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 Dasgir, who is a pediatric neuromuscular neurologist. We're also very pleased to have Dr. Veerapandiyan , Principal Trial Investigator, also known in the field as Dr.
Veerapandiyan, 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 the dystrophin protein. Boys with Duchenne typically gain skills until about six 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 a 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 three-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 one 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 two 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 two data. In this protocol, we've dosed 10 participants aged 2- 12, with a 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 two years old who received dose level two. 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 funactional 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 two participants in the Affinity Duchenne phase I-II trial. There are five participants who have reached nine months post-treatment, with four 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, the 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 dataset 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 five dose level two participants at nine 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 four participants at 12 months post-dosing. Data from these participants were also included in the nine-month dataset. As you can see, our results at 12 months are similar to those seen at nine months.
Consistent with the nine-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 three 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. Veerapandiyan will share a video.
The first video is of a nine-year-old boy at nine months of follow-up. At baseline, he uses handrails to climb stairs with alternating feet. At his nine-month assessment, he is able to ascend stairs without use of handrails. 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 one year, he performs this 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 eight years old at dosing. At 12 months, he is able to complete his four-step climb with quick weight shift, faster speed, and more confidence. Next, we see another eight-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 four-step 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. Veerapandiyan, 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. Veerapandiyan. First off, thank you for joining us today, Dr. Veerapandiyan. 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. To also point out, we are well ahead of our completion of the immunosuppressive regimen. That also is encouraging. All of these underscore the potential impact of this RGX-202. Most importantly, I am also very impressed with the meaningful clinical improvements and how this translates into the real world for these boys with Duchenne. I am looking forward to continue tracking these patients as we continue to follow and see their progress.
Thanks, Dr. Veerapandiyan. Naz, I'm going to turn to you now as a 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?
Yeah, thanks, Steve. I'm super encouraged. Obviously, I'm very positive about this study overall. I love the fact that the data is consistent throughout the 9-month and 12-month period, and after the immune suppression regimen is complete, just as Dr. Veerapandiyan mentioned, hoping that the influence of our immune suppression regimen is completely worn out by the time we're showing this data. I would also like to note that the majority of our patients are older and in the decline phase. Where you would be expecting over a year's period to see decline naturally, we are seeing an improvement in our exact matched natural history control cohort.
Great. Turning back to you, Dr. Veerapandiyan, 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?
Cheers, Steve. I think when we talk about ongoing unmet need, there's quite a lot that I could keep listing. But from a therapeutic standpoint, I always say it's we are in good times having a lot of options for therapies, having challenges, but good challenges, right? I think from an unmet need standpoint, always having multiple innovative therapeutic options that can transform their lives, that can help with maintaining the muscle integrity is important. Then in terms of we are seeing a lot of seropositive individuals out there and also restrictive from a mutation standpoint. 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. Also expanding the age group, especially the newborn screening coming along.
Providing potential options for patients that are diagnosed very early on is also a good thing from my perspective.
That's great. 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'd 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?
Yeah, that's a great question, Steve. That happens every day in our clinic, right, with these options. I spend hours and hours discussing. It really depends on the family. Like I say, every single individual with Duchenne is just that individual, and the right option for them, there's no one size fits all, right? When we discuss this, obviously discuss about all the options, the commercially available options versus 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." We also have families who are going to trust my judgment.
I think it 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, what's the difference there, is there any functional differences or microdystrophin expression difference or 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. 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 family, 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. 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 tell me, "Hey, he has a 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 tells me, "Hey, my son is now able to play longer outside with his siblings," I think that's much more impactful for me. I think that's impactful for the whole family. I think that's what we are seeing. 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 who we expect them to be in sort of a plateau or decline phase. I think how this translates 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. Now I'll turn the call back over to Curran.
Thank you, Steve, Naz, and Dr. Veerapandiyan. 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 Cure Duchenne 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. For our covering analysts, if you'd like to ask a question, please click the raise hand button at the bottom of your screen. Our moderators will address you by name within Zoom and prompt you to unmute. Once your question is complete, please mute yourself again. Thank you.
Hello. The first question of the day is going to come from Judah Frommer from Morgan Stanley. Judah, go ahead.
Yeah, hi, guys. Thanks for the update here. Congrats on the progress, and I appreciate you taking the questions. 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. Separately, just on the functional measures, I think in the November update, there was a 12-year-old who at 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. Thank you.
Sure. Thanks, Judah. I think speaking about enrollment, obviously for these studies, there's a lot of pre-planning and activities and screening well ahead of the dosings. 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. 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 timeline related to top-line data first half of next year and BLA filing mid-next year. 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 safety profile that we feel is very favorable. Regarding the specific data, we're 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. Yeah, 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. I think robust and consistent. 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. I think that's particularly striking since three out of the four boys at the one-month time point are older than eight years old. These are boys that you would definitely be anticipating would be declining. Not only are we seeing stabilization, but we're actually seeing improvement. You mentioned that one particularly impressive boy that Dr.
Veerapandiyan discussed at the nine-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.
Great. Thanks again.
Our next question comes from Gina Wang with Barclays. Gina, go ahead.
Thank you for taking my questions. Let me just follow this variability questions. On slide 17, I'm just wondering how's the standard deviation look like? We do see the control arm, the natural history control arm, the number increased a lot compared to the last update. Is that because now you have more patients, and so therefore the matching part from natural history also will expand? I do have two questions for Dr. Veerapandiyan. The first one is post the one-patient death with Elevidys. What are the patients' views in general on DMD gene therapy? The second question is fast-forward to 2027. If multiple gene therapy becomes available, how would you decide what you have to use? What are the metrics you're looking for, understanding that we will have limited functional data from a control study?
Thanks, Gina. I'll start just briefly and then let Steve speak to your questions regarding the data. 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. 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. We have chosen not to do so. 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. Gina, 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. The five at nine months and the four at twelve months. 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. The last question was for you, Dr. Veerapandiyan.
Hey, yes. I think one of the questions was about how fast-forward in the future if we have multiple options. I think there's a lot of factors that's going to play into role there, right? What data that you have from the study from an efficacy and a safety standpoint, even if the data is limited, just really what we have in hand. It's very individualized from one patient to other patients. Obviously, the safety, effectiveness, and then you have your experience with each therapy that would play into the physician's experience with each therapy would play into role as well. Families, the boys, if they have antibodies to one versus the other, that's going to play into role. There's multiple factors, and I would say it's very individualized and varying from one patient to other patient.
I think one other thing to add would be from a safety standpoint also, it's one of immunosuppressive regimens if that is important moving forward and mitigating a safety profile that would also play into role. 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 with Elevidys?
I'm sorry, I didn't hear that question. I don't know if.
Dr. Veerapandiyan.
I think the question is related to patient view regarding Elevidys since the patient death was reported.
Oh, I see. I think I can, so from a patient's view, yes, there is an extra concern there, but not a lot of concerns in terms of I haven't seen any change in the ones that people are planning to dose. The reason being, I would talk about it. A lot of us would talk about it anyways as a risk factor, even if it has not happened in the program. I think that's what we're seeing. Definitely, when they heard the news, families got, they were scared, concerned, and asked more questions. When we talked through it, I think it turned out to be okay.
Okay. Our next question is going to come from Lily Nsongo from Leerink Partners. Lily, go ahead.
Hi, good morning. Congratulations on the data, and thank you for taking our question. Maybe 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? As a follow-up, do you see consistency within each individual patient in terms of their progress at 9 months and at 12 months? Thank you.
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 four functional measurements, we do see a high level of consistency. We're going to be real excited to follow these patients out to two 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 five 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 a patient is when they're treated, the much higher expression levels we're able to achieve. I think that's the direction that over time this therapy will take is treatment of younger patients, off-newborn screening, perhaps. I think that is where the field will move over time. We are really encouraged to show the data for the young patients to, again, give them the best chance of receiving very little functional decline. We are also excited to see this benefit. We are showing higher microdystrophin levels than other studies in the older patients. That is definitely, we think, one of the reasons we are also seeing better functional outcomes for those patients than might be expected. Steve, do you have anything to follow with that?
Sure. Lily, one good dilemma we have is we do not have very low microdystrophin in any patients. With dose level two, we are seeing very consistent high levels. Unlike historically what may have been seen with other programs where there can be greater variability and even some patients not having any microdystrophin, in that setting, you can look at correlation in a different light. Here, the reality is we are seeing high microdystrophin, and we are seeing both based on the functional measures, but also from the videos that Dr. Veerapandiyan showed across the patients, functional improvements on these measures consistently. That is exactly the type of correlation that we would 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.
We're happy to say that both patients that we reported at nine months are continuing to do very well. Again, you can see that from the videos that Dr. Veerapandiyan showed.
Thank you.
Our next question is going to come from Luca Issi with RBC. Luca, go ahead.
Oh, great. Can you guys hear me okay?
Yep. Perfect.
Great. Maybe two 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 Roctavian over the last few weeks and maybe any implications for your program at all? Any thoughts there? Much appreciated. Then maybe for Dr. Veerapandiyan, 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. Thanks so much.
I'll comment quickly on the Roctavian 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 AAV5 and in our case, using AAV8. 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. We really do see that as incredibly unfortunate, but not really related directly to our study. Steve, do you have anything to add there before we turn over to Dr. Veerapandiyan?
Yeah. The differences that Curran highlighted of different serotype, different disease setting, and certainly the different approach to complement inhibition are critical in this case. More details are needed, as always, in evaluating this. Certainly, the specifics that 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. We've not seen any carryover from discussions with all of our investigators. I think we continue as we go. 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.
I think 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. Certainly, apples and oranges we see from our case. Dr. Veerapandiyan, on the other question?
Sure. Yeah. I think that's a great question in terms of exon skipping coming up and other therapeutic strategies. I think future of Duchenne is, like what I say, it's going to be add-on combination therapy, cocktail therapy. I think there's definitely room for multiple therapies adding on either dystrophin restoration therapy with the muscle targeted therapy or exon skipping, microdystrophin, all of that. Depending on which goes first, it's really, again, an individualist discussion. I'm just glad that we have options, but I think they all have a role in the landscape.
Got it. Thanks so much.
Our next question is going to come from Annabel Samimy with Stifel. Go ahead and talk, Annabel.
Hi. Thanks for taking my questions. And congratulations on a lot of great data here. Just curious, not that I'm not grateful for the amount of data that you put out already. They're really great. We've started seeing signals of improved cardiac function based on troponin levels and ejection fraction from other competing programs. I was wondering, given that you promote the same NOS activity, perhaps even more efficiently through the C-terminal domain, I'm just wondering if you're collecting any of the same type of data, which I think might be even more relevant in an older age group where cardiac function might start seeing some declines. Any comment there that you can share with us? Have you measured any of this? Are the patients that you're looking at, this age range, are they expected to have any cardiac deterioration at this age?
Just a little curious if you have any qualitative information around that.
Thanks, Annabel. It's a great question. I know actually Steve and Naz have been diving into this with some of the conferences they've been attending. I'll defer the question to Steve, and perhaps Naz can add to.
Yeah. 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. 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 for an efficacy standpoint. We really look at this from a safety standpoint, and we do include some of these measures like ejection fraction. 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?
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 three months, certainly, and six months from the increased steroid prophylaxis that's used across the programs. That's why we like to look across the board at 9 months, 12 months, and longer. Certainly, for cardiac, we think it's going to take longer. Naz, you evaluate these patients in your clinic. What's your take?
Yeah. Typically in clinic, when we monitor kids for cardiac disease, you start to kind of see early signs of it around age seven or so, seven to ten. That's when we really start doing the gold standard of cardiac screening, which is cardiac MRI. Prior to that, we do echocardiograms. Echocardiograms, typically in those ages that are younger, do not really show changes unless you have a more cardiac-specific phenotype. There could sometimes be more involvement with certain mutations in the heart. In our patient population, in terms of our inclusion criteria, we select having ejection fractions greater than 55% and a good baseline cardiac exam. Our kids do not have disease at baseline upon entry into the study.
I find that echocardiogram results that are early after gene therapy, like say, for example, three months or even six months, it's too early to see a change. Also, echo is not really the gold standard of evaluating heart function. The gold standard of evaluating heart function is cardiac MRI. We do do cardiac MRI in our study. Our first cardiac MRI is at baseline, and we do a follow-up at 12 months. 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. Again, with the caveat that the kids that enter in our study do not have baseline cardiac dysfunction.
Okay. If I could just ask a quick follow-up or clarification. 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. 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 start seeing deterioration over time? It's just like sort of moving the curve over a little bit. 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.
Yeah. I think just to be clear, in November, the patients that are at the pivotal dose, DL2, were at 9 months. 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. Time will tell, obviously, but we're not seeing any indications to date in our data of a diminishing effect. This is something we'll follow very closely.
Okay. Great. Thank you.
Our next question comes from Ellie Murrell with UBS. Ellie, go ahead.
Might be on mute, Ellie.
Hey, can you hear me now?
Yes.
Great. Sorry about that. Thanks so much for taking our question and 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? If so, what is the vaccine schedule? Just how long is that typically taking before you can begin dosing with eculizumab and then, of course, the gene therapy? I have a follow-up question. Thanks.
Great. I'll defer that to Steve and Naz to cover.
Sure. Naz, can you give a review of that?
Yeah, sure. 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 two weeks. We do double coverage. The vaccinations for the kids can cover the serotypes A, C, W, Y, and B. Those are the vaccines that are available to us. There are other serotypes of meningococcemia that are out there. In order to capture safety coverage for those, we also give antibiotics in conjunction with that. The antibiotics do start the day you start eculizumab.
Dr. Veerapandiyan, I think given this question, it's a good opportunity here 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?
I'm sure. I think, Steve, 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. I don't think it's hindering any sort of recruitment or getting patients in. Also, the other thing we are seeing, the immunosuppressive regimen itself is being tolerated well by these kids. We're not seeing any side effects related to the immunosuppressive regimen as we are adding prophylactic antibiotics and immunization based on the individual immunosuppressive drug that we're using. So far, it's been tolerated well by these kids.
Thanks for the call. 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.
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. As you know, the primary endpoint is a 12-week outcome. Post-announcing completion of enrollment this year, we look towards, as quickly as possible, reporting top-line data on the pivotal study.
Great. Thanks for the caller.
Thank you.
Our next question comes from Alex Jonahan from Bank of America. Alex, go ahead.
Hey, guys. Congrats on the data. Most of my questions have been asked, but two maybe 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. How could enrolling very young patients perhaps negatively influence some of the functional benefits you've outlined today given natural disease progression? Just on the pace of enrollment, I appreciate the reiterated timelines there. Any more granularity you can provide given you did maintain that 2025 enrollment completion target, but I think the study's been more than half enrolled with some air quotes there since I think your one Q call a month or so ago. Thank you.
Thanks, Alex. 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 we recruit for our confirmatory study. I think, again, we feel very positive about the level of activity in screening patients and actually booked dosings that are planned. 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 one and older age group that we're recruiting.
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. 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. I think that will support this nicely.
Got it. Very clear. Thank you.
Our next question comes from Brian Scorney with Baird. Brian, go ahead.
Hey, good morning. Thank you for taking the question. 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 REGENXBIO has had any direct interaction with Dr. Vannai, 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. Some of the attendees for this morning 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. They will have, I think, a strong voice in that roundtable. I'm actually meeting as part of the CEO roundtable, both Prasad and Mackerry, 3:00 P.M. in the afternoon today too. I will let you know. 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.
I think we have both in a very clear way to supply at the time of filing and review. 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.
Great. Thank you.
Okay. Our next question is going to come from Sean McCutcheon with Raymond James. Sean, go ahead.
Hi, guys. Thanks for taking the question. Just a couple of quick ones for me. Now that we've seen Elevidys have some speed bumps, maybe Dr. Veerapandiyan, would dispute that based on his earlier commentary. What are your expectations for the proportion of the prevalent population that's left should RGX-202 get an accelerated approval? 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 one to three-year-old cohort? Thanks.
Great. I'll take the first one on prevalent population. As we know, if we go further back, Sarepta guided to the prevalent population being available out to 2030. 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. I think we probably would update that to more than half based on the sales trajectory that we're seeing. We are 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. Veerapandiyan perhaps comment on the second question.
Yeah. More broadly, certainly over time, we're seeing the trend upward in newborn screening. 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 really you can treat, the better the patients will be. Dr. Veerapandiyan, what's been your experience?
Yeah, I think from a newborn screen standpoint, yes, there are bills passed. I don't know if anyone has actually started screening yet. Ohio, New York, we don't know yet. Once we start screening, of course, we'll see the uptake. Again, from our clinical trial standpoint, our inclusion is one and older, right? If I remember correctly, that starts at one year old. Definitely, yes, catching the younger age patients and the number of patients at this age group would be much higher in the next few years once we actually start doing the screening part.
All right. Thank you.
Okay. The next question comes from Danil Gotland with Shardon. Danil, go ahead.
Yes. Good morning, guys. Thank you all for taking the question and 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? 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? Thank you.
Great. Yeah, the first question is, no, we really haven't seen any changes or inquiries related to our program post that patient death. We have a lot of interaction, as you can imagine, with the BLA on file with FDA, not necessarily related to 202, but more the Hunter program. 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 Mackerry's statement a day or two ago that the trains are running on time. We have firm established dates for facility inspections associated with 121. 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.
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.
Excellent. Thank you.
Our next question is going to come from Paul Choi with Goldman. Paul, go ahead.
Hi. Good morning. Can you hear me?
Yes.
Okay. Hi. Good morning. Thanks for taking the question. I had one clarification question and then one data question, which is just on slide 15, you guys mentioned that your 9 and 12-month data points are 6-9 months after immune modulation regimen. And just to confirm, background steroid use has either ended, and I just want to confirm that, or was there any other rescue or continual use of Deflazacort or Vamorolone potentially used here? This is my first question.
Yeah, I'll just give a brief comment and let Steve and Naz comment. The immune suppression regimen is tapered down by three months. Nine months and twelve months are six months. The nine-month data point for function is six months post that taper. Steve or Naz, do you want to give a little more specific?
I can start. Oh, sorry. Go ahead, Steve.
Please, Naz.
Yeah. No, so basically, we ask for the children to be on their baseline steroids for 12 weeks prior to entering the study. All of their baseline functional assessments are performed on those baseline steroids. Even after we introduce the immune suppression regimen, which is an additional amount of steroids at full dose for two months and then tapering to off in the third month, they taper to off of our additional immune suppression steroids, but then taper back to their baseline, which is those baseline corticosteroids. We ask them to be on a stable dose of either Vamorolone, Deflazacort, or Prednisolone or Prednisone. That stable dose could be whatever works for them. We do not adjust that per kilogram dosing over the course of the study.
Okay. Great. Thanks for that clarification. 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 one-and-a-half 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. Thank you so much.
All right. This is probably a great question for Nas.
Sure. Basically, we're doing exact matching. The exact matching includes the patient's age at baseline, their baseline time function tests, and also their steroid use and availability of the data at that specific time point. If you look on 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 there's more available data at 12 months. 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.
I would say that's the external exact matched cohort, but please also pay attention to the change from baseline as well. The change from baseline is sustained. 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. Obviously, you do expect that over time, decline does take place. Three months, these are not the same patients at nine 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.
Yes. Great. That's very helpful. Thank you.
Okay. The next question is going to come from Yi Chen from HC Wainwright. Yi Chen, go ahead.
Thank you for taking my question. 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 one appears to outperform dose level two for microdystrophin and positive fiber for age group four to seven? Thank you.
Steve, do you want to cover that?
Sure. Keeping in mind the small sample size, particularly for dose level one, I wouldn't say that there's any outperformance there. I think particularly since we have more patients in dose level two that are in the older age group where you don't anticipate having high levels of microdystrophin, we actually see very robust and consistent microdystrophin levels. This, for us, supports what we'd always felt based on preclinical data that dose level two 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. Fortunately, what we're seeing is, again, this very high microdystrophin level. We're seeing all the patients doing better, even these older boys.
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.
Okay. Thank you.
I think I'd add one comment that when we went from dose level one to dose level two, we did see a nice correlation in vector copy numbers as we increased dose. The microdystrophin levels can be quite variable based on all of the patient attributes. We do feel that dose level two is clearly the biodistribution is very acceptable and in line with our preclinical data.
Thank you for the clarification.
Okay. The next questions are going to come from the audience. The first question is a two-part question from Gil Bloom with Needham & Company. Gil asks, "Can you walk us through the burden and/or potential risks arising from the immune management protocol?" The second portion is, "Any thoughts on the level of variability in the microdystrophin expression?
Thanks for the question, Steve, and maybe Dr. Veerapandiyan.
Yeah. I think, Dr. Veerapandiyan, 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 consenting 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?" The second part is, "Any thoughts on the level of variability in the microdystrophin expression?
Got it. Sure. I can definitely say from the immunosuppression standpoint, I think, like I said, we haven't had any challenges from the immunosuppressive regimen standpoint, from a patient's or burden standpoint. The kids are kids. Sometimes they may refuse to take some medicines, and it may be difficult for them to swallow a pill or take liquid. They don't like the taste. 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 regimen as much as we can. Like I said before, when I started, I was skeptical. 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. We feel really positive about, for any age group, meeting our primary endpoint and delivering maximum functional benefit. Understand that there is variability in each patient in terms of their ability to produce microdystrophin. I think that's probably what you're seeing in the data. 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 will end the call. Thank you all for your participation and have a good day. Goodbye.