REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining us. Earlier today, we announced exciting progress and new positive data for RGX-202, our potential best-in-class treatment for Duchenne muscular dystrophy. The first slide is our forward-looking statements, which you should review in detail. Today, I'm joined by Dr. Steve Pakola, our Chief Medical Officer; and Dr. Naz Dastgir, neuromuscular neurologist and Clinical Development Lead for RGX-202. We're also very pleased to have Dr. Aravindhan Veerapandiyan, Principal Trial Investigator, and Dr. Mike Kelly, Chief Scientific Officer of CureDuchenne on today's call to discuss the AFFINITY DUCHENNE program and data and share key insights about how and what they see in the clinic and in the Duchenne community. Moving to Slide 4. For those of you joining from the Duchenne community or those who have may started following REGENXBIO more recently, I want to ground everyone in not only why we believe that RGX-202 is prime to be an important gene therapy for Duchenne, but why REGENXBIO has the expertise to deliver it as the next gene therapy to market. Thousands of patients have been treated with approved and investigational medicines built on our NAV Technology Platform. We have unmatched end-to-end in-house gene therapy experience from early research through clinical development, all the way to commercial-ready manufacturing. Slide 5. I know everyone is eager to see our exciting clinical data today. Before we jump into that, I want to talk a little bit more about why RGX-202 is a next-generation differentiated and potentially a disease altering gene therapy for Duchenne. Our novel construct has the potential for improved outcomes and transforming patients' lives. Today's positive robust data provide important evidence that the way we've designed and developed RGX-202 are truly benefiting patients and changing the course of disease. As we announced today, we are rapidly advancing 202 towards a BLA using the accelerated approval pathway in 2026. And are committed to doing everything we can to accelerate this time line even further, enabling multiple years of access to the prevalent population. We are also committed to building data where limited data exists, particularly for older and younger patients and transparently keeping the community informed so that families can make the best decisions for their children. I'll highlight that 202 uses our high-yielding NAVXpress suspension manufacturing process, which has enabled us to have the highest purity levels of any available or investigational gene therapies. Our process allows for more than 80% full capsids, highest purity levels in Duchenne gene therapy today which means we are delivering more therapeutic drug for the viral load. This enables lower cost of goods and may contribute to the positive results we're seeing in the clinic. Based on these differentiating factors and the ongoing unmet need in the community, we've confirmed with the FDA that the accelerated approval pathway remains very much available to us and as recently as last week, Dr. Peter Marks reiterated that currently approved gene therapy represents Generation 1 with the hope that better gene therapies are emerging. As we proceed through a pivotal study, we will look to build on our already impressive microdystrophin expression, which is our primary endpoint for the pivotal study. In the landscape of approved or investigational microdystrophin gene therapies for Duchenne, RGX-202 is the only one that includes the CT domain, making it closer to naturally occurring dystrophin. Let's dig into what that means. The CT domain plays an important role in muscle health. Our preclinical research that specifically investigated the eccentric force that contributes to the breakdown of muscle in boys with Duchenne shows that microdystrophin with the CT domain better protected the muscle against contraction-induced damage and enable the muscle to maintain stronger force. It not only protect -- better protected the muscle, but also enabled functional gains. The CT domain supports the resilience of the muscle fibers which may lead to improved longer-term outcomes. I've highlighted several exciting differentiated elements of our 202 program. And now I'll turn it over to Steve to get into more of today's great news. Steve?

Thanks, Curran. I'm very pleased that today, we announced the initiation of the pivotal trial for RGX-202. The AFFINITY DUCHENNE trial is now a pivotal Phase I/II/III trial and we've already dosed the first patient, with several more already identified for screening. As aligned with the FDA, the trial will recruit approximately 30 patients, aged 1 and above. To support accelerated approval, the primary endpoint of the trial is the proportion of patients with microdystrophin expression over 10%, which is a recognized threshold of expression that is likely to support clinical improvement. The 100% of patients in the Phase I/II portion of the trial with 12-week biopsy results have reached this threshold. We also evaluate time function tests as secondary end points and NSAA as an exploratory endpoint in patients 4 and older. Based on the I/II phase data that we'll share shortly, I'll note that we are evaluating opportunities to expand the pivotal trial to a broader range of mutations and functional levels to deliver the potential benefits of 202 to a wider set of patients in need of options. Now let's dive into the Phase I/II data and why we're confident in our plans as we've now advanced to pivotal. The Phase I/II study explored 2 dose levels and dose level 2 was selected for pivotal. To date, 11 patients have been dosed in the Phase I/II, ages 1 to 11. And as announced, today, 1 patient has already been dosed under the pivotal protocol. Now we'll move into the data section of our presentation, and we're pleased to have Naz here to walk us through the exciting and positive results we're seeing so far in the AFFINITY DUCHENNE trial. Naz?

Thanks, Steve. So I'll start with safety on Slide 12. I'm excited to share that not only have there been no serious adverse events in this trial as previously reported, but also no adverse events of special interest, or AESI. We have seen no evidence of drug-induced liver injury, neurotoxicity or thrombocytopenia and no myocarditis and no myositis. Common adverse events include transient nausea, vomiting and fatigue, which are common with gene therapy administration. We take a comprehensive proactive approach to safety and immune suppression and I'm pleased to share this approach is working well. The excellent safety profile further supports the differentiation of RGX-202 in terms of optimized construct design and high-purity product manufacturer. Today, we are sharing new biomarker data that demonstrates high transduction efficiency as measured by vector genome copies, allowing for robust microdystrophin expression and localization to the sarcolemma. In ambulatory patients aged 8 and over, these microdystrophin levels are the highest reported cross approved or investigational gene therapies. The vector genome copies are also the highest reported in Duchenne gene therapy. These are very encouraging data indicating the potential for long-term robust and appropriately localized expression of RGX-202 microdystrophin. This data further bolsters the novel attributes of our construct and our confidence in the potential benefit of RGX-202 microdystrophin as we present our first look at functional data. Before I show you the positive functional outcomes we announced this morning, let's discuss the disease trajectory for boys with Duchenne. We typically expect to see these boys gain skills at a slower rate for age, peak and function around 6 to 7 years and then enter a period of functional plateau, then entering a period of rapid functional decline as early as 7.5 to around 8 years of age. This decline continues to full loss of ambulation and continued muscle damage but there is a wide range of clinical heterogeneity in Duchenne patients due to a variety of factors. This level of heterogeneity makes the use of matched controls from an external natural history data set, the optimal comparison for patients dosed with RGX-202. Prognostic factors for disease trajectory were identified and implemented as criteria for matching. These criteria include age, time to stand, time to run walk, time to climb and access to at least 12 months of data from baseline. Utilizing matched controls, therefore, gives us the best lens for evaluating 202-treated patients functional outcomes versus their anticipated untreated trajectory. Moving on to Slide 15. We are proud to share that dose level 1 participants improved in function and exceeded matched external natural history controls at 12 months. This includes time function tests and the NSAA. As I shared, these participants microdystrophin expression range from 10.4% to 83.4%. And at 1 year post-dosing function results have improved in ways that we would be very -- would be very unexpected based on their anticipated disease trajectory, highlighting why we're confident in the pivotal trial endpoint. In this stage, especially with older boys, we'd expect to see decline. And even at our lower dose, not our pivotal dose, we are seeing encouraging improvements. Since we have 12 months of data for our 3 participants dosed with dose level 1, we were able to compare our time to stand, 10-meter walk run and time to climb velocities against the MCID or minimally important clinical difference, which was used by the FDA's Peter Marks and the broader approval of currently commercially available gene therapy for Duchenne. Even at dose level 1, RGX-202 participants are outperforming the MCID, a benchmark. Moving on to dose level 2 on Slide 17. We see that our 2 patients administered the pivotal dose of 2x10^14 genome copies per kilogram of RGX-202 also demonstrate improvement when compared to external natural history controls. Based on natural history, we expect these older patients to be in their functional decline phase. But 9 months after RGX-202 treatment, we are seeing functional improvement. As a pediatric neuromuscular specialists who treats patients with Duchenne, I want to emphasize that an NSAA improvement of 10 points is truly outstanding. On Slide 18, we're showing the mean functional improvement at 9 months in both the timed function tests and NSAA of our 2 participants who received RGX-202 at the pivotal dose. This clearly drives home that we are seeing functional improvements in older ambulatory patients, a population in which you would only expect to see decline. Though this is a 9-month data set, we feel confident in how these participants at the pivotal dose will not only continue to improve against their expected trajectory and potentially for greater -- have potential for greater improvement than dose level 1 at our next update. The functional outcomes we're seeing across both dose levels are positive and highly encouraging. But as a physician who has walked hundreds of families through this devastating disease, families want to know what these deltas versus external controls really mean for their child. As reported by the pediatric outcomes data collection instrument, or PODCI, caregivers for all 5 of these 202 patients reported improved function in the home and community environments. This means that these children are better able to participate in their daily lives with their families and their peers. Now to give you a better idea of what these improvements look like, both in clinic and in the real world, Dr. Panda will share a video.

The first videos are of our 10.5-year old participant who received dose level 1. On the left, you can see his baseline ability to stand on 1 foot briefly, pressing his legs together to stabilize his body. On the right side of the screen, 1 year after dosing, he is able to stand on 1 foot for several seconds on the left and the right without needing to press his legs together for stabilization. The same participant shows improvement in the quality and speed of his time to stand and 4-stair climb. As we know, these outcome measures have been identified as an early prognostic factor for disease progression and loss of ambulation. At 12 months, his 4-stair climb shows improvement in speed and confidence. This next participant was 6.5 years old at baseline and received dose level 1. After 1 year, child has gained 12 pounds, but is able to transition from the ground to standing position with greater speed. For the same participant at baseline, he uses both hands for support to climb stairs. On the right side, we can actually see him 12 months after dosing, using a single hand on the railing and improving in his time to climb the 4 stairs. This pivotal dose participant was 11 years old at screening. You can see his time to stand at baseline on the left side compared to 9 months after dosing on the right side. At 9 months, he is able to perform the test faster. The same participant was not able to hop on either food with clearance at baseline. However, at month 9, is able to hop on both feet with clearance off the ground, demonstrating improved strength and has lower extremities to hop. In this video, on the left side, we see his 10-meter walk run test at baseline. He shows a limited clearance of his feet as he completes his fast walk. 9 months after dosing, he moves faster with periods where both feed are off the ground. On this video at baseline, the child climbs the stairs using both hand rails with effort to extend his hips and knees to climb each step. At month 9, he climbs the stairs using only 1 hand with greater fluidity and speed, indicating improved muscle strength in his lower extremities to ascend the stairs. Lastly, this RGX-202 treated boy is pictured riding his bicycle on a busy New York City Street. At baseline, caregivers reported that the 11-year old child could not ride a bike as measured by the PODCI. After treatment, the child is able to participate with his parent in a community bike ride as the parents shared he rode his bike an entire 6 miles through Manhattan.

Dr. Panda, seeing those videos, I can't help but say, wow, to actually see and hear how well these boys are doing, not just on the study assessments, Naz has reviewed, but also in their day-to-day lives is really remarkable. So now I want to thank Naz and you, Dr. Panda, for walking us through all this positive data and really showing us what this could mean for patients and their families. So to sum up what we're sharing today, we are highly encouraged by these positive safety, biomarker and functional data and the potential of RGX-202 to be a differentiated safe and best-in-class therapy. So with that, I'm now going to turn to you, Dr. Panda and Dr. Kelly. First off, I should say, Dr. Panda, for those in the audience, Dr. Veerapandiyan is affectionately known as Dr. Panda to his patients and colleagues and collaborators. So that's how we'll continue to refer to you, Dr. Panda. So both you and Dr. Kelly, it's really great that you're able to join because we, in the audience will really appreciate hearing your expert perspective on these exciting results. So let's start off at a real high level with what your overall impressions are on the functional data that we presented today. So let's start with you, Dr. Panda.

Thank you, Steve, and thank you for joining the call. I think I'm going to characterize into 3. Like one, obviously, any product we look at the safety. And so far, as Naz presented here, there is no serious adverse events or any adverse events of special interest. I think that's very promising for me when we present to our families to talk about the safety of the product. And then, of course, the microdystrophin expression, it's a robust expression in both dose levels and also the pivotal dose. And more importantly, that's -- I'm very excited to see this functional data, especially in the older ambulatory boys I -- Naz highlighted the 10-point increase in the North Star Ambulatory Assessment in these older ambulatory boys. These boys are supposed to be declining and you don't see improvements in the North Star Ambulatory Assessments. And I think that is highly, highly encouraging for me. And I hope to continue to see these improvements in these boys. And I think this opens up opportunities for those boys in the community with unmet needs.

Great. Thanks, Dr. Panda. So moving over to you, Mike. What are your takeaways as you look at this data?

Thank you, Steve. We're delighted to see this here data. I and many in the in the community have been waiting for this clinical data from REGENXBIO to better understand how to read the gene therapy landscape. For us, it was whether all gene therapy products have a similar risk benefit profile, are they separated into distinct products. And the results that we've seen today, particularly on the video, shows this larger gene construct provides a distinct and significant benefit over what we've seen before. It's reassuring to see positive early look at this profile, and for this drug and look forward to advancing into the pivotal trial.

That's great. So you both hit on unmet need and how these findings could really signal an opportunity to address those unmet needs. Maybe you can elaborate a little more, given you both are very close in the community, of course and looking at all types of data. Maybe you could elaborate on what you see as the ongoing unmet needs for Duchenne patients and families and what you think this update really means for the community.

Take a stab at that. I don't have to step back for second look, the Duchenne community. And indeed, the biotech sector was shocked and disappointed by the failure of Pfizer's gene therapy product. That set back expectations for gene therapy as a meaningful treatment option in Duchenne and many patients, particularly older ones were deeply concerned and troubled trying to make a decision about the risk-benefit profile of a first-time treatment. The unmet need is large as patients try to navigate the decision-making process, recognizing real risks with treatment and not fully understanding the potential benefit, particularly for older boys. And today's update has a number of components that the community will appreciate and tune into. The first is the safety. This alone is particularly reassuring in a community worried about risk, particularly in older patients. The second is the broader age range of the boys and young men who participated in the study so far. The third, obviously, is the construct, a larger dystrophin protein containing a key C-terminal domain that might add additional functionality. And fourth is the high expression of the transgene in muscle. But most importantly, what they've tuned into is the improvements in key function, time function tests, particularly the North Star, which has been a nonresponsive endpoint than previous gene therapy trials, and if I take all of these together, it just highlights a target product profile that the community will welcome and have been waiting to see.

Thanks, Mike. That's a great broad perspective from what you hear in the real world with patient families. Of course, Dr. Panda, you see lots of Duchenne children and families. So let's hear your take when you sit down with a family and think about this data and the potential impact on potential unmet need for the range of patients that you see.

I echo everything Dr, Kelly has said. I think, in addition to that, it's good to have options, right? So now these families have any number of therapies, approved therapies, clinical trials. I think it's always good to have options, not every single Duchenne boy is the same. So it's going to be the expectations, the goals and appropriate treatment for everyone is going to differ from one boy to another boy with Duchenne. So I think when we sit down and talk about these, what data that we have in hand and does this product work good -- is a good fit for you? Or do you want to do this clinical trial? Or is this product a good fit for you? So when we have those discussions, I think the more the data that I show. So my son is 10 years old, and this is where he is, "Can you show me a data from the clinical trial of this age of this mutation?" If I'm able to share the data with them, I think that makes the family more comfortable. So sitting down with them, talking about the options, the pros and cons of each option and see what best fits. And I think we talked about the safety of this. I have to say about the immunosuppressive -- the comprehensive immunosuppressive regimen that we are using. I think so far, these boys have tolerated that well. And to be honest, I had some apprehension when we started the trial, is it necessary to put these boys through all of this. But so far, my experience has been wonderful with these immunosuppressive regimens, proactive immunosuppressive regimen, and we haven't seen any challenges or any risk associated with this immunosuppressive regimen either, which kind of differentiates again, the product safety profile as well. So it comes down to pros and cons, options, I think, opens up options and opportunities for the Duchenne boys.

So it really sounds like from both of you that the differentiated aspects of RGX-202 are really potential major opportunities to have an impact for your patients across the age range. On this differentiation aspect where we're now seeing actual functional outcome measures related to that, I can't help but ask, Mike, obviously, you have close connections with families, but you have a long history on the scientific end of exploration in this field. So I think it would be helpful to hear your sense and your belief in the novel aspects of the construct that were what we consider critical in designing a next-generation construct and how those may translate into actual benefits like what we're starting to see in our data.

Happy to say a few words about that. This has a novel micro gene construct, obviously, that's extended into the C-terminal domain. And that's important in a number of fronts. The C-terminal domain recruits several key proteins at the muscle membrane; dystrobrevin, syntrophin, neuronal nitric oxide synthetized. These are all critically important as they line up with the gene that's in there because they play really important roles in function and signaling. The second thing I would say is this is -- there's no doubt that this is -- there is a great story behind this here science. But whenever you advance it into the clinic with a larger protein and combine it with safety, delivery and expression in patients' muscles and the outcome is a meaningful improvement in key function tests, then this reinforces the importance of the larger gene. It's not just the science story right now. It's actually manifesting itself both from a safety perspective and a functional perspective and transforming treatment options for some of these patients. So that's why I think it actually stands out alone from other genes that we'd look at right now. I know that on a personal level, as I talk to families, they have been waiting for data like this. They wanted to see the data come out from the REGENX study in order to guide their thinking in gene therapy. And this will go a long way in order to inform parents how to make those decisions. So I'm really excited by a combination of things, really great science that has matured along with guiding families with more information and how to make the right decisions with gene therapy.

Okay. So we'll go from the scientific end all the way to what you showed, Dr. Panda, in those videos. And really, the opportunity you've given us to see a bike-riding 12-year-old is really exhilarating and heartwarming for all of us. Let's hear your broader take and any other insights you can give on the day-to-day function that you're seeing in the patients and what you're hearing from patients who've been treated with RGX-202.

Sure, Steve. And as Naz presented, there were improvements reported in the activities of daily living by the families in the PODCI. But as a clinician to me, yes, I get excited about seeing improvements in our traditional outcome measures that we use North Star Ambulatory or time to stand or whatever that outcome measure is, but what's even more meaningful to me is to see these improvements that are being reported that's happening in their day-to-day life and the activities of daily living. You have a boy who was not able to do anything, but he's now doing this thing. So he is now able to ride a bicycle. Duchenne boy aged 12 is riding a bicycle. He was not able to do that before. My boy is now running longer distance. He's able to stay out, play, run and play with his brother for a longer time. I think that's more meaningful for the families, and I think that's more meaningful for me. I would love to see those improvements and I think that's more meaningful for me and for the families. And I think we are seeing that from this patient a dose with RGX-202 and I hope to continue to see those as we expand the program and as we continue to follow these patients long term.

And this is a 12-year old, as you mentioned that this is nothing at all what one would anticipate. It's quite astonishing. I think this harkens back to what you said, Mike, about the particularly telling findings that we're seeing in older boys, both in terms of really high microdystrophin expression levels, which has not been seen previously with other programs. And now we're seeing this translate into these functional findings in the older boys. Let's have both of you say a little bit more about what impact you believe that would have. Maybe Dr. Panda, we'll start with you.

Sorry, Steve, can you repeat the question?

Sure. So given these findings in this 12-year-old and the findings that we're seeing, I'm reminded of what Mike mentioned about these remarkable findings that we're seeing in terms of microdystrophin levels that has not been seen in these older boys in prior clinical trials with other programs, but now seeing this translate into the type of functional results we're seeing in older boys. Dr. Panda, if you could comment on what impact do you think that would have in terms of unmet need.

I think I said before, the microdystrophin expression is fantastic. It's robust, it's important. But how does that translate into someone's function and activities of daily living, I think that's more meaningful and important. And I think we are seeing that in our patients. Not just ones shown in the videos, but also the ones that have been treated, not shown in the videos as well. I think it's -- there is a potential to transform the disease progression in these boys. And I think we need -- we only have a handful of boys right now as we continue to expand the program, as we continue to open up opportunities for other boys to be in the trial. I think we're going to get more positive data, and I hope to get more positive from those long-term follow-up studies and also I'm hoping that we can, at some point, open up the opportunity for those boys that are non-ambulatory as well as high-risk mutations.

Great. And Mike, how about for you when you think about the older boys and their families as they come in to see you?

Yes. I'd certainly go with what Dr. Panda said, older individuals clearly have different concerns in there, particularly those with cardiac issues. This is a really exciting data set. It's the first read of stuff, and I think we're going to look as further data comes through next year and the following. But the thing that I would say really just to sort of look at this in a slightly different way, our expectation of what micro gene -- microdystrophin gene therapy was going to do has really been set by other products -- work that we've done in the mdx mouse or the dog model. And there, that was a much smaller gene than what we're delivering right now with the REGENX product. And it may be that we have to reset our expectations for this larger gene. It appears to be much more functional. And so the data that we're getting out of it exceeds what our expectations would have allowed us to be at based on what we've seen before. So I really look through a lens of wanting to look at this data and continue to look at the boys longitudinally and continue to follow this as we're now in the pivotal with new -- and this is a real function of this much larger gene, much more stable, much more functional, then I think that that's a resetting of our expectations of what gene therapy will likely bring in Duchenne muscular dystrophy.

Great. So these data are highly encouraging, and we've started pivotal. So this is a great milestone for the program and patients and families. So thinking into the future, what do you hope to see going forward in the program? And I'm actually going to first turn it over to Naz. So you're not only the clinical leader for the program, you are a practicing pediatric neuromuscular specialist who sees Duchenne patients in your practice. So you can kind of put your clinical hat on and your drug development hat on. So yes, let's hear your take on what you're hoping to see.

Steve, honestly, on wearing both hats, I'm just delighted by what I've seen. And I'm so excited to be part of this experience with the Duchenne community. This is an experience of continued discovery on what RGX-202 can continue to accomplish not only at the 12-month mark, but beyond. I'm super confident about RGX-202 safety profile. I find that very reassuring to myself just monitoring the study, but also as a clinician and feeling comfortable with offering this as an option to patients potentially, like as an option, I would say, feel good about this drug. It's looking good from a safety standpoint. REGENX puts a huge priority in the safety of the patients entering the study, everything is very well thought out. Everything is very well monitored, and obviously, we're always careful, cautiously optimistic, but what we're seeing so far is exciting. And I'm continuing to motivate -- I'm actually really motivated as well to continue to evolve our program. So pivotal is just the start. Going to patient meetings, meeting with families, we understand that every study initially has some limitations in their inclusion criteria. For example, our study in Phase I/II started off by only allowing children who are ages 4 to 11, then we opened it up to 1 to 3 year olds, now I'm excited with the safety profile and what we're seeing with the functional data to try to expand even further, try to get creative about what else we can do with RGX-202 and how far we can push it because we recognize this unmet need of certain patient populations currently excluded from the study. But I just want those families to know that we are continuously working to include you. We're continuously working to evolve our program and we'll do our best to provide RGX-202 or the potential of RGX-202 to your children in the future.

Thanks, Naz. Dr. Panda, experienced clinical trialist you've dosed a lot of patients already, will be dosing patients going forward in the pivotal trial. What's your perspective?

Thanks, Steve. I really like a comment that Dr. Kelly made, resetting the expectations. And I hope the long-term follow-up of these patients make us do that, resetting expectations on gene therapies. Because right now, when we talk to our patients, it's not a cure. It's going to slow down the progression of the disease. But I think resetting the expectation, that's a huge thing. And I hope that RGX-202 can make that for our patients and for us. As we talked for the pivotal studies, we have patients already lined up to be screened. Everybody's -- the families are excited to be on the trial. But I think I want to reiterate one more thing in terms of what -- this is a push for REGENX team also to consider. I know Naz had mentioned about those patients, unmet need patients, but I want to reiterate that again, consider opening up the possibility for patients with exon 1 to 12 deletions 1 to 17 deletions, including patients with exon 8 and 9 deletion, we need to look on also younger boys, which you're already doing in the pivotal and also into the non-ambulatory boys. I think the proactive immunosuppressive regimen actually puts us in a unique place that we should start thinking about those high-risk patients as well, and we have to do that sooner rather than later. And and I'm hoping to continue to see these positive effects.

Yes. Thanks for adding that, Dr. Panda. So as Naz mentioned, I can only echo, we're very excited to expand wherever we can to help a broader range of Duchenne patients and families. And lastly, Mike, how are you thinking about it when you think of what patients and their families are looking for in next-generation gene therapies like RGX-202 going forward?

Yes. I think there's clear expectations out there that we have to have opportunities that are safer, that are much more effective. Now we've touched on that this morning a number of times, and I think that there will certainly catch the imagination of families that are out there? For me, I totally agree with all that's been said over the last few minutes. I would add in and broaden the discussion around combination therapies that there's a field that's going to be really important over the next few years. We're already doing it in some clinical trials. But I think as other drugs get approved with complementary mechanisms of action that there's going to be a way to broaden the effects and the benefits that we see with products like this here. I think that we're at a really important inflection point in the treatment of Duchenne. The data that we've seen presented today really points to a unique direction for a product that seems to be differentiated from others. And then as we go through the next few years, layering on some combination therapies, I think that we've got a very exciting time ahead of us in order to understand what that's going to do for patients.

Great. So thank you all. Naz, Dr. Panda, Mike, your insightful perspectives are really appreciated, and we look forward to bringing forward more data in the future. So now I'll turn the call back over to Curran.

Thanks, Steve, and thank you to Steve, Naz, Dr. Panda and Mike for walking us through these exciting outcomes and sharing your perspectives. And I'll join Steve with a wow. This is incredible to have a drug development program progress as we've seen today. It's heartwarming to see patients doing well. And we just are committed to go as fast as we can towards an approval. Before I open the call for Q&A, I'll briefly recap what we've shared. Let me reiterate that based upon the ongoing unmet need in the community, we've confirmed with FDA that the accelerated approval pathway remains very much available to us. And as recently as last week, Dr. Peter Marks reiterated that the currently approved gene therapy represents Generation 1 with the hope that better gene therapies are emerging. The totality of our data provides that RGX-202 provides evidence of improving outcomes for boys with Duchenne and altering the trajectory of the devastating disease. The clean safety profile, biomarker data and now positive functional outcomes are setting the stage for accelerated approval to rapidly advance RGX-202 to be next to market as a potential best-in-class product through pivotal phase and BLA submission in 2026. I want to thank our investigators, the participants and their families as well as the Duchenne community for their support as we continue in our commitment to bring a meaningful treatment option to patients. Now we'll open the line for Q&A. For our covering analysts, if you'd like to ask a question, please click the raise hand button. Our moderators will address you by name within Zoom and prompt you to unmute. Once your question is complete, please mute yourself again.

First question will come from Gena Wang, Barclays.

First, I wanted to say congratulations on great data. I have 2 sets of questions. The first one is regarding the FDA feedback on pivotal study. Is there a minimum threshold of the patient who reached 10% in order for approval? Also, do you need to cover all the age group in order to claim a very broad label of over 1 year old? And then second question is regarding the 12-year-old patient data, the performance is truly remarkable. When we look at his biomarker data, it seems within the range, like 40% of protein, positive fiber, 46%, VCN copy is 18 per nucleus. So anything -- what's the natural history matching data for this patient? And what is genetic profile and others make this patient so unique?

Great. Thanks, Gena. Great questions. I'm going to -- I'll talk just briefly about the end of Phase II meeting and subsequent to that, our protocol review that was completed with FDA. I think Steve will have to speak to the 10% microdystrophin, but I think in general, what we see is general agreement amongst our KOL community that 10% or greater represents a highly likely ability of the patient to see good functional outcomes. And so -- that's the basis for how that was set. But maybe I'll turn it over to Steve, so he can give you the detail of how it's actually specified in the protocol. And I think your other question was around the sample size as well, he can confirm that.

Gena, thanks for the questions. So 10% as Curran mentioned for microdystrophin expression is something that's recognized in the field and something we're confident in and certainly what we've discussed with the FDA before incorporating that. You hit on another aspect, which is, well, how many patients or what proportion of patients have to achieve that. And the factor that we took into account was background variability that could exist that we want to make sure that in our population that the proportion above that is not something that could happen by a random chance. So we're actually going to show -- intend to show and have the study well powered to show a statistically significant difference in terms of patients who actually can achieve at least 10%, but actually have a slightly higher bar to actually have that be statistically significantly higher than 10% as opposed to a null hypothesis of no effect or no patients. As you can see from our data set, all of our patients have had at least 10% and the only one close to right around the 10% level was at dose level 1. So we feel we're very well powered to hit on this. And again, reiterating what Curran said, this is what we discussed at -- in the Phase II meeting, addressing any of the questions and comments that the FDA had on this and every other aspect of the protocol, submitted the protocol now after traditional wait period have been able to start the study. You also touched on the age range and what would be needed within different ages. We intentionally look at a broad range because of the exciting results that we have, including in the older patients. And as Naz said, we were excited to expand into the less than 4-year-old age range where there are no available gene therapy treatments. We, again, had discussion with the FDA and are comfortable with our sample size of 30 for assessment of the accelerated approval end point and also assessment there in our confirmatory study for functional outcome. So for us, we believe, and I think that's supported by us being able to go ahead with the study, our goal of a broad label where certainly, we want to show directionally just like we've shown in the existing data set, what we want to see continuation of what we've seen and that would allow for a broader age range. Lastly, you mentioned the 12-year-old and the nice results, really remarkable results that we're seeing there and the natural history. You can get a clear sense of that from the figure that we showed where we actually have the matched natural history control where we match for not just age but these baseline characteristics and as expected, the natural history is declining, not stable and certainly not improving the way we're seeing in these boys.

And Naz, you might want to just give a little color because we -- Gena, we do see the 12-year-old patient is something that hasn't been seen before, we think, in gene therapy trials. Do you want to give a little bit of color, Naz?

Sure. Thanks, Curran. So I mean, right now, obviously, he's 1 of 2 patients that we have 9 months of data on, right? So anything that I could say is presumptuous at best. But we do recognize that he is performing so well, way beyond what we would have ever expected. We're obviously going to watch him very closely to see what might be unique features about him and see if there's additional evaluations that we could possibly do. But at this time, I can tell you that any child entering into this study who's a little bit older will probably fall on the higher end of like better function for Duchenne patients. Now he is one of the children in the video. You could clearly see that he has a diagnosis of Duchenne. You need a clinical diagnosis of Duchenne to enter into the study. But he does have proximal weakness. He couldn't clear his legs when he was running and he wasn't able to ride a bike prior to receiving our drug and he has made functional gains. So he's performing beautifully, but obviously had a deficit that he was able to improve upon by 10 points in the North Star. So he is someone that we're really still trying to learn from. We can only expect better, hopefully, from him, and we're going to keep watching him and any other trial that enrolls in our study to see what might be unique features about some of the kids who might be doing so well.

Our next question comes from Paul Choi, Goldman Sachs.

Congratulations on the data. And thank you for sharing that video. It's very stirring to see the patients improving. I have a few questions. My first question is on the 8-year old in the pivotal dose cohort whose NSAA didn't improve as much. Can you comment a little bit on his baseline characteristics? Is there any sort of functional ceiling, I guess, in your view on patient baseline characteristics? And how are you potentially incorporating that into either inclusion, exclusion criteria or stratification in your pivotal trial? And my second question is, can you comment a little bit on any changes in steroid or steroid tapering that you may be able to describe or characterize or are they still staying on their maintenance doses? Anything there would be helpful.

Great. Steve, you might want to address that with the panel as needed?

Sure. Thanks, Paul. I think the 8-year-old pivotal aspect dose, the NSAA finding, I would just remind, we looked at the totality across the different time function measures as well. But Dr. Panda, you're best suited to address this, given you've seen these patients and have a good handle on how they're doing overall versus what you would expect for these patients.

Sure. I think the 8-year-old, I think if I remember clarity is that -- Naz help me I'm here. But I'll answer your steroid question first. I think as far as steroids, they are staying on the maintenance standard of care steroids. And so I think we are tapering the additional steroids with immunosuppression, but they are staying on their standard of care steroids. I think the other question about the functional ceiling. I think there are some criteria surrounding the functional assessments that's being, I think, with NSAA and also the time to stand that's -- if I remember correctly, that's being incorporated into the inclusion, exclusion in the pivotal study. And I'll have Naz comment more on that in terms of future plans from a certification standpoint.

Sure. So just in terms of functional ceilings, the [ 216 004 ] patient didn't get even close. He was low 20s. The -- oh, I'm sorry -- yes. So -- and then the other child, the 8-year-old child -- so that's the 12-year-old child, the 8-year-old child, one of the unique features of him is that he actually -- so we don't exclude based on a certain BMI, but with the additional immune suppression that you put on during the first 3 months of the study, which every other gene therapy does as well, particularly with the steroids, you can see a certain amount of weight gain. So as the children become a bit more mobile -- again, we're presenting the data on the dose level 2 patients at 9 months I'm hoping that he might -- he did have an 11-pound weight gain in that 9-month period. And I'm hoping that, that's going to kind of wean off a little bit and have less of an effect on him and maybe as he becomes more mobile, he'll lose more weight and then we'll probably hopefully see better improvement on him. So go ahead, sorry.

No, I was going to say, I think in addition to that, it's the key in this decade as he gained weight, but still the quality of the moment that he had the performance in the video itself, it's striking. So I just want to highlight that.

Our next question comes from Judah Frommer, Morgan Stanley.

Congrats on the update here. So I did want to focus maybe a little bit on the older patients again. So maybe you could just help us with -- I don't think there was a match control for NSAA for the 12-year-old. And maybe to further contextualize the 10-point improvement there, do you have maybe some level of expectation of what a match-controlled NSAA would have looked like and kind of how unusual the 10-point gain is especially within such a short period of time? And then also in dose level 1, is there any way you can disaggregate the older patient within that cohort and give us some information on how that patient progressed functionally?

Sure. And I think that one thing to look at, obviously, the data set is in [ NO5 ]. And I think it's important to look at the consistency that we see at dose level 1 leading into now dose level 2. I think that's really an important aspect because there will be variability between patients and we see a clear drug effect at dose level 1, and we see this very enhanced drug effect at dose level 2. And I think what we're seeing really, if you step back, is we want conviction that going into a pivotal study, we have a high probability of completing the study with a positive outcome. And I think that's what we see in the specific data that we have at hand and keeping in mind that we're at 9 months with some of the DL2 patients. Steve, do you want to dig in a little bit on the question more specifically around the 12-year-old NSAA?

Sure. And I'll hit on the technical aspect in terms of the match control. And then I think Dr. Panda, you're best to assess what you would have expected otherwise even though we didn't have an NSAA match controls. So Naz reviewed the careful matching. So we wanted to make sure we had as close a match on confounding factors so that whatever difference we would see from natural history wouldn't be explained by other factors than a potential drug effect. And so we matched on not just age, but these various time function tests. And within our database of natural history, we fortunately had multiple matches for all of the patients, except for that older patient and part of that is because there's a lot fewer patients at the high end of that age range in these. But we know from that natural history curve that Naz showed that these patients continue to get worse and certainly do not get better the way this patient did. But Dr. Panda, you have the real direct experience with patients across the board. You give us your take on whether this is at all anything that could happen without a drug effect.

Sure, Steve. I think to address the baseline characteristics, I think he -- when we -- when I enrolled him and we screened him for the trial, he was a typical Duchenne candidate. There's no question about it. Of course, like Naz was saying that this was sort of an unexpected improvement because wouldn't-- I wasn't expecting his NSAA to go up 10 points higher. So every single boy at this age who is a typical Duchenne boy, they're declining. So I was -- so I think there is something that there is a drug effect that is causing this high increase in NSAA because we see other children, some of them not even able to complete NSAA assessments. So I think yes, I think we are looking into more specifics in terms of anything different, anything unique about this patient, but from a genetics standpoint, from a clinical standpoint, he has -- he was a typical Duchenne kid to begin with.

And Naz, do you want to speak to maybe the thinking around the 9- and 12-month functional readout? How do we see that as being far out from, say, a washout period from immune suppression?

Sure. The reason why we're presenting data at 9 months and not 6 months, for example, is that we wanted to have a picture that was clearly off of immunosuppression for 6 months. So our immunosuppression regimen completely weans off by the end of the third month. So this 9-month data gives us 6 months off of immune suppression. So you don't get a functional data set that's clouded by the potential positive benefit of additional immune suppression.

Our next question comes from Mani Foroohar, Leerink Partners.

Congrats on the data, quite impressive as we mentioned before, I wanted to talk a little bit about operationally where we are, what your experience has been in terms of enrollment, to what extent we should think about the evolving dynamic of what percentage of patients out there are plausibly ineligible due to pre-existing antibodies? And then I have a separate follow-up.

Okay. And I assume you're speaking patients that would be ineligible for an AAV8-based therapy?

Yes.

I'll start with that. I think there's still, I think, evolving data sets on that, including some of our own data. But I think our expectation is that somewhere in the range of 25% to maybe as much as 35% of patients may be ineligible based on pre-existing neutralizing antibodies. I think that as we get through the next 6 or 8 months, we'll have additional data to see if that number -- because part of it depends upon the level, is it low level, medium or high level? And can you treat through as Sarepta does with their program. So I think that, that's roughly how we think about it. In terms of enrollment, we've been really excited with the interest in the program to date. You've seen that we've started enrolling our 1 to 3 age bracket for that expansion or new cohort. And I think I would expect this data will help greatly with enrollment. Maybe I could have Mike Kelly speak to that just a bit.

Sure. Happy to, Curran. Yes, there's no doubt that there is a real massive unmet need within the gene therapy arena right now in Duchenne. And the community has, as I said earlier on the call, the community has tuned into this program, recognizing that we need to move beyond the Generation 1 products. And so I think there is both the unmet need and excitement, and the data that we've seen today clearly will move the community to get more involved in this program.

And I guess I'd add on to that, that we continue to expand our sites and our ability to recruit patients, as you've seen recently, we opened up the study in Canada, which we're excited about. And I think we're getting great feedback there in terms of unmet need in that geography.

Great. And that leads directly into my follow-on. Obviously, the availability of novel therapies varies quite geographically quite a bit. How should we think about the breadth of the global opportunity for you guys, both commercially and also more broadly, when you think about how broadly you could potentially expand the footprint of clinical trial sites to get as global data set as possible?

That's a great question. And I was just reading recently some notes, I think, that we're taking from Peter Marks discussion with Jim Wilson. And I think there are collaborative efforts going on with FDA that could concern sort of ability to leverage U.S.-based studies in Rest of World. So we're paying a lot of attention to that. We do have intention to expand the study, although our initial focus is getting a U.S. BLA filed. But I think in general, we have treated patients from ex-U.S. as part of our current studies. And we see a lot of interest and unmet need in some countries will follow how accelerated approval-based programs are accepted in EU very closely over this time. But I think our next step early next year will be to expand our thinking more globally given the exciting results we have today.

Our next question comes from the line of Annabel Samimy from Stifel.

So just a few questions for me. I guess in the pivotal study, the NSAA is now exploratory. And I just want to -- I understand that the NSAA is a little bit difficult to assess, but was it the FDA to push it to exploratory and especially given the results that you saw in the 12-year-old looks pretty impressive. And then, I guess, secondly, on some of the endpoints, can you help us understand what the time to onset was and what the trajectory of improvement was in these patients? Did it improve over time? So as we continue to monitor these patients, should we expect to see continued improvement, continued separation? And how was the trajectory and what might we see going forward? And then I have one more question after that, but I'll ask afterwards.

Great. Yes, I think on the first question -- actually, on the latter question, let me start with -- on the trajectory. Maybe we'll start with Steve and then Steve, if you could use the panel to help with that.

Sure. So of course, recognizing small numbers at this stage. So there's inherently some variability that you can see, but generally taking into account 1 aspect that Naz mentioned, early potential confounding on the steroid use aspect, but certainly a long enough washout for the increased immunosuppression that's just in the first 3 months. So I think taking that into account, we have seen generally, at least when we look at the numbers, which is what Naz and I can speak to, we see what you'd want to see. Dr. Panda, what did you see in real practice in the clinic as you follow these patients over time?

No, I think so far, I think we're seeing this improvement at 9-month mark. And to answer your question, I think as we continue to follow the expectation, our hope is continued improvement and/or separation from the natural history. I think that's the expectation, and that's what we should be looking for, continued improvement and separation.

Thanks, Dr. Panda. Annabel, on your first question, I can take that to start. So -- yes, you caught the pivotal secondary and exploratory endpoints. We did call out for exploratory NSAA. That was not driven or proposed by the FDA. It actually was based on the historical data from other trials where especially at a 9- and 12-month time point the general view has been that, that is a cruder measure where there's just less sensitivity to detect a potential drug effect. But that makes our findings, I think, all the more remarkable. So we didn't see the 12-year old, for example, results when we had set this up or some of the other results that actually look like we are seeing even on the NSAA, very impressive findings. And you pair that with the time function test that really has us encouraged for not only hitting our accelerated approval endpoint, but continuing to see the kind of data that we've seen in these initial patients. I'll go back to you, Dr. Panda, in terms of how you think of NSAA relative to time function tests in terms of sensitivity or how you look at these different measures in terms of belief and what's helping your patients or not?

Sure, Steve. I think you said it right. I think from NSAA, it's 0, 1, 2, right? And there's -- 1 is like performing with difficulty. Within that 1, there's a lot of 1s, but there's a lot of variable...

Dr. Panda, we can't hear you. You may need to unmute your phone.

Sorry, can you hear me now? I had been talking without unmuting. Sorry guys. Now you said that right, Steve. I think from the NSAA standpoint, it is sort of a crude measure is 0, 1 and 2. 1 is performing without difficulty. But within that 1, there is a lot of variability, and we are not capturing that. And from our experience, we know it's going to take a long time, longer than 12 months, at least, to show us significant difference with NSAA, whereas with some of the time functions as they are more sensitive to change in a shorter time frame, like time to stand or force to climb. So I think it is reasonable to consider NSAA as an exploratory or secondary endpoint rather than a primary endpoint, even because we cannot do placebo-controlled trials and other things for -- even with the natural history for 2 years because there's such an unmet need I think we need to bring these products into clinics as soon as possible. So I think it's I think it's reasonable to consider that as a secondary outcome measure or non-exploratory outcome and use of this time-sensitive -- some of the time test as the primary outcome measures as other clinical trials have done that and had received approvals from FDA based on those. I hope this answers your question.

Yes. That's helpful. Can I just ask one other question to you, Dr. Panda? How will you make your decisions now facing several options, there's exon skippers, there's one other gene therapy now that's approved and now that you have this trial. So when you look at your patients, how do you make the decisions to choose one option versus another?

I think that's a great question. Like I have addressed before, we would have to present all the options, including the commercially available products, gene therapy, if they're qualify for exon skipping agents that one, and then also givinostat as well as the clinical trials. The key is the amount of data that you have in hand and how the data -- which one -- I think the family is asking for the data that best matches for their own kid, for their son, right? I have an 11-year-old with exon -- I'm just making it up, with exon 40 deletion. Do you have a data on this patient from any of the studies? I think that's what they're wanting to know. So the more data that I have in hand, the more that I shared with the families is very helpful. So it's presenting the options, talking about the risk and the benefits and what best suits for the -- what's the best fit for that in particular patient because it's obviously every single person is different. And also talking about goals and expectations, setting the goals and expectations, what is that particular patient's goal, that particular family's goal in terms of seeking this treatment. But it is -- yes, it's good that we have a lot of options, and it's mainly discussing these options and coming up with what's best for the family and the patient.

Thank you. Could I ask a question? With the emerging data you see today, on functional outcomes, coupled with the safety. Would you say that conversation is sort of more data based and more compelling than it might have been a month ago?

Definitely, yes. I think safety from the get-go from the different data points that we have presented so far, safety has always been -- we have a clear safety profile and definitely the conversation would change as we get more data. And this data that we presented today is going to be impactful. Again, take into account we're still presenting on a few number of boys, but I think definitely that will change the conversation and the discussion that we have with the families.

And Mike, how would you see the advocacy groups seeing this data? What do you think the direction would be in terms of how they view the program?

I think they're looking at it through a lens that we've just talked about with Dr. Panda. The thing that the question was really trying to compare different modalities in here even when we -- first of all, exon skipping patients are mutation-dependent. And even if we combine all of the drugs that are approved, they will only cover about 29% to 30% of all patients that are out there. So there's still an enormous unmet need for individuals who can't go on the pathway of exon skipping. And that's where gene therapy becomes important. And I think the calculus has definitely changed as we look at the safety profile of this and the benefits that have come out and I think it makes it a lot easier for the community. The constant feedback that we get at CureDuchenne is one where patients are trying to make decisions in a very complex environment. And in the case of gene therapy, that's a one-off decision. And so that there's a much tougher one than going into a product like exon skipping, where you can decide to switch around. So I think in this case, it has changed the landscape out there for patients and it's most welcome.

Our next question comes from the line of Luca Issi, RBC Capital Markets.

Congrats on the data. Can you just maybe talk about the strategy for Phase III in terms of the prophy? If I recall it correctly, you've used SOLIRIS and sirolimus in addition to steroids so far. So wondering if that is the plan going forward as well for the pivotal? And maybe kind of bigger picture, how big of an obstacle is that in terms of adoption given, again, Sarepta, to the best of my knowledge only uses steroids as prophy. And then maybe a question 2 on the accelerated approval, just to be 100% clear, can you get accelerated approval based on expression for both 4 and older as well as 1 to 4 years of age? The only reason why I'm asking is because you're using different sets of endpoint to capture functional benefit. So I just want to make sure that the accelerated approval path here is open for both age groups.

I'll take the last one, and then I think I'll have Naz comment on the immunosuppression regimen. I think the way we see a potential approval via accelerated approval, we're not looking for a narrow outcome here. We are already seeing data in boys across multiple age groups. Certainly, more pronounced benefit right now where we have the large proportion of older patients in our study. The reason I think you could look back that we announced we're dosing children in the 1 to 3 age categories, we want to, at the point of filing be able to say we have long-term safety data associated with multiple patients in the 1 to 3 category. And yes, we are looking at different functional outcomes for the younger patients. But the goal is to provide a comprehensive package that's sort of agnostic to age, based on the totality of data that we're accumulating. Naz, do you want to comment on the immune suppression as it carries forward into pivotal?

Sure. Thanks, Curran. Yes. So we're continuing with the same immunosuppression regimen. It's been very well tolerated. We monitor a lot of different labs to kind of see if there's a complement activation that happens. And AAV8 is a vector and it's a viral load, and we're suppressing a complement activation with the drugs that we're giving. And we understand that what we're doing is being -- is helping with our safety profile. One can also question if it could potentially help with transduction as well, but we don't know that. That's a very prelim state to state -- statement to make, but that's something that we hypothesize and we're going to keep looking at the data to kind of see if it helps with that. But it kind of really makes us all feel very comfortable. I know Dr. Veerapandiyan has been giving this regimen, and I think he's developed a level of comfort with this and feels it's like a good safety net. So we don't have to deal with adverse events -- serious adverse events, honestly. I'd rather not at all. So basically, I think that this is a good investment for 2 months of full dose and then you come off of it, and then you feel like you've passed over a hurdle and you could potentially be at ease for the rest of the duration of the study.

Our next question comes from the line of Ellie Merle, UBS.

Congratulations on the data. Just a couple for me. Just a follow-up on the enrollment question. I guess, what's your expectation for the age distribution for enrollment in the younger versus the older patients, given the availability of Elevidys? And then just a second question for the physicians. It's kind of a high-level one, as we think towards getting the data from this study in 30 patients, I guess, how will you compare the data to Elevidys? And I guess what data do you need to see for you to recommend this product instead of elevidys? Obviously, this is very encouraging initial data, but Sarepta has much more real-world experience at this point. So maybe just for the physicians, what you would need to see to say, "Hey, this is a product I want to recommend to my patients."?

Great. Maybe I'll pass the enrollment question to Steve, and then you could also utilize the team on the second question.

Yes. Great questions, Ellie. So enrollment, Mike and Dr. Panda have raised broadly that this data is really going to embolden the community to consider next-generation gene therapy. On the broad age range, we actually expect to see a good opportunity for enrollment across this. We look at the 1- to 3-year-olds there, there is nothing available on the market for gene therapy. And the older boys greater than 4 years old, this is where this impressive data that we're actually seeing very impressive and consistent microdystrophin expression and now functional data in this toughest-to-treat age range where we know there otherwise is inexorable, meaningful decline in these boys. So Dr. Panda, you see these patients, as you said, you explain all the different options for these patients. What do you think about the potential for enrollment across the age range?

I think we have been -- there's -- as I said before, there is a huge unmet need for sure, whether it is patients looking for other options or whether it is antibody -- pre-existing antibodies or difficulties access to the commercially approved therapy. So there's several reasoning that we could think of, but I don't see challenge or problem in terms of enrolling for the study. And as you have previously said, we had dosed international patients, and I think that's always another strategy to think about. But I do not expect any challenge in recruiting for trials. We have -- we already have several in this sort of "waiting list".

And I guess one aspect of this, Ellie, is that for the Elevidys approval, for patients that are in the sort of 8 and older category that we're talking about, we've already treated a very similar number of patients in that age group to what was the case upon approval for Elevidys. So I feel like we're in good shape with the 1 to 3 category enrolling as we speak, we're very optimistic. If you think about it, we've enrolled or will have enrolled by year-end, 10 to 12 patients with only a couple of sites active all year, we're expanding that dramatically. So enrolling 30, including -- let's not forget that we may be able to include our dose level 2 patients that have already been treated in the Phase I/II study. We'll be able to enroll and have patients, I think, in a broad spectrum of age available at the time of filing.

Great. And then just a second question for the physicians.

So Mike, could you give your perspective on when you have the patients come in and you see their families and you described this, how you see potential need where a next-gen treatment could be of use?

Happy to expand on that, Steve. The thing that I would say at the beginning is that this is a very informed community. The Duchenne community are really engaged in what's going on both with approved drugs as well as those experimental medicines that are in clinical trials. And we mentioned it before, but I would underline this as one of the most important components for them and that's the safety benefit profile of this particular drug that we're talking about. They recognize that gene therapy is a onetime treatment. And once you get one, you're unlikely to switch on to a different one. And that feeds into this -- the informed nature of the community. And so I think that what we're looking at today is a scenario where I would expect the community to lean heavily into the data that we've released today. And really, we will have tuned into the safety profile and the benefit that we've seen, and that will go a long way to help them make the decisions into trial recruitment, particularly in the pivotal. So I look forward to seeing that manifest itself as the community really starts to absorb what's come out today.

Thanks, Mike. And Dr. Panda, on Ellie's other question of looking forward when we have 30 patient data, what would you be looking for to see there?

I think I will -- as we said before, I think we are hoping to see the continued -- data continued improvements. To me, I think consistency is important as we have to -- there is a consistent dystrophin expression, consistent -- and that matches with the consistent functional outcomes. I think that's critical to differentiate. And like you said before, there are several strategies that you could think of one versus other. Of course, it comes down to the consistent data -- the ability of us to share the data that to the families and they have to have the buy-in that, okay, this is a product that I want for my -- this is -- okay, this is safe, this is working. I think this is what we want. I think having that -- more the data, more consistent data. And one thing that keeps coming during our conversation is every single family that I'm talking to, they're asking, "Hey, do you have -- can you show me a kid that was dosed in the trial with my sons, like I said, before my son's genetic change." And I think that granular level data, if I am able to share that, I think that is going to make the change also. They want to know. But I think as we move forward, I'm hoping to enroll more patients, we continue to see these improvements, see the differentiation between the natural history and the treated patients. And so we can -- as the families can make informed decisions about the therapeutics.

Our next question comes from the line of Alec Stranahan, Bank of America.

I want to offer our congrats on the great data as well. First, curious how you're thinking about pairing the VCN copy number with microdystrophin expression, are these correlated in your view? And is there maybe a threshold for transduction that's guiding your decision to go with the higher dose? Or is this really driven by the functional benefit? And secondly, given what we've heard from the physicians on the call today and from our own KOL checks, that breadth of addressable patients could be an important differentiator if it does get on the label. Maybe just to put a finer point on it, how are you incorporating age, exon status, et cetera, into your pivotal, obviously, balancing the scope and the size of the study?

I'll take the vector copy number. It's certainly something that we look at really to establish 2 things. One is, are we getting a dose response in terms of -- at the higher dose, are we seeing higher vector copy numbers in the biopsy samples that we're taking. And you can see from the data set that that's happening per expectation, that we're seeing a nice increase in the biopsies at DL2. There's a few things we think about second to that, that I think Naz would certainly remind us. It's not just having the good biodistribution, but also ensuring that we're getting good localization such that where the microdystrophin is residing is likely to give a functional outcome that's beneficial. The other aspect we think about with the higher vector copy numbers, and I think we're showing the highest vector copy numbers that I think have been published. We're hoping that it could lead to durability advantages as well. Maybe that's -- these numbers are a result of the immune suppression, the serotype promoter, you name it. But I think there's all kinds of aspects. But hopefully, this would lead long term to better durability of the drug effect. So maybe I'll turn that over to Naz to comment as well and then also answer the second question.

Thanks, Curran. Yes, I agree with everything that Curran just said. We are excited to see kind of like a doubling of the vector copy number almost in the dose level 2 patients. And that translates on our immunofluorescence that we see where the antibody stating does go to the sarcolemma. So we know that not only is it getting to the muscle tissue, but it's getting to the muscle tissue in the correct place. We hope that our transgene design with our unique C-terminal is helping with that. We also have the unique feature of a hinge 3 in our transgene that will create a more stable protein that does its job right. And so we're excited to kind of see where this vector copy number is going to take us and how long it can continue to support the muscle cells. For the other question that you had, the incorporated age for pivotal is 1 and older. So we have no upper limit of age, but obviously, we have functional criteria for entry. So that will probably self-limit in some cases. Exon status, we currently will take anybody with any mutation in exons 18 and above. But as I mentioned before in the presentation, we are looking to hopefully soon evolve our program to open it up to include more patients with mutations outside that range.

Our next question comes from the line of Brian Skorney, Baird.

Congrats on the data and the start of the pivotal. I guess kind of jumping off of Ellie's questions, would you expect a substantial number of patients under 4 to enroll in this study? I guess, from Dr. Panda's point of view, are most of your patients diagnosed with DMD before turning 4 at this point? And when you talk about patients who are sort of in the queue for starting this study, are they falling into this younger age or is it more traditional 4-plus? And can you also just remind us what the cutoff you're using for seropositivity in AFFINITY DUCHENNE? Are you specifically only looking at AAV or are there thresholds for other vectors as well like Rh74?

Okay. Great. Naz or Steve, do you want to start that off?

I'm happy to -- Steve, go ahead.

So yes, we're only looking at AAV8 seropositivity and we're including any seropositivity in terms of exclusion. And to your next question, that was really explicitly for Dr. Panda. So how many...

I can answer that, Steve. I think -- to your -- in terms of questions about the diagnosis, I think the -- still there is the diagnosis is typically for an older age of diagnosis. There are very few with family histories or smart clinicians who check a CK level or pick up some minor things and we get -- the diagnosis happens, the anger age, but the typical diagnosis is still in 4, 5 sometimes older than that. In terms of the patients waiting, a majority of them are 4 and older, and there are also my own patients, few that we were able -- that are younger 1, 2 less than 4 are also on there.

Mike, do you have any comments on sort of newborn screening and how that might be evolving over time?

Just briefly, I think there's 3 states now that have instituted newborn screening for Duchenne. Excited to see that happen in line with therapies like this going to younger and younger age groups. I think that's certainly where the future is going to be. And the next few years will be really helpful and informative to understand the phenotypic change of going in a very young child and following them for the first few years. So newborn screening leans heavily into this curve.

And our final question comes from the line of Danielle Brill from Raymond James.

Congrats. So I have a few, I'm curious about the confirmatory trial. Did you discuss the requirements with the FDA? Will you need a separate study? And can you use an external control comparator arm? And then on the data themselves, at the patient level in the 12-month data, did the functional measures, were they consistent at the patient level, the benefits and the correlation there? And was there a correlation between functional improvement and the magnitude of microdystrophin expression? And then also curious how the CK data look.

I'll speak briefly to -- the focus of the end of Phase II meeting was primarily on the pathway to accelerated approval. So there's still I think ongoing dialogue required with FDA regarding a future confirmatory study. I would say though, our expectation is that many of the patients that are -- will enroll in the pivotal study that we've described really for the confirmatory, it would be largely just following their functional outcomes out to a year. And then the discussion really on confirmatory would be more around the eventual sample size needed for confirmatory if it's at all different from what we're pursuing for the accelerated approval. So I don't see a significant change in our trial design to roll into a confirmatory study down the road. And then Naz maybe you could describe the -- or answer the question regarding the 12-month data points in CK.

Sure. Yes, our 12-month data is only from dose level 1 so far. And we have seen similar functional improvements across the board in all the patients. What I can say is that, as we mentioned in our primary end point, our primary end point is to kind of get over a 10% threshold. We haven't done like a rigorous study yet because, again, it's too early with so few data points to see if there's a correlation. But it really just seems like you just need to get over a certain threshold to have functional beta -- benefit. So just in this dose level 1 data, just like looking at it on the fly, it's not going to be, as we have seen historically, academically in literature. It's not a one-to-one correlation between microdystrophin levels or dystrophin levels and function. What you're seeing is you just need that little boost to get you over the hump and then once you get over that hump, you get improvement. So that's something that I think we have seen. And for the CK data, we have some CK data from dose level 1, we're seeing sustained decreases. But again, that data still has to be QC in terms of like what values and what amounts. But it is a sustained decrease. And we'll see -- we'll check and see as time goes on because we intend to follow these kids up to 5 years out, how -- for how long the CK can be decreased for. So we'll comment on that. I'm sure at a later date.

That is the last question. And I will turn the call back over to Curran for some closing remarks.

Chris, thank you. I'm really thrilled with the data that we've been able to present today. I hope that all of you on the call were able to get your questions answered. We're extremely excited about this program. We're moving as quickly as possible towards an accelerated approval and I think the enrollment outlook from this data will be really, really positive. I do want to just thank Dr. Panda and Mike Kelly for joining us today. I think it's really, really important that you hear from the key people we have associated with the program, both internally and externally, and I really want to thank them for their contributions. We look forward to executing as well next year as we have this year and guiding towards the 2026 BLA filing for this program. We've ticked off, I think, almost every box we wanted to this year in terms of the problems to the program, and we're going to be going 100 miles an hour to try to get this drug on the market in the future. So thank you very much, and we'll talk.