Let's maybe go back to last week. Data was a landmark, as you described it. There's a lot of debate among the investment community around regulatory and why waiting?
Yeah.
You guys have been pretty clear that you'd like to wait to submit that data set until the new leadership team at the FDA is in place. There's maybe a counterargument to be made that control the controllable.
Yeah.
That's something you can control. Just maybe walk us through what are the primary advantages of actually waiting to submit this data set?
Yeah, I actually would probably want to clarify. The waiting aspect of that is further discussions with FDA. What we're looking to do is see FDA stabilize in terms of new leadership, additional changes last week, as everybody saw. I think we look at all the changes as really, really positive in the sense of particularly in rare disease, where the patient advocacy groups and patients are in great need for alternative therapies to come to market. As it relates to the Duchenne data, we think the top-line data checks every box that you need for accelerated approval. Our plan is to begin initiate filing the BLA in Q3 this year. That rolling BLA process will complete in Q1 of 2027. That gives us plenty of time in 2027 to secure an approval.
I think that part got commingled with when would we meet with FDA leadership. We obviously want things to settle down there, let the new leaders in FDA get assimilated into the organization, and then get their support for what we're trying to achieve.
Got you. That's helpful. I'll probably bouncing back a little bit between the data and the regulatory piece. I think there was some confusion last week around you show expression for 30 patients or so, but then you saw the functional data only for nine patients.
Yeah.
Is that simply a function of timing, meaning the patients, because if I recall it correctly, expression was an earlier time point versus the functional data, I think 12 weeks versus 52 weeks?
Yeah.
Is the fact that we haven't seen the remainder of the functional data just simply a function of timing because those patients have yet to reach that landmark?
Yeah.
Is that more complex than that?
Absolutely. We, in real time, continue to get patients through their 12-month assessment. What you saw in the data set was safety on all 30 patients or 31 actually in the study. You saw microdystrophin levels for all of those patients. The functional assessments, keep in mind, we finished enrollment late October, early November of last year. Those patients' 12-month data point won't occur until later this year. As time goes on and as we initiate our BLA filing process, the nine patients that we saw in our top-line data release will grow to maybe double that over time.
Are you committed to continuing to show that data as they accrue in term of function? There was a fantastic correlation between function and expression.
Yeah.
Are you committed to ultimately show kind of the same data set with all 30 patients, or is it a little too early to comment on that?
Over time, we will certainly show that. There's no commitment if you think about from a protocol perspective, there was no pre-specified number of patients that had to be correlated to microdystrophin level. That's flexible. We think the strength of the data, the P value associated with the microdystrophin result, and then the correlation of function to microdystrophin, those are very, very strong tenets of the accelerated approval approach. Keep in mind, for ELEVIDYS, correlation of microdystrophin to functional outcomes was nowhere near as strong as what we're seeing. I think that was an element of the review process that concerned the review team. We feel this data will be convincing of the role of the surrogate biomarker.
Got you. That's helpful. Maybe just sticking to the data, let's comment quickly around safety. The broader field of DMD gene therapy has had some tragedies and setbacks. Can you just maybe comment on your safety? I know you have a differentiated approach in terms of your prophylactic regimens and whatnot. However, last week, I think we saw for the very first time two SAEs. How should we think about all that?
Yeah, I think we were pretty detailed about the two SAEs out of the 30 patients that we've treated. In both cases one was a liver injury and the other was myocarditis. Those were resolved without sequelae, fairly easily managed. I think if you think about contextualizing those results, you can compare them to what's on label for ELEVIDYS. We're about a 10th of that liver injury level. It's a result we think of both the construct, the purity of the product, and the IS regimen that we're using. The other, I think contextualization is the levels of SAEs that we've seen in the N of 30 is below what has been seen historically on Zolgensma. I think that is an important comparative to think about as we think about safety and the benefit to risk ratio that we feel is very positive for our product.
Yeah. I'm glad you brought up Zolgensma. I'm not sure if that was a comp I fully appreciated. Bouncing back again to regulatory. It feels to me that there is a little bit of an hesitation in kind of fully committed to a confirmatory trial that is placebo-controlled randomized. I appreciate that running that trial will come with meaningful number of operational challenges, and there's some ethical considerations, some whatnot.
Wouldn't be more forthcoming about that going to give you more leverage with the FDA, meaning you go to the FDA and say, "I want to get approved on accelerated approval, but at the same time, I'm fully committed to get to the bottom of this, so I will run a randomized clinical trial to actually show that there's a tangible benefit to make for these patients." How should we think about not being so forthcoming about a randomized clinical trial?
Yeah, I think there's-
For confirmatory.
I think there's probably two answers to that. One is that, one, we're very comfortable with the magnitude of effect that we're seeing in our current study. Keep in mind, we also have a confirmatory study running behind it that's almost fully enrolled at this point. That will be an N of 60 patients data worth. As these patients move out to two years, it'll be impossible for an eight-year-old to continue showing the functional benefit relative to natural history. We think we have a very clear and significant magnitude of effect that supports the AA approach. Second part to answer, though, is all the way back to JPMorgan, we disclosed that we plan to run an ex U.S. study, which will be a RCT-based design. We will have that in place at the time of review.
We've already gotten feedback from EMEA on the design of the study. We do plan to move forward with that. It's not an either/or. We're doing actually all of these and should, I think it's speculative, but should having that study in place help with an accelerated approval pathway.
We'll be in a good position to support that.
Got you. That's helpful. Again, we already kind of talked about this, but I think in the press release last week, at some point, there was a language around FDA has recommended a randomized control trial. Was that in the context of accelerated approval, or was that in the context of the confirmatory trial?
I think the context isn't fully known. I think that is a statement you'll see just about on any response in a discussion around trial design. Even in the Duchenne trial design guidance, you'll see a recommendation for an RCT-based study. Having said that, within that same guidance, there's an allowance for an accelerated approval pathway. Both are valid. We have had good discussions with the review teams about the nature of our study and what we would need to bring to a BLA to support accelerated approval. I think when we look at the data now that we have in hand, I keep saying the same thing, it checks all the boxes in terms of the magnitude of effect overcoming any potential bias associated with an external control strategy, NSAA values that are 4.5 times or 4.5 NSAA units better than control or baseline.
Those are levels well beyond the variation in natural history that you could see. Keep in mind, the controls that we're using are based on data from hundreds of patients, not one or two, but databases that we've been able to access for modern studies that are up to the current standard of care.
Yeah.
I feel like, the FDA in that same meeting indicated a willingness to look at the data in the guise of how accelerated approval reviews should be done. We feel confident we're in good shape. Again, we're trying to cover all bases. I think we always have to keep in mind, number one, the unmet need is huge. The prevalent market is growing in Duchenne, and if everyone is required to do an RCT-based study, there will not be a new gene therapy approved based on what I see in development, until 2030. I think that's completely untenable.
Yeah.
I think the data that we have would be supportive to meet that unmet need. I know from lot of discussions in the last two weeks with patient advocacy groups, they're going to be pushing very hard on regulatory agencies to make these therapies available.
Sure.
Not just ours, but in general.
Sure.
I think that's an important aspect of this.
Sure.
Speed counts, time is muscle is what we hear from the patients.
Yeah. Time is muscle is pretty powerful. Maybe just quickly on, I think you already touched upon it, but I want to double-click on it. You showed some very impressive functional benefit last week, appreciate there's a large natural history cohort at this point, which is not something we have in every rare disease that is available out there, I guess. Can you speak about whether any of those benefits were not only compared to natural history, but also just compared to baseline? Are on any of these endpoints, any of those kids actually getting functionally better?
Yeah.
Than baseline? Just maybe talk a little bit about that part.
Yeah. We have comparisons to the external control databases that we access. We compare it to incoming baseline characteristics. We also use the CTAP model, which is a predictive model, which accesses the same data in some ways. In all cases, we see benefit. I do think the surprise for us, especially when treating patients eight years and older is going in, stabilization would have been a great outcome, that their baseline level of function is maintained. In several of the patients that we've reported, they're actually improving. I think that's really, really interesting, and I think that we think is a basis of the design of the construct, which includes the C terminus.
Sure.
It's a differentiated product, I think interestingly, FDA has recognized our product as differentiated from ELEVIDYS, for example. I think that's important that they'll look at our program as a unique construct in Duchenne that provides this type of benefit.
Yeah.
That goes all the way back to our preclinical data where we saw restoration of function in the mdx mice to wild-type levels.
Yeah. Got you. That's helpful. Maybe let's talk about a prophy regimen. Obviously, you use a different prophy regimen that includes steroids, eculizumab, and sarilumab, which is obviously different versus some of your competitors out there. Obviously, the data so far is in the context of the clinical trial. How practical is to actually use the prophy regimen in the real world, if you will? Maybe if you could comment on the dose of steroids that you use. Is the fact that you're using eculizumab and sarilumab allow you to use lower doses of steroids versus your competitor? How should we think about all that?
The steroid levels are doubled during the three months of IS where we increase and then we taper down. By three months, the IS regimen is complete. I think what I would say is as we've expanded sites, which was our main goal in the confirmatory study, was to access new sites with new investigators. It was to get a read on exactly what you've asked about, which is how widely will this be accepted. Now we have 10s of investigators instead of single-digit investigator level giving feedback on our program. To a T, I think every one of them is saying, "This is very manageable." The reason they like it is the level of post-treatment surveillance is less because you're treating up front.
We're not sweating over every lab result, hoping the patient is doing okay and not knowing if they can intervene in time. In our case, by intervening ahead of time, the lab values stay stable, and they don't have to worry as much about patients post-treatment. I think in general, we don't see any obstacles to this in a commercial setting.
Got you. Maybe last one on DMD before I pivot. Maybe what's your view on kind of the competitive landscape? Obviously, Sarepta has had some setbacks, but there's still a commercial product available out there. There's Solid also in the mix here that has obviously a construct that has a different molecular biology, if you will, behind it.
Right.
You have the C terminus domain versus they have the nitric oxide domain and whatnot. What's your view on the broader field? Maybe just kind of remind us differentiations for your product versus some of the others?
I think if we look at where we are, roughly 2+ years post-launch of ELEVIDYS, the prevalent market is larger than it was two years ago. The uptake is less than people had planned for. I think there are concerns. One of the things that we hear from patient advocacy groups is when people are considering a gene therapy is safety. Am I going to get the benefit for the risk that I'm taking? I think that's an answer that we're trying to give with our program is we're likely to deliver the intended level of microdystrophin. We see that in our data in a safe manner, and then that gives you the best possible chance for functional benefit.
I think underpinning what differentiates us in some ways, and I think in a major way from our competitors, all U.S.-based manufacturing in-house under our control, high product purity, and a really attractive cost of goods, which is not important to a patient, but important to access. I think we're positioned very well to, for example, move quickly on a BLA process. Our CMC approach on the Hunter program, we had no observations in our manufacturing facility. The CMC package was complete and without any delays that you see in other CRLs, we're leveraging that in this program, I think in a very strong way.
Got you. That's helpful. All right, maybe pivoting to wet AMD. Obviously, we're all waiting for the pivotal data here, ATMOSPHERE and ASCENT. Maybe what's your latest thinking on probability of success and confidence around it? Maybe remind us, I believe both trials were upsized, this is years ago.
Yeah.
Quite meaningfully versus what was the original plan. What was the driver behind that decision?
I think that occurred around the time that the partnership with AbbVie was consummated. They have, I think, a philosophy of powering a study even on secondary endpoints to 80% or greater. That was one of the reasons the size of the study was expanded. The other reason, which is very important, is adding additional sites in Europe was a priority for a global submission. We actually got tremendous recruitment in Europe faster than expected. There's a great unmet need there as well. I think it has a high probability of success based on that powering, based on the way the studies have been conducted. There's two doses, don't forget. Two ways to win. Our data from the phase I/II was very compelling. We would expect, if we think about the target product profile, 50% or greater of the patients hopefully rescue free.
At one year?
Sorry?
The 50% or greater injection-free patients, is that the time point at one year?
Yeah. Correct.
Okay.
What we've seen in our phase I/II data historically is that roughly an 80% reduction overall in treatment burden, so less injections. If we're near those values in our pivotal setting, then we feel like we've met our target product profile and this is on its way to hopefully a commercialization effort.
Got you. Okay. That's actually very helpful. I know we're already almost at time, believe it or not here. Just a quick update on Hunter, the MPS II program. We're seeing standard of care making progress. We've seen, obviously, the approval of Denali. What's your take on that approval, just give us an update on your program and where you stand in the context of obviously the clinical hold recently being lifted.
Yeah. We think the Denali approval was significant in terms of evaluating our CRL. We feel strongly that our submission met many of the, if you read the approval letter for Denali, we met many, if not all of the criteria on which that program was judged. We've been having good discussions with FDA. We filed an appeal to the CRL itself, and I believe we have fresh eyes looking at this in FDA. We're optimistic that this can move forward. We know for sure that the Hunter patients out there are looking for alternative therapies. The burden of treatment, even with the really great approval for Denali to give patients options, it's a weekly infusion for a young child, and a one-time gene therapy, we think has substantial benefit in terms of burden of treatment.
We feel very strongly that that program should be approved, and we're working collaboratively with FDA to move that forward, hopefully.
Got you. That's helpful. I know we're almost at time here. Maybe let's close with an open-ended question. Curran, what do you think is the most underappreciated aspects of the REGENXBIO story today?
I think the thoroughness of the science that we conduct, I think we hold a high standard in terms of protecting patient safety. The way we approach, even where we deliver programs like the retina programs, they're immune privileged, so we don't see a lot of things that affect safety, like intraocular inflammation. I think we think about the way we design our programs starting with the patient and what their experience will be, and obviously trying to ensure that they get a meaningful benefit from the therapies that we provide. I think that permeates all of our programs in the way we approach things. I think these are turbulent times. Occasionally, I meet with investors that say, "Oh, you're the boring company.
Nothing ever goes sideways on things." Well, it's a little more turbulent now than we'd all like it, but we're sort of pushing through this in a very linear fashion, and I'm very optimistic we're going to have a good outcome at the end of it all.
Got you. We're out of time. Curran, appreciate you joining us. Thanks everyone.
Thanks you.
for joining us for the conference here, and we'll talk soon. All the best. Thanks.