you would like us to compare it to, Alec. I don't know all of the details. All I know is, you know, we certainly have an age range that's different and wider than, you know, many other trials that have been run in the background of the Sarepta program, but they've had other cohorts where they've included older patients as well. I just don't know that we've seen as much of the data from some of those cohorts and evidence, but certainly groups including Pfizer and Solid have previously reported on older boys and also, you know, shown evidence of measurable microdystrophin protein expression. So I think, you know, we're just really pleased with the weight and age of this patient at this stage in our trial to see something that we think is a very pronounced signal, and we'll be looking carefully, as we alluded to, to, you know, more of the functional outcomes to be able to guide where we're going there. I, I do think that, you know, what we wanna keep doing going forward is stay focused on broad access for Duchenne boys with RGX-202, as long as the, the profile continues to be safe and is supported by our partners and the caregivers in particular, who are seeing the boys. You know, there may be opportunities depending on, you know, what's, what's available to us for enrollment. But on a regulatory basis, you know, there is a precedent right now for 4-5, and I think also, you know, labeled evidence for, you know, data in the 4-7 range, which I think is leverageable. And I think 8-11, though, will not be left behind. I think it's an important part of the unmet need. I think it's an important part of the execution and the reason for improving on, you know, preexisting microdystrophins is, if we can show more, even if we show the same levels of protein, but we can show more function, we might have responses in boys. As Dr. Panda alluded to, I, I think he might have been talking about ASOs as well as gene therapy. But, you know, when you get new science involved, you might be able to show responses even with some of the same levels of, quote, unquote, "measured," you know, biomarkers, but, but things that are more functional, more potent. And, and I think that's how we'll be approaching the next period of time is dose escalation, you know, efficient enrollment to be able to support getting treatments to, age ranges and, and, and mutational backgrounds and natural history backgrounds of boys with high unmet need as quickly as possible. Great. Thanks for the color. Thank you. Please stand by for our next question. Our next question comes from the line of Ellie Merrell of UBS. Hey, guys. Thanks so much for taking the question, and congrats on the data. Just in terms of the functional data next year, can you just give us more color on, I guess, what strength and functional assessment endpoints that you plan to report, and how you expect these to compare to other gene therapies in the space? And big picture, just how we should think about, like, when and what could show proof of concept for the CT domain translating into potentially greater benefit. And then second question, just can you elaborate a bit on your Western Blot method you used, and I guess how we should think about that method relative to others used in the field in thinking about data comparisons? Thanks. Yeah. I'll let Steve and Dr. Panda maybe talk about how the functional assessments are conducted in the trial and where things are going. Sure. So I'll start. Yeah, so next year will be great that we'll have longer-term follow-up. And we've talked before about three months, you know, certainly being too early. But once you move into 6 months and even more so one year, then some of these functional outcome measures take on more weight. So we'll certainly be looking at NSAA, of course, but also timed function tests, measures of strength, and also even caregiver-reported outcomes. So these are all the totality of a lot of the different ways we can assess these patients. Dr. Panda, maybe you can elaborate on the types of functional outcomes that you'd look for. Yeah, yes. I think you have, you have covered it. I think it's kinda comparable like, you know, any other studies that use outcome measures for functional assessments. The North Star, you know, time to stand. And I think, you know, these are some of the things, and 10, I think 10-meter walk--10-meter walk and, or run tests. These are standard functional assessments that we use in the clinics and also being done in the, in other clinical trials. And I think we are also using some imaging, the MRI of the skeletal muscle and the cardiac muscle, as an exploratory endpoint as well, in addition to the, the patient-reported outcomes. ... Yeah, good point to highlight the imaging work as well. And Ellie, with respect to the Western blot work, you know, we, I mean, you know, Western blots as a case for, you know, measuring protein, have been around for like 40 years or more. And, you know, the team was obviously focused on this in the beginning of the development because of, you know, methods that people had been using to characterize microdystrophin expression in other programs. And then there were groups that also came forward and kind of indicted Western blots, you know, historically and moved only to other certain methods like LC-MS. I think we sort of chose to strike right down the middle of the fairway, and, you know, basically leverage, I think, things that are useful about Western Blot, but basically use more modern technology like instruments and methods that are more automated, I think allow for more precise measurement with the Western Blot concept, that things that have, you know, really emerged just in the last five or 10 years at the most. So that's what we have, is it's basically an automated and I think, more precise method of measure for Western Blot technology that is called the Jess platform, Jess instrument. And at the same time, we worked on, you know, validating an LC-MS method and look at correlating results between those two. On a, I think, a basis of what we've seen so far, we're confident that the methods we've designed are gonna be useful to us going forward to support the regulatory and continued development plan. Great. Thanks so much. Thank you. Our next question comes from the line of Luca Issi of RBC Capital Markets. Oh, great. Thanks so much. Just take one question and, congrats on the data. I have, three quick ones, if I may. So one on maybe CK versus expression. Can you just talk about that? It looks like both patients had similar reduction in CK despite higher level of expression for patients one versus patient two. So just wondering how we should think about that. And then maybe second, on the prophy, how should we think about Soliris and tacrolimus as part of the prophy? Will you continue to use them going forward, or are you maybe planning to take them off and just do steroids? And then maybe three, on regulatory. Can you just expand a little bit more there? Should Sarepta get full approval, will that limit your ability to get accelerated approval there, or, any thoughts there? Much appreciated. Thanks so much, guys. Right. So no, we don't, we don't believe that, you know, a conversion to a full approval will limit the plan that we have outlined for the use of the accelerated approval pathway based on RGX-202 microdystrophin expression. I think that's, you know, been a consistent statement on our part. Remember, you know, one of the emphasis of kind of my introductory remarks are there's still boys that, you know, in the uniqueness of AAV gene therapy, even in the same classes, there's boys, there will be patients in other diseases, largely boys, only boys in this case, that won't be able to access treatment because of preexisting immunology, antibodies, neutralizing antibodies, or maybe for other reasons. the fact that there would be another, you know, similarly designed, you know, whether it's improved or not, with something like the CT domain, something else that's out there that would be accessible to boys because of a change in, you know, the serology of the AAV capsid is an important thing to keep an eye on when it comes to thinking about, you know, the ethics and the reality of accelerated approval. So I would highlight that for everyone. I think... I don't remember the middle question, Luca, but I can go back to the CT point, and let me answer the second one. Dr. Panda mentioned already, you know, CK is something that, you know, it's early, we're encouraged by. It's clearly a marker of, you know, muscle damage and, you know, but also something that is, you know, has elements of nonspecificity that can be affected by different things. But, you know, these reductions, I think, are, you know, not just noise, but I think things that, you know, represent, you know, changes that are occurring with respect to, you know, something to do with the intervention. I guess it was the immune suppression now that's coming to me. You know, we talked about the fact that, you know, we have an immune suppression protocol that we've introduced to think about the totality of evidence that exists in the field to, you know, again, speaking to a range of patients from 4-11 and having dosed a 10-year-old, that make this introduction of this treatment as appropriate and safe as possible for a wide range of patients. And every patient that's gotten to a point where the protocol has ended, we've finalized the immune suppression protocol per protocol. So we're feeling very good about it. We're feeling like the continuation of it is appropriate to collect more data. And, you know, on CK, let's be encouraged about it, but, yeah, I don't, I think there's enough noise there that probably explains why there's not the dose dependency. I don't know, Dr. Panda, do you- Yeah. Can I just add that thing about the immunosuppressive regimen, right? And I think, you know, that's overall, I can comment that the field itself, for AAV-based gene therapy, is kind of moving towards more pre prophylactic immunosuppressive regimen. And I think having that in place may also open doors for some of the kids with what we know have have genetic changes that some at risk for having certain immune-mediated side effects. So I think having that is an advantage. And then talking about the CK, I think we already talked about that. I think it is encouraging that it's, you know, dramatically gone down, and there might be other confounding factors, and this is the discussion among all microdystrophin studies. Could this additional steroids or other immunosuppressive regimens contribute to that? But I think, you know, following them out long-term, even after they're out of this immunosuppressive time period, the CK continues to go down. But it is, you know, an encouraging result to see that. Got it. Super helpful. Thanks so much. Thank you. Standby. Our next question comes from the line of Brian Skorney of Baird. Hey, good afternoon, guys. Thanks for taking the questions. I'll just have a few real quick ones. I guess this is less relevant than protein expression and, and CK, given how robust those look. But can you share the vector genome copies per nucleus? I assume this was measured. And then on the Western, just a technical question, I guess. I see two controls, and it looks like the dark band is probably positive wild type control. What's the, what's the lighter band? Is that a dilution of the normal? Or, you know, I've seen other companies present a vector sample. And then lastly, can you just comment on any non-SAE safety? Like, do you see standard transient increases in ALP? Anything to be watchful of there, and any sign of excess complement activity? Thanks. Thanks, Brian. You loaded in some good stuff there. We didn't have, you know, vector copy number results to report with this update. I think, you know, my understanding from the team is that those are things that are coming in, and so have the opportunity to update that on a future basis. But from, you know, the observations of the expression we're seeing here, I would be confident that we're gonna see good results there on sort of a, you know, per diploid basis, you know, well within the range, if not above the range of, I think, what others have reported based on our experience. With respect to- The two controls. Two controls. Oh, yeah, that's an easy one. I mean, yeah, the. So the, you know, these, these Westerns, or in this case, the Jess method, that's a Western-like, but also kinda overlaps with a capillary electrophoresis type thing. There's actually multiple control lanes that are just calibrators, Brian, so we're just showing things that, you know, resemble how you sort of interpret the band. And then on the third point, Brian, well tolerated, so not just no SAEs, but really no noteworthy other events of particular note. Okay, great. Thank you. Thanks. Thank you. Our next question comes from the line of Andreas Argyrides of Wedbush. Oh, yeah. Hey, guys. Can you hear me? Yes. All right, great. Congrats also from us, and just a quick one. Lots of good questions already were asked. And it may be too early, and that's kind of the question, but do you think, and maybe this is for Dr. Panda as well, but do you think these data provide evidence that the inclusion of the C-terminal domain is a differentiator? Thanks. Dr. Panda, I'm gonna put that one to you, and like, I mean, it's early, right? I mean, I can, I can address. I think it's, it's too soon to comment on that because we only have two patients. But, you know, from what- Yeah ... from the other studies, there's also a range between, you know, 10-15%, all the way up to 50 or 70%. But I would say with just having the two patient, three patient, or, you know, information, it's too soon to comment on that. Yeah, that's... You know, we'll be looking at the functional assessments at later time points, and I think, you know, the continued feedback from the trialists and the investigators and the clinicians like Dr. Panda to sort of help interpret, you know, differentiation, even with small numbers, as we get to later points in the follow-up with these patients. And then we'll be adding more patients and dose escalating and dose expanding and working in the pivotal phase to build even more evidence. I think, that's when the C-terminal domain hypothesis will have a chance to express itself, so to speak, Andreas, and- Great. Great. Yeah, that was kind of the follow-up to that, is at what point would you be able to tell? So, okay, we'll look forward to those results. Congrats again on the initial ones. Thank you. Thank you. Our next question comes from the line of Mani Foroohar of the Leerink Partners. Hey, guys. Congrats on the data. I'll stick to one question, a sort of follow-up to Luca's question, or I think around the translation between% reduction in CK and the Western Blot. I know CK can be noisy. This certainly looks like the most orderly noise I've ever seen, given the level of baseline CK, defined period of volume,% reduction. Obviously, we can't make assumptions about dose response or lack thereof, but Dr. Panda, to what extent do you interpret this as potentially suggesting there might be a ceiling effect on efficacy around this level of CK reduction? And might dose escalation may not be necessary? Dr. Panda? Yes, sorry, I'm talking without unmuting. Sorry about that. You're good. No, I think from a I wouldn't just look at the CK to decide on the, you know, in terms of the higher dose. You know, we are using both effective doses from preclinical studies, and I think it's a good approach to look at the, you know, if this dose is the lower dose is tolerable, and I think it's to move ahead and see what's gonna happen with the high dose. And if that other dose safety is good, and we're also seeing more dystrophin expression, then I would continue with that dose. But if there are safety issues come up, then we may have to back off to this dose. But I wouldn't just base that on the CK level, as you were saying. You know, we need more long-term CK follow-up also to determine if this is gonna be consistent, if it is out of the-- Is it only the microdystrophin that's doing it, or are there other things contributing to that as well? That's really helpful. Yeah. I would add, Mani, you know from us that we, you know, we wanna come into a discussion about pivotal phase with regulators with, you know, a level of confidence and ideally a dose curve. You know, and we've been through this with RGX-314 and RGX-121 as we've set up pivotal trial designs. And, you know, it wouldn't naturally occur to us, even if we saw, you know, and have seen the type of data that I again sort of feel has, you know, met or exceeded expectations for us. But we have also been really confident that 2e14 is something that we need to explore, and the safety profile has supported it. It's in two different weight and age ranges of boys that really open up opportunities for us to want to explore. We wanna bring that type of data to FDA in a dose decision for pivotal, and something that now we think we're set up for to do next year by initiating that dosing immediately. So, yeah, I think that's another fine point on, you know, I think for the regulatory pathway to be most efficient, it always helps to have a clinical dose curve as well. That's really helpful. Dr. Panda, you mentioned longer-term CK follow-up, obviously, additional patients. Given that- Yeah ... the CK at 10 weeks, I mean, these patients have been followed, in one case, out to 6 months. Do we have just CK data from additional blood draws, some detail that you could give us? I guess that's a question for you, Gavin. Gavin Ted, rather. Yeah, I think, I, I mean, we plan with, you know, more long-term follow-up and, and more assessments to bring more long-term data forward, Mani, absolutely. And I think that would, you know, be anticipated not only when we get to points of time that are relevant for some of the functional assessments that are going to be done, but also for other things that we think are important to represent, you know, response in the drug and improvement in, in clinical outcomes in the kids. And I think, you know, I, I... CK will be measured. It will play a role in that. Okay. That's helpful, guys. Thank you. Yeah. Thank you. I would now like to turn the conference back to Ken Mills for closing remarks. Sir? Just wanna thank everyone again. We're really pleased to be sharing these encouraging results and discussing the updates. Thank you, Dr. Panda, for joining us from South Carolina, taking the time. Good luck with the conference, and thanks for representing the entire team and your colleagues in the trial on the data. Look, this is all enabling us to accelerate our development of RGX-202 with the goal of reaching pivotal phase faster. We should be dosing dose level 2 in the near future and before the end of the year. We anticipate to make that pivotal dose determination and initiate the pivotal program in 2024 with a clear path that we've been describing for the use of the accelerated approval pathway based on RGX-202 microdystrophin. We will have the ability to share strength and functional updates in the assessments here. We'll be scaling up our manufacturing production using this commercial-ready process that we've been investing in for years and was one of the pictures of our manufacturing team on the first slide. You know, sharing in the sort of joy and the encouragement and the passion that we have for supporting the Duchenne community for this pivotal program and beyond. So no doubt for me that this establishes RGX-202 as a key part of our 5 by 25 strategy. This will be one of our 5 in late phase or commercial by 2025. Thanks, everyone, for listening in and talking with us, and we'll see you all soon. This concludes today's conference call. Thank you for participating. You may now disconnect.