REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining us. Earlier this morning, we announced new positive Phase I/II interim data for RGX-202, our potential best-in-class investigational gene therapy for Duchenne muscular dystrophy. We may make forward-looking statements on this call, so please refer to this slide. Back in November, we shared initial positive Phase I/II functional data. Today, I'm very pleased to provide additional updates on the continued great progress with our trial and discuss our new positive functional data. I'm joined today by Dr. Steve Pakola, our Chief Medical Officer; and our Clinical Development Lead for RGX-202, Dr. Naz Dastgir, who is a pediatric neuromuscular neurologist. We're also very pleased to have Dr. Aravindhan Veerapandiyan, Principal Trial Investigator, also known in the field as Dr. Panda, on today's call to discuss the AFFINITY DUCHENNE program, its data and share key insights about what he sees in the clinic and in the Duchenne community. Duchenne is a severe progressive degenerative muscle disease caused by mutations in the DMD gene, which encodes for dystrophin protein. Boys with Duchenne typically gain skills until about 6 years old, at which time they reach a plateau in function and then begin to lose ambulation and rapidly decline. While there is an approved gene therapy on the market, significant unmet need remains for additional treatment options that can improve function and long-term quality of life. We're working with the utmost urgency to bring this potentially transformative therapy to patients and making great strides in our ongoing clinical program, AFFINITY DUCHENNE, to advance RGX-202. Recently, we expanded the AFFINITY DUCHENNE trial to include an even wider range of patients in pursuit of a broad label. The ongoing pivotal study is beyond 50% enrolled, and we expect to complete enrollment in the pivotal phase of the trial this year. With the potential FDA approval in the first half of 2027, we're quickly approaching our goal of delivering RGX-202 as the next gene therapy for Duchenne. I want to give an overview of our innovative and differentiated therapeutic approach that we've carefully designed for improved outcomes in Duchenne. Today's positive update is a testament to how our development of RGX-202 is truly benefiting patients and changing the course of disease. Here, you can see an overview of the many elements that make up our differentiated therapeutic approach. Starting with our construct, RGX-202 uses AAV8 and is the only microdystrophin construct that includes elements of the C-Terminal domain. With the CT domain, RGX-202 is uniquely designed to better preserve and protect the muscle as demonstrated in preclinical studies. Second, we use an immune modulation regimen designed to proactively mitigate safety events that can occur with high-dose AAV gene therapy. We believe this 3-month course is contributing to the positive safety profile we have seen in RGX-202 to date. As indicated in the bottom right, we developed the clinical program with both speed and breadth in mind. The ongoing pivotal trial is in patients aged 1 and older and designed to demonstrate meaningful change in disease trajectory in pursuit of accelerated approval and a broad label. Last but not least, our in-house manufacturing process is also a key differentiator. This suspension-based process has demonstrated consistent yield and product purity levels of greater than 80% full capsids, which supports delivery of a high-dose AAV with a favorable safety profile. Before I turn it over to Steve and Naz, I want to emphasize that while Duchenne families have options, they continue to face significant unmet need. Families and physicians need to make informed decisions about their treatment options, and that's why we're very excited about the data we'll share today. With that, I'll turn it over to Steve.

Thanks, Curran. As you said, we're very happy to share this exciting and positive new interim Phase I/II data today. The Phase I/II portion of the AFFINITY DUCHENNE trial is a dose escalation and expansion trial, with dose level 2 selected as the pivotal dose. As Curran referenced, safety is our top priority, and we're proud of our proactive immune modulation regimen, which has provided our investigators greater confidence in the risk-benefit profile of RGX-202. Today, we'll focus on our Phase I/II dose level 2 data. In this protocol, we've dosed 10 participants aged 2 to 12, with the majority of the participants we'll discuss today being 8 and older at dosing. This is the age range when you expect to see functional decline. In our Phase I/II trial, we continue to have no SAEs and no adverse events of special interest, or AESIs. The excellent safety profile further supports the differentiation of 202. Turning to biomarker data. I'm pleased to share new results from a participant aged 2 years old who received dose level 2. This participant's microdystrophin expression was 119% compared to control. Overall, we continue to see consistent robust expression, transduction and localization of RGX-202. To date, all participants have demonstrated microdystrophin expression levels above 10%, which is the primary endpoint in our ongoing pivotal study. Now I'm pleased to introduce Naz, our clinical lead for the 202 program, to walk us through the new positive Phase I/II functional data. Naz?

Thank you, Steve. I'm very pleased to be here today and discuss the positive data we announced this morning from dose level 2 participants in the AFFINITY DUCHENNE Phase I/II trial. There are 5 participants who have reached 9 months post treatment, with 4 of them reaching 12 months post treatment. These participants were approximately 6 to 12 years old at dosing. Based on their age and baseline function, majority of these patients are expected to be in the decline phase of their disease trajectory. Given the wide range of clinical heterogeneity in Duchenne patients and our desire to clearly evaluate 202-treated participants' functional outcomes versus their anticipated untreated trajectory, we leveraged a large recognized data set and applied a rigorous rules-based process when matching to external controls. Criteria included age, steroid use, time to stand, time to run-walk, time to climb and access to at least 9 or 12 months of data from baseline. Now on to the exciting functional data. Here, you see results of 5 dose level 2 participants at 9 months. The blue bars show average change from baseline, and the gray shows what's expected based on matched natural history controls. As you can see, RGX-202 participants demonstrated improvement in function and exceeded external controls on all measures. On NSAA, RGX-202 recipients improved an average of 4 points from baseline and 4.8 points compared to natural history. Here, you see results of 4 participants at 12 months post dosing. Data from these participants were also included in the 9-month data set. As you can see, our results at 12 months are similar to those seen at 9 months. Consistent with the 9-month time point, RGX-202 participants demonstrated improved performance on timed function tests and NSAA, exceeding external natural history controls. It is not shown on this slide, but all participants within this cohort demonstrated improvement on all timed function tests compared to baseline. A mean 6.8 improvement in NSAA score compared to natural history control further supports positive functional benefits. Here, you can see at 12 months, time to stand, 10-meter walk-run and time to climb velocities exceed the MCID, or minimally clinically important difference, which was used by the FDA in the broader approval of the currently commercially available gene therapy for Duchenne. In summary, these functional results are highly encouraging and demonstrate a potential robust and durable effect. Not only are participants improving, but many are also meaningfully exceeding their expected disease trajectory in a time period of expected decline. These positive results support our confidence in the pivotal phase of the trial and give us a clear picture of the potential benefit of RGX-202. We're also highly encouraged by the caregiver-reported outcomes. They provide important insight into how the functional improvements we just shared translate into these participants' day-to-day activity. As reported by the Pediatric Outcomes Data Collection Instrument, or PODCI, at 12 months, caregivers reported improved function in the home and community across 3 key dimensions of this tool: transfer and basic mobility, sports and physical functioning and global function. This means that these children are better able to participate in their daily lives with their families and their peers and in stark contrast to their expected function. Now to give you a better idea of what these improvements look like, both in the clinic and in the real world, Dr. Panda will share a video.

The first video is of a 9-year-old boy at 9 months of follow-up. At baseline, he uses hand rails to climb stairs with alternating feet. At his 9-month assessment, he is able to ascend stairs without use of hand rails. This next clip on the left shows a 12-year-old participant's baseline time to stand assessment. On the right, we see his same assessment at 12 months after dosing with RGX-202. At 1 year, he performs his task more swiftly and has maintained the ability to transition from the floor to standing position without using his arms to push on his body. The next participant was 8 years old at dosing. At 12 months, he is able to complete his 4-stair climb with quick weight shift, faster speed and more confidence. Next, we see another 8-year-old participant. At 12 months, he has maintained the ability to transition from a low squat to standing position without using his hands and even gives a quick hop to transition to the final testing position. The next participant was 5 years old at baseline. At 12 months, he demonstrates improvements in the quality and speed of running on the 10-meter walk-run test. This same participant demonstrates greater speed, confidence and body control as he nearly jogs up the stairs in his 4-stair climb test. The first home video shows a boy who was 8 years old at dosing, followed by several videos of a boy who was 5 years old at dosing. These boys are able to participate in activities with their peers and families, the activities that require muscle strength and endurance like climbing up a bouncy slide and sliding down, biking and jumping. I'm always grateful when these families share these insights into their daily lives.

Wow, Dr. Panda, thank you for sharing these impressive videos. It's compelling to see how your patients are doing on functional tests in the clinic, but to also get to see how well these boys are doing in a real-world setting is quite exciting. Particularly at this age where these boys are expected to be in a stage of plateau or decline, we're really pleased to see these boys are demonstrating improvement and able to participate in such activities. Now let's discuss these results further with you, Dr. Panda. First off, thank you for joining us today, Dr. Panda. Let's start off at a high level with your overall impressions on the functional data we've presented today.

Thank you, Steve, for having me today. The functional data that was presented is very promising and encouraging for me, particularly the consistency of the functional improvements at the 9- and 12-month mark in these boys, especially the ones like you said, in the plateau or decline phase of the disease. And to also point out, we are well ahead of our completion of the immunosuppressive regimen that also is encouraging. All of these underscores the potential impact of this RGX-202. Most importantly, I'm also very impressed with the meaningful clinical improvements and how these translate into the real world for these boys with Duchenne. I'm looking forward to continue tracking these patients as we continue to follow and see their progress.

Thanks, Dr. Panda. Naz, I'm going to turn to you now as clinical lead for the RGX-202 program and, I can't help but add, also a neuromuscular specialist who actually treats Duchenne patients. What does today's data update tell you about RGX-202 and this program?

Yes. Thanks, Steve. So I'm super encouraged. Obviously, I'm very positive about the study overall. I love the fact that the data is consistent throughout the 9-month and 12-month period and after the immunosuppression regimen is complete. Just as Dr. Panda mentioned, hoping that the influence of our immunosuppression regimen is completely worn out by the time we're showing this data. And also, I'd like to note that the majority of our patients are also older and in the decline phase. So where you would be expecting over a year's period to see decline naturally, we are seeing an improvement in our exact match natural history control cohort.

Great. And turning back to you, Dr. Panda. You've discussed these encouraging results with 202. Maybe as some context, can you step back and tell us more about what you see as the ongoing unmet need for Duchenne patients and families that you see in your clinic?

Sure, Steve. I think when we talk about ongoing unmet need, there's quite a lot that I could keep listening. But from a therapeutic standpoint, and I always say it, we are in good times, having a lot of options for therapies, having challenges or good challenges, right? I think from an unmet need standpoint, always having multiple innovative therapeutic options that can transform their life, that can help with maintaining the muscle integrity is important. And then in terms of -- we are seeing a lot of seropositive individuals out there and also restrictive from a mutation standpoint. So I think expanding into the broader -- including more patients with deletions that are not studied in other clinical trials, I think it's providing more data to support us to discuss these in the clinics with these patients. And also expanding the age group, especially the newborn screening coming along, so providing potential options for patients that are diagnosed very early on is also a good thing from my perspective.

That's great. And to hear you talk about the good times with lots of options, but still very significant unmet needs, both in terms of the exon mutations that in our trial, we've expanded and also the age range that now we're at the 1 plus age range, I think, is encouraging for this program. The aspect of the many options, I think it would be great to hear your perspective when you actually think of the patients and the families that are coming in with these results. How does that inform your discussions when you think of discussing current options with your patients and families?

Yes, that's a great question, Steve. That happens every day in our clinic, right, with these options, and I spend hours and hours discussing. It really depends on the family. And it's -- I would say every single individual with Duchenne is just that individual, and the right option for them is there's no one size fits all, right? So when we discuss this and, obviously, discuss about all the options, the commercially available options versus -- and the ones in the clinical trials, if they would be eligible for clinical trials, we weigh the pros and cons from a safety as well as the efficacy standpoint. We do have families who come to me knowing what they know, and they say, "Hey, this is what I want. I want RGX-202. I want to be in the trial." And we also have families who are going to trust my judgment. I think it's really very individualized. And having these options and discussing all the options, the commercially available versus being in the clinical trial and how the monitoring differs, what the construct looks like, how -- what's the difference there, is there any functional differences or microdystrophin expression differences, safety, all of it comes into play when we make this decision presenting these options.

I like the reminder that you often bring to the discussion that every patient is an individual. So I think that makes all the more impactful, some of those videos that you showed earlier. Since you're the one there with the patient and the families as you see these clinic videos taken and these assessments made and then also the caregiver videos, can you give us some more insight in what you're actually seeing? And what are the clinical meaningfulness aspects of what you're seeing in terms of these boys' daily function?

I'm sure, Steve, like I have said this in other forums as well. To me, I think what's happening with these boys in their real life is much more important than the scores that we assess in the clinics. You can all -- you can tell me, hey, he had 6-point increase in NSAA, a 4-point increase in NSAA. But what's much more important and personal to me is if a family comes and tell me, "Hey, my son is now able to play longer outside with his siblings." I think that's much more impactful for me. And I think that's impactful for the whole family. So I think that's what we are seeing. And if I'm seeing that in any product, any drug that I'm using, I think that's much more impactful for me. Like we shared in the videos, we have boys who are jumping in the trampoline, who are sliding up and down in the slides and who are riding a bicycle. Especially the older boys, we expect them to be in sort of a plateau or decline phase. And I think how these translate into their real life and the joy that brings into this kid and also the family is much more important for me.

Great. That's so helpful to hear that real-world perspective that you're hearing from the patients and the families and your own expert perspective on all of these findings. So now I'll turn the call back over to Curran.

Thank you, Steve, Naz and Dr. Panda. To sum up what we've shared today, we are highly encouraged by the robust biomarker, favorable safety profile and consistent positive functional data seen in our Phase I/II trial. Participants are demonstrating meaningful functional improvements compared to their expected disease trajectory, underscoring the potential of RGX-202 to be a differentiated and best-in-class therapy. Before we turn the call over for Q&A, let me remind everyone where we are today in the pivotal phase of the AFFINITY DUCHENNE trial. Our pivotal trial is beyond 50% enrolled, and we are experiencing high demand and enthusiasm from the Duchenne community and physicians. With robust biomarker data and positive functional improvements, we remain in an excellent position to submit a BLA in mid-2026 using the accelerated approval pathway. Just a few weeks ago, I was grateful to attend the CureDuchenne annual meeting with our team and hear firsthand from families, physicians and advocates the significant ongoing unmet need for these patients. They need a new option that can provide favorable safety and consistent functional benefit. Today's positive data builds on the totality of evidence demonstrating the potential of RGX-202 to improve outcomes for boys with Duchenne and alter the trajectory of this devastating disease. Now we'll open the line for Q&A. [Operator Instructions] Thank you.

The first question of the day is going to come from Judah Frommer from Morgan Stanley.

Congrats on the progress. I guess, first, I was hoping, Curran, maybe you could further characterize enrollment progress relative to where you thought the pivotal enrollment might be at this point and maybe help us with whether the community is more excited about the trial given the competitor safety issue that we saw a little while ago, relative to where you thought you would be currently. And then separately, just on the functional measures, I think in the November update, there was a 12-year-old who had 9 months was showing really strong NSAA improvement. Just curious if you could help us with kind of distribution of functional benefit that you've seen and whether there are some "super responders" that are impacting any of the bars.

Sure. Thanks, Judah. I think speaking about enrollment, obviously, for these studies, there's a lot of preplanning and activities in screening well ahead of the dosings. And I would say just looking at what we have planned for the remainder of the year, we see a lot of excitement, a lot of interest in the studies, a lot of activity in the screening logs at sites. And I think that will translate to a really high level of confidence that we'll enroll the study this year and stick to our overall time line related to top line data first half of next year and BLA filing mid next year. So I think overall, we feel great about this. We hope this data will also reinforce the enthusiasm and interest because I think we're showing a really clear benefit in terms of benefit to risk, really incredible functional outcomes that are both seen in the data and on the video that we were able to provide and the continued safe profile that we feel is very favorable. Regarding the specific data, we are choosing to display the data going forward as a composite of the larger data set. I'll let Steve speak a little bit to the consistent effect that we're seeing, not just on the one patient you mentioned, but also across all of the patients basically in terms of their functional outcomes. Steve?

Sure. Thanks, Judah, for the question. Yes, I think the important aspect is if you look at those means and you recall Naz's comments that all the patients are doing better than external natural history and also doing better than baseline, even when you look across a broad range of functional endpoints that are the standard ones to look at, so I think robust and consistent. And I think if you look at those numbers, it's clear that not one patient is driving that if all of the patients are doing better. And I think that's particularly striking since 3 out of the 4 boys at the 1-month time point are older than 8 years old. So these are boys that you would definitely be anticipating would be declining. And not only are we seeing stabilization, but we're actually seeing improvement. You mentioned that one particularly impressive boy that Dr. Panda discussed at the 9-month time point. That patient continues to do well. But again, there's no super responder that's driving this since we know all the boys are doing better.

Our next question comes from Gena Wang with Barclays.

Maybe just follow this variability questions. So on Slide 17, I'm just wondering how the standard deviation look like. And we do see the control arm, the natural history control arm, the number increased a lot compared to the last update. Is that because of now you have more patient and so therefore, the matching part from natural history also will expand? And quickly, I do have 2 questions for Dr. Panda. So the first one is post the one patient death with Elevidys, what are the patients' view in general on DMD gene therapy? And the second question is a fast forward 2027, if multiple gene therapy becomes available, how would you decide the drug to use? Like what are the metrics you're looking for, understanding that we will have limited functional data from a controlled study?

Thanks, Gena. I'll start just briefly and then let Steve talk -- speak to your questions regarding the data. But I think the important element here that we're trying to reinforce is, number one, at 9 months and 12 months, you're seeing very similar trends in all of these functional assessments. And as Steve mentioned, we're seeing consistency amongst the full patient group as well. It's hard to run a lot of statistics around such a small N of 5. And so we've chosen not to do so. But we do want to point out that in general, all of the patients that have been treated at DL2 are showing either stabilization or improvement. Steve, do you want to speak a bit to the controls?

Sure. So Gena, you're exactly right. The increase in the N for the external controls is based on the fact that, fortunately, we have more patients to discuss today than we had in November, so the 5 at 9 months and the 4 at 12 months. So when you add those additional patients to have exact matching from our databases, that allows for a greater N, and that gives greater confidence as well. So the last question was for you, Dr. Panda.

Yes, I think the question is about how -- fast forward in the future, we have multiple options. How do we -- I think there's a lot of factors that's going to play into role there, right? So what data that you have from the study from efficacy and a safety standpoint, even if the data is limited, just really what we have in hand. And it's very individualized from one patient to other patient, so obviously, the safety, effectiveness. And then you have your -- the -- your experience with one -- each therapy that would play into -- a physician's experience with each therapy would play into role as well. And then families, the boys if they have antibodies to one versus the other, that's going to play into role. So there's multiple factors. And I would say it's very individualized and varying from one patient to other patient. And I think one other thing to add would be from a safety standpoint also, it's -- immunosuppressive regimen if that is important moving forward and mitigating a safety profile, that would also play into role. So I think there's a lot of factors. I hope that answers the question.

Right. And just one quickly, the patient view in general, DMD gene therapy post the patient death, this Elevidys.

I'm sorry. I didn't hear that question. I don't know if...

I think the question is related to patient view regarding Elevidys since the patient death was reported.

I see. So I think I can -- so from a patient's view, I -- yes, there is an extra concern there, but not a lot of concerns in the terms of -- I haven't seen any change in the ones that people are planning to dose. The reason being you -- I would talk about it -- a lot of us will talk about it anyways as a risk factor, even if it has not happened in the program. So I think that's what we're seeing. Definitely, when they hear the news, families got -- there was care, concern and ask more questions. And when we talk through it, I think it was -- I think it turned out to be okay.

And our next question is going to come from Lili Nsongo from Leerink Partners.

Congratulations on the data. So maybe a little -- so building on the question that were asked before in terms of individual results in the functional data, do you see any correlation between dystrophin expression and individual performance in the functional assessments? And then as a follow-up, do you see consistency within each individual patient in terms of their progress at 9 months and at 12 months?

I can take a stab at the second question first. I think we're actually really thrilled to see the consistency between the 9- and 12-month data. I don't know that we had any prior views of whether those would be consistent or inconsistent, but the fact is across all 4 functional measurements, we do see a high level of consistency. And we're going to be really excited to follow these patients out to 2 years because we feel with the high vector copy numbers we're seeing, the chances of expressing good durability in terms of microdystrophin expression are quite high. I think in terms of your second question, I think it's too early with a sample set of 5 to correlate microdystrophin levels to specific functional outcomes. There's certainly variability in the functional assessments. There's also variability in the biopsy measurements as well for microdystrophin. What we do see is a clear trend that the younger patients -- the younger patient is when they're treated, the much higher expression levels we were able to achieve. And I think that's the direction that, over time, this therapy will take, is treatment of younger patients off newborn screening, perhaps. And I think that is where the field will move over time. And so we're really encouraged to show the data for the young patients to, again, give them the best chance of receiving very little functional decline. We're also excited to see this benefit. We're showing higher microdystrophin levels than other studies in the older patients. And that's definitely, we think, one of the reasons we're also seeing better functional outcomes for those patients than might be expected. And Steve, do you have anything to follow with that?

Sure. So Lili, one good dilemma we have is we don't have very low microdystrophin in any patients. So with dose level 2, we're seeing very consistent high levels, so -- unlike historically may have been seen with other programs where there can be greater variability and even some patients not having any microdystrophin. So in that setting, you can look at correlation in a different light. Here, the reality is we're seeing high microdystrophin, and we're seeing both based on the functional measures, but also from the videos that Dr. Panda showed across the patients' functional improvements on these measures consistently. So that's exactly the type of correlation that we'd like to see at this stage. The other question you asked about, consistency going from 9 months to 12 months, which is very important to show, of course, for durability, and we're happy to say that both patients that we reported at 9 months are continuing to do very well. And again, you can see that from the videos that Dr. Panda showed.

And our next question is going to come from Luca Issi with RBC.

Great. Can you guys hear me, okay?

Yes. Perfect.

Great. Great. Maybe 2 quick ones. Maybe, Steve, I appreciate this is totally different disease and very different settings, but what was your reaction to the tragic news over at Rocket over the last few weeks? And maybe any implications for your program at all? That would be -- any thoughts there, much appreciated. And then maybe for Dr. Panda, it looks to me that the exon skippers are making meaningful progress here with conjugating construct from Dyne, Avidity and others. How are you planning to use the exon skippers versus gene therapy in your practice going forward? Who gets the former versus the latter versus potentially the combo? Any thoughts there, much appreciated.

I'll comment quickly on the Rocket patient death that you spoke to, and then I'll let Steve add to that. I think we're talking about a very different study using AAV9 and, in our case, using AAV8. And also, we don't have a lot of information about the specifics and don't typically comment on other studies. But certainly, the method of complement inhibition in their study is different than the C5 inhibitor that we're utilizing. So we really do see that is incredibly unfortunate but not really related directly to our study. And Steve, do you have anything to add there before we turn over to Dr. Panda?

Yes. The differences that Curran highlighted, different serotype, different disease setting and, certainly, the different approach to complement inhibition are critical in this case, and more details are needed as always in evaluating this. But certainly, the specifics have been put forward. We also have our own database that there's no less significant findings that would presage anything like that, given our clean safety profile to date that we've highlighted in our presentations from our Phase I/II data. So we've not seen any carryover from discussions with all of our investigators. So I think we continue as we go. And I think one of the key things I'd highlight is we have a lot of experience in evaluating immune modulation, including considerations that other companies have to go through just based on our own programs and all of our licensees that we track closely. So I think we -- just as the other safety issues that have been discussed, if anything, the greater spotlight on safety has been viewed as encouraging for our program, although, of course, all of us in the field are, of course, disheartened by any deaths in any of the other programs. But certainly, apples and oranges we see from our case. Dr. Panda on the other question?

Sure. Yes, I think that's a great question in terms of exon skipping coming up and other therapeutic strategies. I think future of Duchenne is -- and I always say, it's going to be add-on, combination therapy, cocktail therapy. So I think there's definitely room for multiple therapies adding on -- either dystrophin restoration therapy with a muscle-targeted therapy or exon skipping, microdystrophin, all of that. Then depending on which goes first, it's really, again, an individualized discussion. And I'm just glad that we have options, but I think they all have a role in the landscape.

And our next question is going to come from Annabel Samimy with Stifel.

Congratulations on a lot of great data here. So just curious -- I'm grateful for the amount of data that you put out already. They're really great. But we started seeing signals of improved cardiac function based on troponin levels and ejection fraction from other competing programs. And I was wondering, given that you promote the same NOS activity, perhaps even more efficiently through the C-Terminals, I'm just wondering if you're collecting any of the same type of data, which I think might be even more relevant in older age group, where cardiac function might see -- you might start seeing some declines. So any comment there that you can share with us? Have you measured any of this? And are the patients that you're looking at this age range, are they expected to have any cardiac deterioration at this stage? So just a little curious if you have any qualitative information around that.

Thanks, Annabel. It's a great question. And I know actually, Steve and Naz have been diving into this with some of the conferences they've been attending. So I'll defer the question to Steve, and perhaps, Naz can add to.

Yes, I'll start, Annabel, and hand over to Naz from a clinical perspective, which I think is important. The reality is you are hitting the nail on the head as far as what do you expect to see, depending on age. And for us, if patients are in an age where you're not seeing any clinical evidence of cardiac dysfunction, it's really not a stage where you can be evaluating from an efficacy standpoint. So we really look at this from a safety standpoint, and we do include some of these measures like ejection fraction. So for us, especially if you are already starting from a normal or relatively normal standpoint on things like ejection fraction and some of the other measures, what exactly does it mean to have an increase in those things, especially given background variability that can exist? And I think the other aspect is the earlier you look, the less confidence you can have on evaluating improvement because you still could have those early effects at 3 months, certainly in 6 months from the increased steroid prophylaxis that's used across the programs. So that's why we like to look across the board at 9 months, 12 months and longer. But certainly, for cardiac, we think it's going to take longer. Naz, you evaluate these patients in your clinic. What's your take?

Yes. So typically, in clinic, when we monitor kids for cardiac disease, you start to kind of see early signs of it around 7 age -- like age 7 or so, 7 to 10. That's when we really start doing the gold standard of cardiac screening, which is cardiac MRI. Prior to that, we do echocardiograms, and echocardiograms like typically in those ages that are younger don't really show changes. Unless you have like a more cardiac-specific phenotype, there could sometimes be more involvement with certain mutations in the heart. And in our patient population, we select -- and in terms of our inclusion criteria, we select having ejection fractions greater than 55% and a good baseline cardiac exam. So our kids don't have disease at baseline upon entering into the study. And I find that echocardiogram results that are early in -- after gene therapy, like, say, for example, 3 months or even 6 months, like it's too early to see a change. And also, echo is not really the gold standard of evaluating heart function. The gold standard of evaluating heart function is cardiac MRI. And we do, do cardiac MRI in our study. And our first cardiac MRI is at baseline, and we do a follow-up at 12 months. And we're hoping that once we get all that data and we can analyze it, we'll be able to present it to you and give you an idea of how our drug is potentially benefiting the heart but, again, with the caveat that the kids that enter in our study do not have baseline cardiac dysfunction.

Okay. And if I could just ask a quick follow-up for clarification. So you mentioned that all the patients are seeing stability or improvement. I'm just wondering, in the patients that you reported out in November -- I guess some of them were 12 months already. So in those patients who are at 12 months, you're still seeing consistency and stability from that point? Or is this going to be something where you see improvement and then you see -- you start seeing deterioration over time? So it's just like sort of moving the curve over a little bit. So I'm just trying to understand how to think about gene therapy long term. It may be too early to comment on that, but maybe you can provide some clarity there.

Yes. I think just to be clear, in November, the patients that are at the pivotal dose, DL2, were at 9 months. And so the 12-month data you're seeing now is just a continuation of what we saw at 9 months. The 12-month data was on DL1, which is not the pivotal dose that we're moving forward. I think it is a bit early days on durability, but we are really encouraged by the biodistribution we're seeing and the vector copy numbers and the microdystrophin levels that we think will contribute positively to longer-term durability. So time will tell, obviously, but we're not seeing any indications to date in our data of a diminishing effect. But this is something we'll follow very closely.

And our next question comes from Ellie Merle with UBS.

You might be on mute, Ellie.

Can you hear me now?

Yes.

Great. Congratulations on the data. Just wanted to ask on safety. Since you're using a complement inhibitor as a pretreatment, are you requiring any vaccine schedule or regimen before putting these patients on immune suppression? And I guess, if so, what is the vaccine schedule? And just how long is that typically taking before you can begin dosing with eculizumab and then, of course, the gene therapy? And then I have a follow-up question.

Great. I'll defer that to Steve and Naz to cover.

Sure. Naz, can you give a review of that?

Yes, sure. So yes, you are correct. You are required to be vaccinated prior to starting on eculizumab. The minimum period of time prior to starting eculizumab is 2 weeks. But we do double coverage, so the vaccinations for the kids can cover the serotypes ACWY and B. Those are the vaccines that are available to us. But there are other serotypes of meningococcemia that are out there. So in order to capture coverage -- safety coverage for those, we also give antibiotics. In conjunction with that, the antibiotics do start the day you start eculizumab.

Dr. Panda, I think given this question, it's a good opportunity to hear in your setting of actually enrolling patients. What have you seen as far as your comfort level of our immune regimen and how that weighs into how you look at the risk-benefit profile?

Sure. I think -- Steve, I can -- I think I've shared this with you before. When I first started, I was a little skeptical. But I think as we started using the immunosuppressive regimen, I'm feeling more confident and comfortable from a safety standpoint. And I don't think it's hindering any sort of recruitment or getting patients. And also, the other thing that we are seeing, the immunosuppressive regimen itself being tolerated well by these kids, so we're not seeing any side effects related to the immunosuppressive regimen. Yes, we are adding prophylactic antibiotics and immunization based on the individual immunosuppressive drug that we're using. But so far, it's been tolerated well by these kids.

Just a quick follow-up. When can we expect the next update on this functional data and just what your expectations are for what we'll see there in terms of further number of patients and length of follow-up?

Thanks. We haven't guided to additional follow-up for the Phase I/II study. That's something we'll consider in future communications. What we're really pointing towards is top line data in early next year of completion of enrollment. So as you know, the primary endpoint is a 12-week outcome. So post announcing completion of enrollment this year, we look towards, as quickly as possible, reporting top line data on the pivotal study.

And our next question comes from Alec Stranahan from Bank of America.

Congrats on the data. Most of my questions have been asked. But 2 maybe on -- both on enrollment. First, curious if you expect an enrichment in younger patients in the pivotal population that maybe aren't on label for the approved option. And how could enrolling very young patients, perhaps, negatively influence some of the functional benefits you've outlined today given natural disease progression? And then just on the pace of enrollment, I appreciate the reiterated time lines there. Any more granularity you can provide given you did maintain that 2025 enrollment completion target, but I think the study has been more than half enrolled, with some air quotes there, since I think your 1Q call a month or so ago.

Thanks, Alec. I think on enrollment, again, what we're able to do is see a few things. Number one, increase in sites that are activated, and that's just continuing. We will be exponentially increasing the number of sites over the course of this year and into next year as well as we recruit for our confirmatory study. And I think, again, we feel very positive about the level of activity in screening patients and actually booked dosings that are planned. And so like I said, we'll update as quickly as we can upon completion of the N equals 30 patients. I do think on age groups, to your question, we're seeing a really nice distribution in the 1 and older age group that we're recruiting. And so we expect at the time of filing to have a really balanced set of ages that were enrolled, which will include patients as we've shown today, older patients where it might be a little easier to show the drug effect because of the functional decline, but we expect to have ample safety data for the younger patients at the time of filing as well. Our overall pursuit is in pursuit of a broad label. So this -- I think that will support this nicely.

And our next question comes from Brian Skorney with Baird.

The new CBER director has been a very outspoken critic of his predecessor's decision to approve Elevidys as well as just generally criticizing the use of biomarker-based endpoints. I know he and Dr. Verdun are holding a roundtable discussion in a few minutes here. But I'm just wondering if REGENX has had any direct interaction with Vinay specifically since his appointment to confirm pivotal endpoints for 202 or 121 and just, in general, if you think the DMD community or MPS community will have any meaningful representation at today's roundtable discussion.

I think a couple of things that I could mention. One of the -- some of the attendees for this morning's session are representatives of the Alliance for Regenerative Medicine, which I think has a broad industry, especially in rare disease development approach that sort of represents all of our views and now have, I think, a strong voice in that roundtable. I'm actually meeting, as part of the CEO roundtable, both Prasad and Makary, at 3:00 in the afternoon today, too. So I'll let you know. But I think all the messaging we're hearing now that he's in his formal role supports exactly the data that we're showing today that the surrogate biomarker approach has to be supported with functional and preclinical data -- functional data from clinical studies and preclinical data supporting the biomarker. And I think we have both in a very clear way to supply at the time of filing and review. So I'm feeling really good that we are -- and the way our program has been developed is directly addressing some of the concerns that we've heard.

And our next question is going to come from Sean McCutcheon with Raymond James.

A couple of quick ones for me. Now we've seen Elevidys have some speed bumps, maybe Dr. Panda would dispute that based on his earlier commentary. But what are your expectations for the proportion of the prevalent population that's left should RGX-202 get an accelerated approval? And then on newborn screening, can you speak to the trend line on early diagnosis and whether you're seeing a bit of acceleration at your study sites with the impetus from your 1- to 3-year-old cohort?

Great. I'll take the first one on prevalent population. And as we know, go further back, Sarepta guided to the prevalent population being available out to 2030. And when we look at enrollment rates -- I'm sorry, when we look at rates of launch now for the commercial product, we definitely see that at least half of the prevalent market should still be available by our potential approval date in 2027. And I think we probably would update that more than half based on the sales trajectory that we're seeing. So we're excited, and that's one of the reasons we pointed to building commercial inventory as soon as this fall in anticipation of hitting the market in 2027 with sufficient doses to really make an impact in the great unmet need that still exists. I'll let Steve and Dr. Panda perhaps comment on the second question.

Yes. More broadly, certainly, over time, we're seeing the trend upward in newborn screening. So we'd expect, over time, not surprisingly, that curve of when patients are being diagnosed fortunately moving earlier, which is great for the patients and families since the earlier you can treat, the better the patients will be. Dr. Panda, what's been your experience?

Yes, I think from a newborn screening standpoint, yes, there are bills passed. And I don't know if anyone is actually screening -- starts screening yet. Ohio, New York, we don't know yet. But once we start screening, of course, we'll see the uptake. But again, from the -- our clinical trial standpoint, our inclusion is 1 and older, right? If I remember correctly, this starts at 1 year old. But definitely, yes, catching the younger-age patients and the number of patients at this age group would be much, much higher in the next few years once we actually start doing the screening part.

And the next question comes from Daniil Gataulin with Chardan.

Yes. Congrats on the progress. Just a couple for me. First, have there been any changes as it relates to your interactions with the FDA or messaging from the FDA following your competitor's fatal adverse event a few months ago? And the second question, in terms of CMC, can you talk about the outstanding requirements for product validation or any outstanding questions that need to be addressed before the potential BLA submission next year?

Great. Yes, the first question is, no, we really haven't seen any changes or inquiries related to our program post that patient death. So we have a lot of interaction, as you can imagine, with the BLA on file with FDA, not necessarily related to 202 but more of the Hunter program. But no, we haven't seen anything there that's different or new questions that have arrived. On CMC, the beauty is we're in the middle of a process now with the Hunter program. I would agree with Makary's statement a day or 2 ago that the trains are running on time. We have firm established dates for facility inspections associated with 121. And that's going to pay huge dividends on 202 in that we will have already completed process validation for one program and potentially have a licensed facility ahead of when we have the inspection for the 202 program. So a lot of -- if there are lessons to be learned, which we feel great about our CMC approach in general, we'll know them ahead of 202 and can add those learnings to the program and make sure that we have a high probability of success.

And our next question is going to come from Paul Choi with Goldman.

Can you hear me?

Yes.

I had one clarification question and then one data question, which is on Slide 15, you guys mentioned that your 9- and 12-month data points are 6 to 9 months after immune modulation regimen ends. So just to confirm, background steroid use is either ended or I -- and I just want to confirm that. Or was there any other rescue or continual use of deflazacort or vamorolone potentially used here is my first question.

Yes, I'll just give a brief comment and let Steve and Naz comment, but the immunosuppression regimen has tapered down by 3 months. So 9 months and 12 months or 6 months -- well, the 9-month data point for function is 6 months post that taper. Steve or Naz, do you want to give a little more specific?

I think -- sorry. Go ahead, Steve.

Please, Naz.

Yes. No, I -- so basically, we ask for the children to be on their baseline steroids for 12 weeks prior to entry in the study, and all of their baseline functional assessments are performed on those baseline steroids. So even after we introduced the immune suppression regimen, which is an additional amount of steroids, for -- at full dose for 2 months and then tapering to off in the third month, they taper to off of our additional immunosuppression steroids but then taper back to their baseline, which is those baseline corticosteroids. So -- but we ask them to be on a stable dose of either vamorolone, deflazacort or prednisolone or prednisone. And that stable dose could be whatever works for them, and we don't adjust that per kilogram dosing over the course of the study.

Okay. Great. Then just can you maybe help us understand the data for the natural history cohort a little bit better? Between the 9-month point and 12-month point, there's about a 1.5-or-so point decline between month 9 and month 12, which seems to be driving a bit of the delta -- a fair amount of the delta that you say there. Can you help us contextualize that rate of change? It seems fairly significant. Is it just the sample size? Is there actually that much worsening in the natural history cohort? Just some color there and context would be helpful.

This is probably a great question for Naz.

Sure. So basically, we're doing exact matching, and the exact matching includes the patient's age at baseline, their baseline timed function tests and also their steroid use and availability of the data at that specific time point. So if you look on like Slide 16, for example, the N of 65, just as an example, for the time to stand, is those patients that meet that criteria at that specific time point for the time to stand availability. That changes at 12 months probably because it's just there's more available data at 12 months. So the number of the N in the external cohort goes up. If you're talking about the decrease, I think I see what you're talking about, which I never actually fully paid attention to, so thanks for pointing that out, that the external cohort, that's what's available to us at that specific time point for the exact matching. But I would say that's the external exact matched cohort, but please also pay attention to the change from baseline as well. So the change from baseline is sustained, and the exact match is what we have access to at this time. In the future, we hope to get access to more databases to be able to kind of bolster that number a bit and kind of see if that changes at all. But obviously, you do expect that over time, decline does take place. So 3 months, these are not the same patients at 9 months that are being evaluated at 12 months. These are the patients at 12 months that have the exact matching. I hope that clarifies that.

And the next question is going to come from Yi Chen from H.C. Wainwright.

Could you comment on how close the correlation is between biomarker and functional improvement across different age groups in the trial given the fact that the dose level 1 appears to outperform dose level 2 for microdystrophin and positive fiber for age group 4 to 7?

Steve, do you want to cover that?

Sure. So keeping in mind the small sample size, particularly for dose level 1, I wouldn't say that there's any outperformance there. And I think, particularly since we have more patients in dose level 2 that are in the older age group where you don't anticipate having high levels of microdystrophin, but we actually see very robust and consistent microdystrophin level. So this, for us, supports what we'd always felt based on preclinical data that the dose level 2 would be ideal for advancing into pivotal, which, of course, is what we did. On your first question about correlation, we hit on this, to some extent, in an earlier question. But fortunately, what we're seeing is, again, this very high microdystrophin level, and we're seeing all the patients doing better, even these older boys. So I think with small numbers, to try to -- not really a setting where you can quantitatively be looking at that yet. But certainly, on that very high level, that's exactly what we'd want to see.

I think I'd add one comment that when we went from dose level 1 to dose level 2, we did see a nice correlation in vector copy numbers as we increase dose. So the microdystrophin levels can be quite variable based on all of the patient attributes. But we do feel that dose level 2 is clearly -- the biodistribution is very acceptable and in line with our preclinical data.

And the next questions are going to come from the audience. The first question is a 2-part question from Gil Blum with Needham & Company. Gil asks, can you walk us through the burden and/or potential risks arising from the immune management protocol? And the second portion is, any thoughts on the level of variability in the microdystrophin expression?

Thanks for the question. Steve, and maybe Dr. Panda?

Yes. And I think, Dr. Panda, you started to hit on these aspects in an earlier response. Maybe you can highlight it again with any other color on how all of this fits together when you're considering patients and actually proceeding with enrollment and dosing and follow-up.

Sure. I think when we're talking about multiple, maybe I missed the first part of the question. Is it about the other options? Is that, Steve?

The question from Gil was, can you walk us through the burden and/or potential risks arising from the immune management protocol? Second part is, any thoughts on the level of variability in the microdystrophin expression?

Got it. Sure, I can -- definitely, from an immunosuppression standpoint, I think -- like I said, we haven't had any challenges from the immunosuppression regimen standpoint, from a patient's or burden standpoint. The kids are kids. Sometimes, they may refuse to take some medicines. It may be difficult to -- for them to swallow pill or take liquid. They don't like the taste. But more than just your typical challenges, we didn't see any practical issues with that. So far, we've been able to successfully do that and keep the kids on the immunosuppressive regimens as much as we can. And like I said before, when I started, I was skeptical, but when we started implementing it, it's been going well.

I think I'd make a final comment on microdystrophin that I think it's important at DL2 to realize all of the data points that we've collected today, they're very age dependent. But every data point is well above the threshold that we set for the pivotal study primary endpoint. So we feel really positive about, for any age group, meeting our primary endpoint and delivering maximum functional benefit but understand that there is variability in each patient in terms of their ability to produce microdystrophin. And I think that's probably what you're seeing in the data, but all of it is in an area where we feel very likely to provide functional benefit from this level of microdystrophin. Thank you.

Thank you. At this point, we have no further questions, and we'll end the call. Thank you all for your participation, and have a good day. Goodbye.