Chief Medical Officer. I don't know if you guys wanted to give a quick overview before we dive into the questions.
Sure. This is a super exciting year for us. Following all the great execution of last year, we're excited this year for a number of milestones, one of which is imminent, which is the completion of filing for our first BLA for RGX-121, which is intended for Hunter syndrome. Coupled with that timeline, we're also thrilled to talk about the closing of the deal with Nippon Shinyaku for the commercial partnership that we've developed with them. A lot of really interesting updates on 121. Our Duchenne program, which is really in focus this year, is actively recruiting. Steve's team is out, pushing hard on enrollment for the pivotal study, which we're excited to have started late last year.
Through the course of this year, we'll be giving out additional updates on not just safety and microdystrophin levels, but now venturing more into the functional outcomes for the patients, which we've been really excited to begin reporting last November. Earlier this year, we talked and issued a press release jointly with AbbVie about our retina program, which we're thrilled to be planning for a diabetic retinopathy study using our suprachoroidal delivery method. On top of that, this year, we intend to close enrollment on ATMOSPHERE and ASCENT , which are the two large global studies that are being conducted for subretinal. It is just an exciting year. All of the work we've done over the last, I think, 15 years of the history of the company, culminating into some of these major events for late-stage programs.
That's great. Maybe I will start with the DMD program. I think for the phase II update, I think a previous guidance first half, so late first half, so I assume second quarter, the data update. Maybe any additional color regarding the number of patients and type of data you'll be presenting and a follow-up.
Sure. You will recall in November, we had exciting initial data, both robust and high consistent microdystrophin expression at both those levels. Importantly, that included high expression levels even in eight and older patients. We had our initial functional data that was supporting that we are seeing those expression levels lead to functional improvements at both those levels. At that point, we had 12-month data for the first dose level one patients, the three patients. We had two patients with nine-month data. Our philosophy has been to wait till at least nine months so that you have any potential impact of initial immune suppression and steroids out of the system so that you really know whether you are seeing a treatment effect or not.
I think what you can anticipate this half of the year is that we'll have more patients at dose level two where we have the microdystrophin levels. We'll also have those nine-month dose level two patients out to 12 months. They won't necessarily be at exactly the same time point. We want to have the ability to give an update on additional microdystrophin levels and then also have more patients that have reached these different milestones. Another aspect is even in the dose level one patients, they've gotten through 12 months. Before too long, we'll have through 18-month data. We're really reaching a pretty good inflection point in terms of a lot of patients with microdystrophin levels across an age range and also more and longer functional data outcomes, which is really what the clinicians want to see.
They really like the microdystrophin levels, and they want to see that translate into functional benefit. Another key aspect for us is, as you know, there is no approved gene therapy for under four years old. We have a cohort; we have the only cohort in trials in the U.S. that's looking at under four, so one to three-year-old patients. We announced the start of that cohort. When we give the microdystrophin update, we'll include the initial data that we have from that cohort. We'll be able to extend the microdystrophin data that we already have from four years to 12 years, but also be able to start to have data in the under four-year-old age group.
The second quarter update, should we see the patient less than four years old, the biomarker data?
Yes.
Okay. Good. How many should we expect?
I think it's likely that we'd have one when we first announce it. It all depends on the timing of when the data actually comes out. We have an earnings update, obviously, tomorrow where we can update guidance.
Okay. Okay. Good.
Along the way, I think you'll see enrollment updates from us. I think one thing that I do want to convey is we're not just focused only on the enrollment and on the data outputs, but also on pulling forward all of the BLA enabling activities. One thing that's really exciting is that we're starting our process validation runs this year for the future's BLA submission. That material, the first batch we make as part of process validation, would be eligible for commercial sale. It's really marking the beginning of our build for inventory for a potential launch in 2027.
Okay. Maybe going back to the functional data, and you do have a wide range of patient age, right? Maybe what kind of functional data you will be sharing with us in September?
Sure. I think you can look for the same measures that we've already presented on. The usual suspects, so NSAA, but we'll also look at the traditional timed function tests, like Time to Stand, 10-Meter Walk/ Run, Time to Climb. I think that you can think of that not trifecta, what's more than that, the quartet of endpoints. We've seen very good results across those. Even the NSAA, which has been beat up quite a lot since the Elevidys, data didn't really show much of an effect on NSAA, even once you got above the age of four to five. We've been seeing pretty encouraging results there at both those levels. We're excited to see if with more patients, we can confirm that, but also see consistency over time.
I know you will not comment on the competitor data, but in a way, we did see, say, Solid show pretty impressive protein expression, right? The three patients, like all above 100%. Maybe from your perspective, do you think what could be the key differentiating there? If we just look at the nominal protein expression level, yours looks a little bit lower. What are we missing or what should we look at when we look at the data?
Sure. I think one aspect is a lot of us in the field think of a certain threshold effect where if you have more than 10% microdystrophin expression, that's when you would anticipate that you'll see a translation into a phenotypic event. The key factors are, can you get substantial microdystrophin levels? And can it be consistent? Because even with the approved agent, you see on a mean basis a reasonable microdystrophin level, but it's quite variable from 0%-150% increase. What does that mean? There are some patients that you'll treat who have no increase in microdystrophin. I think it's going to take more patients than the three to really understand what kind of variability exists.
I think the other factor we know is, well, what's the potency pound for pound or on a molar basis of how much you get in there and how durable that will actually be, which depends a lot on the construct. Solid has their view on inclusion of the nNOS component. We certainly are very excited about our C-terminal domain that we include because that's actually within the Becker dystrophin construct. That gives us already clinical evidence to believe that this is a microdystrophin that for whatever % expression you have, that that can translate. We've actually also, I think we're the only ones who've ever done this. We've shown in preclinical studies with the mdx recognized mouse model for DMD that 202 microdystrophin with the C-terminal domain leads to better functional outcomes traditionally measured in this model than the same construct without C-terminal domain.
When you look at that epidemiologic consideration in terms of Becker and then also that aspect of actually preclinically demonstrating that, we feel we're positioned very well for this. I think also the other aspect is we've actually shown the microdystrophin levels in older boys. No one's really shown what we've shown, whether approved or any experimental agent, having these type of robust microdystrophin levels, even in older boys with very diseased fibrotic muscle.
Okay. Very helpful. I do want to make a comment that younger than four years old, when we did our DMD doctor panel, the doctor actually highlighted that why it's so meaningful because he actually felt frustrated that when it's four or five years old, it's already have the symptoms, and then you think that the benefit should be earlier than that. You are the only one doing that down all the way to one year old. He actually highlighted that that will be one important differentiating factor there.
Yep. Time is muscle. I think with increasing newborn screening, that's going to become even more of a demand in the field.
Right. Maybe for the BLA submission, and what kind of data package now you also may have less than four-year-old data. Regarding the safety, of course, different modality, right? I think it was Avidity. It's excellent. Skipping is slightly different, but FDA did say want a 25-30 patient safety, and I think it's over 12 months as a safety package for accelerated approval, like 30+, 30-something patients. In your case, did the FDA say anything about the follow-up time minimum in order to be sufficient for the safety package?
Yeah. Just circling back, we had an end of phase II meeting with FDA last summer. After that meeting, we provided them with our pivotal protocol. Steve can cover some of the detail around that. In terms of the safety database, 30 patients was what we prescribed in the protocol itself. That was part of the review for FDA. We feel confident that an end of 30 for the pivotal study is sufficient. Do you want to talk about time frames on safety assessments?
Sure. For the efficacy under accelerated approval, we, of course, just need the three-month time frame.
I think an important aspect is with the patients we've already been discussing that we've been enrolling, if we consider completing enrollment in the second half of this year that we've already discussed and having primary endpoint readout early next year, we're going to have a lot of patients that are well over a year. I’ve mentioned some patients that are going to already be out 18 months very soon. We feel very good about the sample size, but also having a robust number of patients that are out a longer time frame. On your aspect of the under four, with 30 patients, we aren't required to have some set number at each of these different buckets of ages, if you will. We certainly plan to have a reasonable number in one to three, four to seven, and eight and older.
From the demand that we're seeing in the patients' families that are coming into the funnel, we're seeing a nice mix. We think we're going to be in a good position to really support a broad label of one and over.
On safety, we're also able to give a 120-day safety update post the initial filing. There will be ample opportunity to, I think, provide a comprehensive view.
Okay. Very helpful. Maybe switching gear to the 314 program that we're able to be subretinal now, that will be 2026 data, right? Maybe any thoughts on the two data potential outcome and then the next step? I understand AbbVie took over mainly, is in their hand. I don't know, whatever you can comment, that would be helpful.
I'll let Steve comment on the trial design and outcomes. We are still conducting the enrollment. We guided to completion of that this year, which is really exciting. I think one of the strengths of the top-line data and then subsequently filing the BLA, this will be a large data set, almost 1,200 patients. That is where AbbVie, having, I think, 700 people in their regulatory group, will be really, really important to turn that as quickly as we can as we get close to filing. Maybe you want to speak to the potential outcomes?
Sure. We have ATMOSPHERE and ASCENT, two non-inferiority one-year endpoints on the traditional best-corrected visual acuity. One study is against monthly Lucentis, and the other is against the active comparator Eylea, loading doses plus the standard every other month dosing.
The concept here, of course, we got to show safety and show non-inferiority. I think a key aspect here is that non-inferiority in a tightly controlled trial setting where you know the control arm is getting the doses that they're supposed to be getting, both because they're more compliant patients in general, and they're in a very tight protocol, that if you can show non-inferiority in that setting, that's going to translate to actual superiority in the real world because we know in the real world, patients are simply not getting the injections they need, and they're actually going on to go blind. That's why for us and AbbVie, it's clear that the value proposition isn't just decreasing the treatment burden. It's by doing that and having sustained anti-VEGF activity that you can actually have better visual outcomes for these patients.
Okay.
I think on ASCENT, we're excited that we are now recruiting in Europe as well as part of AbbVie's strategy to globalize the program. I think since the partnership and now the evolution to where we are today, increased the robustness of the study and increased the global outlook for the program itself, which is really exciting.
Okay. Very good. The diabetic retinopathy, the suprachoroidal delivery part, maybe any updated thoughts, phase III trial design, and the status moving forward?
Sure. We are very excited that we had a successful end of phase II meeting late last year as we had guided to the fact that we were going to have that meeting. Given that successful meeting, we and AbbVie were happy to announce at the beginning of this year, advancing plans for pivotal development to start this year. We have not given specific details, but I think this is such a well-trodden regulatory path, fortunately, because of prior repeat anti-VEGF agents like Lucentis and Eylea that have gotten the indication treatment for diabetic retinopathy. Interestingly, those are not being taken up by the community. I think less than 1% of patients are actually being treated because the treatment burden, repeat injections, is never going to be an option for this patient population.
What you need is one-time in-office treatment, which we can provide to really take on this indication. That is why we and AbbVie are excited about this, not only the big unmet need, but the clear regulatory path. Fortunately, there is the validated Diabetic Retinopathy Severity Scale where if you can show better outcomes on that than a negative control, in our case, a sham control, you can at one year, the standard endpoint time point, get approval. That is a lot of de-risking because you know not only the design that is accepted, but you also have a lot of confidence in what is seen without treatment. We know that patients who do not get treated do not magically get better, and they only inexorably advance in diabetic retinopathy. We feel confident, AbbVie feels confident in designing such a study.
Those are the basic design elements, superiority against no treatment, in our case, sham injection.
Okay. Very good. I do want to say from investor perspective, it seems very easy beta thesis for them to push back for the eye indication with the gene therapy, always good standard of care, nobody will use it. Maybe how would you, I know it's a long journey, how do you refute this thesis? I know when AbbVie and drug approval launched, then that's the time you say, "See, this is the revenue, how much we can generate." Before that, what kind of messaging you can communicate with the investor to tell them you are wrong?
I think for diabetic retinopathy, it's very straightforward that in this case, it's an in-office procedure. The safety data to date has been tremendous, which is what's been a problem with a lot of other gene therapy studies is the therapeutic window is quite narrow, and matching efficacy and safety has been a challenge. I think for DR in particular, it addresses the unmet need as opposed to that. Now for subretinal, Steve, you might want to comment on what do you hear from investigators that are part of our study around the promise of the drug?
Sure. Even before the investigators, AbbVie's confidence in this, not just in the U.S., but globally, I think is important validation that a company with AbbVie's global experience and also experience specifically within eye care, I think is a strong support. It is not just REGENXBIO saying this. We say this precisely for the reason Curran is alluding to that we speak to all our investigators, we speak to other thought leaders in the space. If you are seeing a patient after a procedure not need any injections for four years or more, which is what some of our investigators have seen in our phase II study, and you also see patients who have not been, let's call them complete responders, but they even have fewer injections, certainly the patients are excited about that, and that makes the investigators excited about that.
We have a fellow eye study that we've reported on where we show, fortunately, in this bilateral disease that we can treat both eyes. I can say, being on the ground and hearing the investigators, that the patients want to have their fellow eye treated if they actually have active disease in their fellow eye. I think the other aspect is this is a massive multi-billion dollar space. Are all patients going to be amenable to subretinal administration? No. Our investigators and also thought leaders say, "Well, maybe 20-25% of my patients would I consider this treatment." A fraction of that is a pretty sizable proportion of the market. We see a very good value proposition here.
I think the statistic that was developed was something like one in nine patients is lost to follow-up. Many times some of the investigators come to our meetings and articulate they know who those patients will be. They're moving to Florida, etc., and they're not going to be staying on a constant regimen. I think maybe one way to look at it as well is people think of it as we're trying to cut into an existing market where there's a very established practice, but the market is growing and potentially doubling in the next five years or so. Retina centers are already overburdened. I think our alternative is a way for them to manage growth as well. I think that's maybe what AbbVie sees in it and certainly what we see in the indication.
Good. Last one minute, maybe quickly on MPS II, is that on track? Should we expect potential approval in the 3Q?
Yes. Everything is absolutely on track with the filing of the third module. It's just literally going through some final QC, and we expect to submit imminently. The partnership with NS Pharma has been kicked off. We're through Hart- Scott-Rodino review, so that deal is closed. We have a clear line of sight to PDUFA date in the fall and really excited about the program. I think it's exciting for those of us that have worked on this program for more than 10 years to see this for any company, it's great to file your first BLA, I think. We were able to get a really huge short-term win on cash as part of the deal with the upfront milestone and then preserved a lot of the long-term value of the program as well through that.
We feel great about where we are with Hunter.
Okay. Great. Thank you very much. Maybe look forward to tomorrow's earnings call .
Absolutely. Thank you.
Thank you. Bye-bye. Thank you.