Good day, and thank you for standing by. Welcome to the REGENXBIO Rare Disease Program Update conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Ken Mills, President and CEO of REGENXBIO.
Good afternoon, everyone, and thanks for joining us for this exciting event. The slides for this presentation are available in the webcast. It was November last year when REGENXBIO began work on pipeline prioritization plan that enables us to focus our capabilities and resources on large commercial opportunities, where product candidates are differentiated, can be expedited, and support meaningful value generation soon and for the long term. Our priority programs are ABBV- RGX-314 program for the treatment of wet AMD and diabetic retinopathy, being developed in collaboration with AbbVie, RGX-202 for the treatment of Duchenne, and RGX-121 for the treatment of MPS II. Early on in 2024, we've experienced exciting progress for each of these programs.
A few weeks ago, we hosted a call with leading retina experts to review our new positive clinical data for our treatment for wet AMD using in-office suprachoroidal delivery. Today, we get to focus our attention on our rare disease pipeline and two amazing milestones. In Duchenne, we announced completion of enrollment in cohort 2 and additional positive interim data from our ongoing clinical trial. We're thrilled to see that RGX-202 is demonstrating strong microdystrophin expression across a wide range of patients. For MPS II, we achieved a major breakthrough, with statistically significant results from our pivotal trial on which we are filing a BLA. Patients receiving this treatment have showed continued improvement in neurodevelopmental skill acquisition for up to four years, and evidence of discontinuation of standard of care intravenous enzyme therapy.
A few weeks ago, we hosted a call with leading retina experts to review our new positive clinical data for our treatment for wet AMD using in-office suprachoroidal delivery. Today, we get to focus our attention on our rare disease pipeline and two amazing milestones. In Duchenne, we announced completion of enrollment in cohort 2 and additional positive interim data from our ongoing clinical trial. We're thrilled to see that RGX-202 is demonstrating strong microdystrophin expression across a wide range of patients. For MPS II, we achieved a major breakthrough, with statistically significant results from our pivotal trial on which we are filing a BLA. Patients receiving this treatment have showed continued improvement in neurodevelopmental skill acquisition for up to four years, and evidence of discontinuation of standard of care intravenous enzyme therapy.
Steve Pakola, our Chief Medical Officer, will provide an update on our clinical program for RGX-121 for the treatment of MPS II and the results from our pivotal trial. He will welcome and engage in a discussion with our two guests, Dr. Paul Harmatz and Dr. Raymond Wang, who are both world experts in MPS disease. Dr. Harmatz presented the pivotal results this morning from MPS II RGX-121 in San Diego. At the end of the call, we'll open up the line for some Q&A with all four of us on all and any of these rare disease update topics. So let's continue moving to the discussion about RGX-202, our potential one-time therapy for the treatment of Duchenne and the new data. On slide five, we highlight a few things that makes RGX-202 special, including among AAV-mediated microdystrophin treatments.
First, remember, it expresses a new differentiated microdystrophin with important biology that is most similar to what occurs in nature as shortened dystrophin, sometimes found in boys and men, that actually protects from muscle degeneration. The fact is, RGX-202 has only microdystrophin design that is unique to deliver a transgene that includes functional elements of the C-terminal domain found in naturally occurring dystrophin. But all that really means is that it's designed to be the closest thing to recreating healthy muscle throughout the body as a treatment. The other things that are important about RGX-202 is it's designed to be great for targeting muscle, and it represents a potential alternative for many boys who may not be eligible for other therapies. Slide six presents our outline of our current clinical trial design for RGX-202 and its enrollment and safety status.
We are enrolling boys who are genetically confirmed with Duchenne between the ages of four and 11, who are ambulatory. The primary endpoints of this study are safety and tolerability at 12 months, but across the 12-month period, we will complete a number of assessments, including of strength and function of the voice. At three months, we take our important measure of the microdystrophin expression, which gives us the evidence that our gene therapy is expressing in muscle and exists as one of the strongest and most validated biomarker predictors for the likelihood of clinical benefit. Now, we've announced to date that we've enrolled five boys in this study, three at the dose level one, and we confirmed today that we've completed two patients in enrollment at dose level two.
We will have the opportunity to enroll additional boys in this study, but to date, overall, the data has shown that RGX-202 was well tolerated in all five patients treated. Now, last October, we shared initial safety and microdystrophin data from the two patients from the first dose level for whom results were available. But on slide seven is where we get to see today's new data. Represented here is the third patient enrolled, a six-year-old patient whose RGX-202 microdystrophin expression was measured to be 83.4% compared to control. This is the largest increase in microdystrophin expression we've observed to date in this trial. Microdystrophin expression was measured by Western blot, and as usual, we compared those results also with a liquid chromatography mass spec method.
Also, in this patient, a reduction from baseline in serum creatine kinase levels of 93% was observed. This is one early way we can find that supporting evidence of potential clinical improvement. Now, moving to slide eight, what we see here is all three dose level patients in one table, and as a group and individually, they're showing really encouraging increases in expression of RGX-202 microdystrophin and reduction from baseline in serum CK levels. Also, we're observing that the microdystrophin is getting where we want it in the muscle. This data has us very excited because we've been discussing with the FDA, and we plan to use RGX-202 microdystrophin expression as a surrogate endpoint to support a BLA using accelerated approval. And based on these data, we're working with greater urgency to fast-track the development of 202.
To achieve this in the coming months, we'll further assess microdystrophin expression, dose level two, in order to make a pivotal dose determination by mid-year. Along the way, we'll have opportunities to share strength and functional assessments of the boys at both dose levels, and before the end of the year, we expect to start our pivotal trial. That's the new data that was presented this morning on RGX-202, which we continue to be enthusiastic about the progress, and I'll talk about more after the Q&A in terms of summary. Now comes the time to discuss the pivotal trial for RGX-121 for the treatment of MPS II, achieving its primary endpoint. We've confirmed alignment with the FDA on key elements of an expedited BLA plan.
With today's announcement about statistically significant achievement of the primary endpoint in the pivotal trial, we remain on track to support a BLA filing in 2024 using the accelerated approval pathway. RGX-121 would be the first gene therapy treatment for MPS II. Speaking of MPS II, on slide 10, MPS II is a serious genetic disease that can present an inherited pattern in boys. It's caused by a gene defect of an intracellular enzyme called I2S. It's characterized by the unwanted accumulation of carbohydrates, called glycosaminoglycans or GAGs for short, throughout cells in the body due to the failure of this missing enzyme to remove these carbohydrates. The defect results in some serious systemic and CNS symptoms and early death. Although some boys have little to no CNS symptoms based on their genetics, most boys do. Probably over 70% is estimated.
There is a standard of care for the systemic disease that involves regular infusion of missing enzyme, but nothing exists as a treatment for the CNS symptoms. The goal of RGX-121 is designed to deliver and restore the gene that's missing in the brain of boys with MPS II and reduce this carbohydrate or GAGs accumulation. Its primarily intended clinical benefit is to prevent the CNS disease, significantly improve vital brain function, reduce potential neurodegeneration, and avoid early death. It's been established that measuring levels of GAGs in the fluid around the brain among boys allows us to distinguish between the severity of disease, including those at risk for CNS disease, versus those who may have no CNS symptoms.
The RGX-121 development program is using that fact, in particular species of GAGs in brain fluid, one in particular called D2S6, a form of heparan sulfate, as a surrogate endpoint that is reasonably likely to predict clinical benefit among boys with brain disease or CNS-based symptoms for MPS II. An interesting observation from today's data that I know Steve is going to touch on is that as we've continued along with the development of RGX-121 for the CNS symptoms, we've also observed that it may reach tissues beyond the CNS, including some of the systemic manifestations of the disease. Now I'm going to turn the call over to Steve so he can review our clinical data, updates on the achievement of the primary endpoint for MPS II, and start the discussion with Dr. Harmatz and Dr. Wang. Steve?
Thank you, Ken. We're excited to present this interim update on the RGX-121 CAMPSIITE study, including the top-line pivotal results that Dr. Harmatz presented for the first time earlier today at the WORLD Symposium. First, on slide 11, briefly reviewing the study design of the CAMPSIITE study, which has two parts. The design of part one, the dose-finding portion, is shown on the upper left of the slide. We previously presented interim updates on this portion of the study, and today we'll share another update. On the upper right of the slide is the design summary of the part two pivotal component of the CAMPSIITE study, with the enrolled 10 patients encompassing the BLA pivotal population. Slide 12 shows the Part One summary results update. In Part One, RGX-121 has been well tolerated in the 15 patients treated across three dose levels.
CSF D2S6 levels were reduced to attenuated levels and approached normal levels in participants who received dose level three , the pivotal dose. Developmental skill acquisition has also been observed up to four years after RGX-121 administration. Of note, investigators are choosing to discontinue standard of care IV enzyme replacement therapy, or allow patients to remain IV ERT naive, supporting a potential systemic as well as CNS effect of RGX-121. We will continue to follow these patients' ERT status in the future. Now on slide 13, we move to Part Two and the pivotal results. The pivotal trial primary endpoint was met with high statistical significance, with eight out of the 10 pivotal patients achieving CSF D2S6 reductions to below maximum attenuated levels, and the other two patients also exhibiting large reductions of 55% and 85%.
Overall, in the 10 patients, there was an 86% reduction in CSF D2S6. These results confirm the meaningful reductions in D2S6 approaching normal levels seen in dose level three participants from the dose-finding portion of CAMPSIITE. So in summary, RGX-121 has been well tolerated in the pivotal study and has met the CSF D2S6 primary endpoint with high statistical significance. CSF D2S6 is a surrogate endpoint reasonably likely to predict clinical benefit, and therefore, these results support our plans to file a BLA in the second half of this year, utilizing the accelerated approval pathway. And now, having presented these results, we have the benefit of having Dr. Paul Harmatz, investigator and presenter of these results at WORLD Symposium, and additionally, Raymond Wang, who is also an expert in treatment of lysosomal storage diseases, including MPS II, as well as an experienced clinical trialist.
So first, thanks to both of you from San Diego, for taking the time to meet with all of us. We know how busy you are out there at WORLD Symposium. Paul, since you presented these results, let's start with you. What are your key takeaways from the results that you presented today?
Thanks, Steve. I think the key takeaway is how exciting it is to be in a phase three level of evaluation for a treatment of a disease we've watched kids be devastated by. So you know, it moved very smoothly from the part one to the part two, and in the end, we were just pretty well blown away by the top-line data that we had this strong a response in a well-defined group of patients. So I'm sort of breathless that we're at a point where we can take something to FDA and really push them to make firm decisions.
Hearing from Peter Marks, who preceded the symposium today, it sounded very promising, at least in his talk, that 2024 will be a sort of new look at surrogate endpoints, biomarker use of heparan sulfate, and consideration that how hard it is to study a rare disease with small populations, a lot of heterogeneity, genetic variation, all of it working against us. And this basically proved that we could replace the enzyme, do it on a long-term basis, remove a therapy that's quite expensive and takes out a day a week, and by being able to remove proof that we are getting a systemic effect. So I think, yeah, I don't want to take all of Ray's discussion, but it, I think it's a pretty miraculous day to have to reach this point.
Thanks. Thanks, Paul. That's very helpful. So, let's turn to you, Ray. Now that you've seen these pivotal results, what are your key takeaways?
Thank you, Steve. I would say on top of what, Dr. Harmatz has already mentioned, I just want to add that, it's impressive for such a large reduction in D2S6 glycosaminoglycan in the CSF in such a short period of time. I mean, 16 weeks is barely enough time to get it into the cells to get them to start making the enzyme and then to start breaking down the substrate. To get it down, you know, almost 90% is really fantastic.
Great. Thanks. Thanks, Ray. So you both hit on the biomarker and Paul, your comments about Peter Marks's comments and the direction he's going in terms of biomarkers in general... You both, of course, have spent your careers considering pathophysiology, interventions, and how to translate that type of evidence into clinical benefit. I think it'd be great for our audience to hear how you think about CSF D2S6 in terms of prediction of ultimate clinical outcome. So Ray, why don't we start with you this time?
Sure. So, don't wanna get too much into the biochemical weeds here, but, D2S6 is what we call a pathologic GAG. It is the specific species of glycosaminoglycan which can't be digested or is not digested when there's a deficiency of I2S. And so, it builds up when there's an absence of I2S, and then obviously, the correlate is that when I2S is subsequently expressed by the gene therapy, then the D2S6 goes down, and that represents a reduction in the bad player, if you will, in causing the pathology in MPS II.
Thanks, Ray. Paul, anything to add on that?
No, exactly. It's what Ray said, that we're just really amazed at the reduction of this marker and how long it lasts, and the fact that we can take away the really effective standard systemic treatment that these kids are on.
So Paul, you hit on a key item that often comes up, which is how long it lasts. What's the durability that you can anticipate with gene therapy? We have a lot of clinical evidence on durability for our NAV platform of vectors, including AAV9. And actually, Ray, you have direct experience with RGX-111 for the treatment of MPS I, and actually are presenting an update on your IIT patient tomorrow. Shameless plug. So it'd be interesting to hear your take, Ray, you know, from your own experience, how do you think of potential durability of gene therapies delivered to the CNS, such as AAV9-directed gene therapy?
Yeah. Thank you, Steve. Looking forward to that presentation tomorrow. Very excited about that. But, you know, the big question that people have is: How long does this last? Is it really going to be a one-shot deal for my child or for my patient? And, you know, we have more than 3.5 years experience from RGX-111. You know, there's plenty of long-term data from CAMPSIITE to see that, you know, there's sustained D2S6 reduction, as well as neurocognitive improvement in the early-treated MPS II kids, is a direct sort of opposite of what you would expect for a Hunter's patient who isn't getting any kind of therapy for the CNS.
Great. Thanks. Thanks, Ray. We've been focusing on the CNS aspects or effects that we're seeing from these trial results. Paul, one of the other findings that you presented was the intriguing aspect of part one, that investigators are actually often choosing to take patients off systemic enzyme replacement therapy. So as an investigator, was this your experience? And what might be the implications of this for your patients?
You know, it was remarkable data that we were able to show. We had a sense that we were taking single patients off, but I didn't have an overall sense of the whole study of how powerful this was. It's a difficult process. The parents have spent years, for some of them, being told, "Don't miss a week of enzyme. You have to keep it up." And it sometimes takes a significant discussion, negotiation to let you try one to two months without enzyme. And with this data, we, we can now really effectively talk to the families and show them that, that it's an important step in the process. As we say, it, it would- it will change the dynamic of their week. The kids will stop missing school one day a week.
So, the cost savings are very significant, and we even wonder on a theoretical ground whether pulsing with enzyme weekly is stimulating antibody production. And I'll feel much more comfortable when I have kids off enzyme or naive patients that have never started, not starting enzyme and protecting against this problem that develops with enzyme therapy... So I'm really, I think this is one of the strongest parts of the data we've presented.
Great. Well, thank you both again for sharing your insights on these results.
Steve, can we add one thing that-
Sure. Yes, please.
The Newborn Screening National Committee approved adding MPS II to the recommendations, the recommended screening panel, and this will begin rolling out in various states. This is gonna. This is perfect timing for a treatment that can effectively prevent or reduce the brain disease that we see in these boys. And it's, it adds so much to the. We have the newborn screening, so we will identify patients at birth, and this will be an effective therapy. So I can't tell you how important the two things are together and how lucky both came together in the same one-to two-year period.
Thanks, Paul, for that important point. Actually, thank you to both of you again for sharing your insights on these results. So at this time, I'm gonna turn the call back over to the operator to take questions from the audience. Operator?
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please limit yourself to one question, and you may requeue for any additional questions. One moment for questions. Our first question comes from Gena Wang with Barclays. You may proceed.
Thank you. I think it will be a little bit difficult for me to ask just one question since you have two great data updates on two different programs. So I will just ask one question on each program. So for the MPS II, one question is for Dr. Wang and Dr. Harmatz. Like, with current data, how would you use RGX-121 in your patients, and how many do you expect to treat in 2025 once drug receive approval? For DMD, third patient from dose level one already show very impressive protein level. How would you decide at dose level one and dose level two selection, a real possibility of a non-prophy SOLIRIS as part of the decision-making data points?
Thanks, Gena, for those good questions. Paul, Ray, do you wanna give Gena some feedback about, based on this data, how you view the, the clinical use of RGX-121 in practice?
Well, we're all hoping that the FDA approves it on an accelerated basis. But, you know, I think that we have to consider how many patients we have who have the neuropathic disease, and also consider the babies that will be identified by newborn screening and have a really in-depth conversation with the families, because this is all gonna be brand new for them. I don't think I'm gonna be able to provide any kind of number projections for you because of that, because this is all brand new to them.
Thank you.
Paul, any other observations, Paul, about that?
Yes. Our estimate is, and it's similar to MPS I, in California, Ray and I both live in California, we'll have probably three to four newborns a year that would fit the category of neuropathic disease, and we're about 10% of the country. So you would imagine just in the newborn screening, that potentially 40-50 patients a year would fit that category. It's also the MPS II, along with MPS I, is the most common and treated patients in the MPS group. And I don't have a precise number, 200-300, probably in the U.S. on enzyme therapy. These are all ranges of age, so you'll probably, if the therapy may be directed at a younger group in that population, that that would be another group that you'll be discussing this with.
I think it's the newborns that will, especially if there's no alternate therapy at that point, this will be a real breakthrough to treat that population.
Thank you for that. Gena, with respect to the dose determination midyear, you know, I think we talked about in October when we presented the initial data from dose level one, that, you know, we've established preclinically that, you know, dose level two has a profile of, you know, something that we think could be more encouraging. And I don't think that we continue to be concerned about the clinical or commercial implications of these short immune suppression profiles that we've introduced out of an abundance of caution. So I think our decision is... Really gonna be based on if, you know, dose level two is safe.
We're expecting, you know, that based on what we've seen preclinically, higher expression, you know, of course, it's more potent, and there's more virus that's got the potential to reach muscle cells when we dose escalate by a factor of two. Yeah, I think we're pretty encouraged that dose level two could be our dose, and it may even guide us to, you know, dose expansion as part of the bridging path to the final dose determination, to continue to build momentum and evidence to be able to accelerate that dose into not only a pivotal trial, but a totality of evidence for an accelerated approval BLA argument. So we really like where we are.
I mean, these, microdystrophin results at dose level one are, you know, I think really, really encouraging, and we're really enthusiastic about it, and we think we can do better, and we're seeing good safety so far, so we're gonna do that. Thanks. Operator?
Thank you. One moment for our next question. Our next question comes from Vikram Purohit with Morgan Stanley. You may proceed.
Hello, everyone, this is [inaudible] . Thank you for taking our call. I have a question on the DMD program in terms of, what do you anticipate the pivotal study to look like in terms of, size and scope?
Yeah, thanks, Gospel. I mean, you know, it's January, and we're giving sort of pivotal initiation guidance at the end of the year. But we, you know, we look at kind of the support and the interactions that occur with the agency. We look at the basis of the accelerated approval decision for, you know, ELEVIDYS, as really relying on about 14 boys worth of data when you kind of look at the sort of assessments of microdystrophin in four- to five-year-olds. Obviously, there's additional consideration for safety exposures, but, you know, I mean, this is rare disease.
I mean, I think we heard Paul mention the fact that, you know, the FDA is out and about in the rare disease world, you know, engaging with stakeholders, both the physicians, the sponsors, the patients, talking about how to take advantage of things that could provide for acceleration. We think our experiences are being quite reasonable about it.
So, you know, we, we would expect to be able to have a discourse with them as we have this data and have additional data for dose level two, that, you know, puts us in a place that's probably a similar range to, you know, what, what we're doing, maybe a little bit larger than something like what we're seeing with MPS II, but, you know, not something that sort of runs away with a very, very large trial, but something that is achievable in a short period of time. Because these medicines are, are so important, and when you see something like the differentiation of 202 against the backdrop already of things that are working in some kids, but other kids can't get it, I, I think we wanna move quickly here.
I think, you know, we're gonna be, I think, really excited about that next engagement. Sir-
Thank you.
Thanks.
Thank you. One moment for questions. Our next question comes from Alec Shanahan with Bank of America. You may proceed.
Hi, guys, this is John I'm on for Alec. First of all, congrats, congrats on the data. Just two questions from me. First one for Dr. Wang and Dr. Harmatz. I think it was mentioned that there were decisions of discontinuation of ERT. I just wanted to check in and could you guys actually elaborate, you know, what went into making that decision for maybe some of your patients? Could you maybe walk through your decision-making process? And ultimately, you know, what did you have to see in order to make that decision? And also, if you could shed some light on what are your current clinical observations on the patients that have discontinued ERT, that would be great. Second question for Ken and Steve.
Have the team kind of already had interactions with the FDA on future plans for the one-to-one? And what is the current status on that? Could you just shed some light on maybe on what they're saying and what's going on there? Thanks.
Okay, sure,[inaudible] . Good question. The decision really involves the parent talking to my team first, discussing the option of withdrawal, the advantage, the monitoring, which we do when we withdraw. We will tend to do weekly urine GAG and heparan sulfate measurements in order to convince these families that we're going to be able to know whether their storage is increasing, and they need to restart enzyme. It's a hard decision for them. They've been on it for years, and suddenly you're taking away a drug they've sort of... It's become part of their lives. Then, the sponsor, we discuss with the sponsor once we have a decision with the parent, that they might be willing to go forward.
If the sponsor, looking at the data that's available, you know, feels that they've had a good response-
...biochemically, CSF is showing changes that we hope for, then we try to move forward. There's always, as you're doing these urine GAGs weekly, you have a two- to three-week lag between collecting the sample and getting a result back from the laboratory. So that's why you're doing it so frequently. So by six weeks, I can have a three-week look at whether their GAG is gonna be going up suddenly, and then I'll start spreading out how often. I tend to do more GAGs than other people might do, but it gives reassurance to the parents that we're watching it very closely. Most of the patients, in fact, all of them, I haven't put anybody back on because of a failure. And there is some variation.
You know, one time it'll be a little bit higher, and the next time, lower. There's variation in the GAG measurements. But yeah, excuse me, be a little bit patient and, but and we've the other group that are the naive patients, and we try not to start ELAPRASE or encourage them to start. We'd rather see the response to the gene therapy and then follow to the urine GAG, hopefully get a good two-thirds, three-quarter, you know, 70%-80% drop from their baseline level, and then they've been very steady after that. We, that group, we monitor as well, 'cause three months, six months later, if it starts rising, we'd have to reconsider. But so far, we haven't seen that. So I've been extremely pleased. I think it's, I can't tell you if there...
I haven't seen a change clinically in the patients that are taken off, but, we're not sort of at the stage of looking at whether it correlates with any of our, functional outcomes, for instance.
That's fantastic, Paul. Thanks for that, insight for people. And, you know, it's amazing to hear that experience, even for us as the sponsor, as you're describing it and you participated in it. It's still, amazing to hear you talk about it. With respect to regulatory interactions on 121, John, I mean, we've talked about that. At the end of last year, early fourth quarter of last year, we had our first, RMAT meeting, and we really worked through with FDA, a lot of confirmation on alignment on things about, CMC or manufacturing strategy, adequacy of safety database, and confirmatory study design.
So it was really, you know, coming into the beginning of this year, was about the finalization of meeting the, you know, adequacy of the pivotal endpoint and with the statistical significance, as Steve described today and that we announced, that Paul presented, we really feel like that was, you know, one of the final pieces to fall in place. We have agreed with the agency to continue to follow patients for a year based on safety. You know, I think this is gonna be a, an amazing potential event for, you know, the first approval of a, you know, direct to CNS, CSF at least, gene therapy with AAV. And so in that regard, you know, we find that acceptable for this.
I think, you know, going forward, though, we could envision once that validation is there for, you know, I mean, we're using a four-month endpoint on biomarker. I think we've continued to see really well-tolerated experience with the direct-to-CSF approach, both, I mean, as Steve and Ray shared about our, you know, experience in, in MPS in general. So, you know, feel very confident about the strategy for BLA filing in the second half of this year and that alignment.
Thank you.
One moment for questions. Our next question comes from Ellie Merle with UBS. You may proceed.
Hi, this is Sarah on for Ellie. Thanks for taking our question, and congrats on the data. Two quick questions. I guess on your commercial strategy for MPS II, what kind of infrastructure are you thinking that you would need to build here to support the launch? And is that something you're looking at starting near term or a longer-term thought? And then on the DMD data that you showed today, is there anything outside of patient ages and the baseline characteristics that you think might inform the differences in microdystrophin levels that we're seeing? Thanks so much.
Sure, Sarah. Thanks a lot. I think, you know, we're not really getting deep into commercial strategy right now on 121 . I think we've got the top-line data report today. We, you know, have the guidance in the second half of the year. I think that additional discussion about strategy for maximizing value of 121 and including commercialization, is a second half of the year discussion I think you can expect to have with us. With respect to, DMD and the, you know, I mean, we're obviously dealing with a small N here. I think, you know, it's established that there is heterogeneity in the disease, even, you know, within the same age groups.
I think that what we've been most pleased about with respect to dose level one is, we've seen robust expression in all the patients. You know, in a four-year-old, which is, of course, more in the sweet spot of the ELEVIDYS accelerated approval. And then more recently, the six-year-old patient, obviously, a higher amount. I think that the, you know, feedback we might get from, you know, experts in Duchenne would be, well, there, you know, there can be different, of course, genetics, different disease progression, even between a, you know, four-year-old and a six-year-old that might suggest what muscle there is to preserve or on an adjusted basis, how we might achieve or how they might respond to a gene therapy.
I mean, I think, you know, while, while we have an approved AAV based on accelerated approval, I, I still consider it to be early days here. And again, I think our, our goal and our mission has been to find, you know, a really broad range, as broad a range as possible for boys who will respond to AAV gene therapy. And I think we've been pretty consistent about that since we started our trial and as we've continued to enroll. So I think, again, you know, for us, heterogeneity a little bit is, I think, going to be part expected. But I think what we really also would start to expect now from, two...
to a dose level one, and I think at dose level two, is, you know, we have a floor of expression that we think is robust and has the potential to be really clinically meaningful, including in older boys.
Thank you.
Thanks, Sarah. Go ahead, operator. Thanks.
One moment for questions. Our next question comes from Annabel Samimy with Stifel. You may proceed.
Hi, thanks for taking my question, and congratulations on the data. I have some questions for both MPS and DMD. First, for the physicians, I want to ask about the neurocognitive benefits that you saw. How meaningful have these benefits been? I mean, we obviously see the pattern and the improvement, but can you put it into context for us, what that means as far as, you know, how these patients are improving? Are all patients benefiting, or only those who are less neurocognitively impaired? And then I guess, in the same vein, how do you think about the age group being treated here? Are these patients typically younger than when they typically would have been initiating treatment on ERT? And if I could just save a question for DMD for after their responses. Thanks.
Sure. Paul or Ray, did you get that question? It was basically, you know, thoughts about the neurocog responses that we've seen so far, obviously mostly in, almost exclusively in part one of the dose finding for 121. One of you want to pick that up?
Sure, Ken, I can tackle that. So I think it's important to keep in context that the patients enrolled in this study were kids who have the neuropathic version of Hunter syndrome. They're going to develop neurodegeneration. It's, you know, whether it's based on a sibling or a family member or their genetic makeup, it is known that, you know, most, well, large percentage of children, they keep gaining milestones. And because of this terrible disease, patients who have neuropathic Hunters are gonna slow down their pace of developmental milestone gain and then plateau and then actually start to lose skills, and we've all lost patients due to that neurodegeneration.
So the fact that, you know, there are patients who are continuing to learn and to gain additional milestones, you know, when they were expected to lose milestones, is a tremendous win for the community, in a community that has been desperate to see something that can reverse that neurodegeneration. There's nothing worse, you know, than seeing your child essentially get slowly erased, who they are and their personalities. It's just really terrible. So I would say, yeah, that would be kind of the, you know, there's numbers on a graph, but what's actually, you know, in front of you is, you know, it's revolutionary.
As far as the age group that's being treated versus how you typically treat or when you typically start treating?
We haven't had newborn screening online yet, so it's pretty unusual to get a young patient. We have one sibling pair in the study, and the older patient was about 2.5, very affected, non-verbal, hyperactive, fearful, and then a one-year-old younger brother. They've been... Even the older patient is much more in tune with the mother, following simple commands, much less fearful. The younger patient has been developing what you would call very typical. Language is behind, but virtually everything else is, you know, understanding, comprehending, following commands, which you'd expect at his age level. So, the contrast was just so dramatic between the two, and it, they're severely, they have a severe mutation, and you would expect the younger patient to follow a similar course.
Now, we have the younger patient past the age of where the older patient started therapy. You can appreciate the big difference in outcome.
If I may add, I mean, that was one of the main reasons that newborn screening for MPS II was added to this recommended uniform screening panel. Because, you know, when before this, the Hunter patients would, especially the neuronopathic Hunter patients, would often be diagnosed pretty late in their disease course. It's not usually the first, second, third, or even the tenth thing that, you know, pediatricians or neurologists are necessarily thinking about. And so there would often be a long delay in diagnosis and probably, you know, the kids would get to a point where only if there was a family history of a prior family member who was affected, would they get diagnosed early and have a benefit. So the existence of newborn screening really leverages the power of early treatment.
Okay, great. And just if I can follow up on a DMD question. Ken, you mentioned that, that, you know, the data today potentially allows you to further accelerate the DMD program, which already seems to have been somewhat accelerated moving into, this level two and potential pivotals this year. What other steps can you take to accelerate that development?
Sure. I think, you know, it's really... I mean, I think with the reinforced results and consistency of being, you know, at robust microdystrophin levels, Annabel, I think that, you know, we kind of feel like we have the opportunity to work with data sets now that, you know, might be a little bit more consistent. Meaning, you know, we're seeing results that are encouraging in a wide range of boys, and we're not seeing, so far, anything that tells us that, you know, we're not achieving something that could be clinically meaningful.
So, you know, I think if you looked at data sets coming into this, different than, you know, RGX-202, you might have said, "I don't know, you might, you know, you might not see results." You might, I mean, I think that we've encountered those headwinds even in discussions with all of you, you know, about, you know, why are you doing older patients? And I think now, you know, we're seeing a really strong outcome in a six-year-old. We're further, frankly, reinforcing, I think, the observations that we had in the 10-year-old dose. And what that means from my perspective, is accelerating around age groups in ways that may not have been as apparent before we started.
Okay. That's, that's great. Thank you.
Thank you. One moment for questions. Our next question comes from Brian Skorney with Baird. You may proceed.
Hey, thanks for taking the question, guys. Maybe for Ken and Steve, just on 202, what sort of factors are you really considering when selecting the dose for pivotal and DMD? Seems like you have really good expression at 10^ 14. I suppose you can always have more dystrophin, but given biopsy variability, can you really have confidence that there's a difference? I guess maybe asked another way, it seems like cost and safety could only be theoretically worse at a higher dose. So I guess, what can you see on the efficacy side at 2 × 10^ 14 to convince you that it's the better dose to move forward in pivotal with?
Yeah, Brian, I think what we've seen preclinically is that there is a difference. We talked about this at last October when we presented the data, and we actually went back and reran preclinical studies comparing 1 E and 2 E 14. I mean, previously we had done dose ranging to select doses, and we had done, like, one, three, and five, for example. So we continued to see statistically significant differentiation between one and two in the animal modeling, and so that gave us a lot of conviction. You know, we're dealing with a different background in terms of our approach to manufacturing, maybe than people are used to. I don't think that cost of goods is something that is a concern for us.
We're trying to get the absolute best treatment out there, based on, you know, what we think will be a correlate to, higher microdystrophin levels. And I think the, the preclinical data is telling us is that two is gonna be higher than one. And I think, you know, on a safety basis, I mean, we're starting to answer that question a little bit right now, but that will be the, probably the primary driver, Brian, is, is 2E14 as safe as 1E14.
Great. And maybe just to ask a quick follow-up. Is there any room in the current study to just amend the protocol to be sort of a pivotal as opposed to just an entirely new protocol? Just trying to think about speed here, given sort of the competitive dynamics with the commercial gene therapy.
Yeah, no, I mean, I really like the way you're thinking and how you've characterized it. I mean, I think we designed in the notion of expansion to support something that could at least be a bridge to pivotal. Again, we kind of view the approach to a pivotal... you know, plan and program overall is creating a, you know, a strong argument for totality of evidence in microdystrophin at whatever it is that we want a dose to be approved at. And, you know, I would say, so in a partial answer to your question, I think is yes, you know, being able to add more patients through an expansion phase, I think is, you know, pivotal-like.
But, you know, one of the biggest reasons we did that is because, you know, we don't wanna delay the opportunity to get more data and more boys on treatment while we are working out, you know, some of the final understandings between us and regulators. Thanks for the question. Good talk.
Thank you.
Thank you. One moment for questions. Our next question comes from Mani Foroohar with Leerink. You may proceed.
Hi, good afternoon. This is Larry Sangalon for Mani. I just had a quick follow-up to a question that was asked earlier. In terms of differences in baseline characteristics between the patient in the DMD study, I was wondering if you could comment on potential differences at baseline in creatine kinase levels and whether you think that could influence the observed results?
No. Yeah, the question is about CK levels as kind of a contribution to prospectively understanding differences in responses. I mean, we have looked at baseline CK, and we sort of actually take an average of multiple time points when we look at baseline, because, you know, it's known to be something CK, CK-MB, and other sort of muscle-related blood biomarkers that can bounce around a lot. Frankly, if we're moving by, you know, like single-digit percentages or, you know, something much lower, I think it would be in the noise when you're seeing things that are 40%, 50%, 90%. You know, those are representative things that I think are a bit more clinically meaningful.
But otherwise, no, I mean, again, a small n, but we haven't specifically heard from the team that there would be that type of correlation in a way that I think we would lean into right now. But we do like the idea. I think all of us want to be able to see what we can do to find, you know, and stratify boys and patients that would have greater response. I know, and I'm sure you know, our colleagues in the space are thinking about those types of things as well. You know, and I think, you know, we'd be encouraged if we found something.
I think right now, though, on a prospective basis, you know, we're relying on the genetic diagnosis, we're relying on, you know, the expectation of the natural history curves, and we're relying on the fact that, you know, sooner is better, which is, you know, again, true to a degree. I think people have seen, you know, differences in progression, maybe not between a 12-year-old and a four-year-old, but we certainly have heard, you know, a 4.5-year-old versus a six-year-old can have overlap in terms of, you know, muscle that may be there to, again, restore as near healthy. Thanks for the question.
Thank you.
Thank you. One moment for questions. Our next question comes from Luca Issi with RBC. You may proceed.
Oh, great. Thanks for taking our questions. This is Lisa on for Luca, and congrats on the data today. So I have one on DMD and one on MPS II. So first on DMD, you know, as you have been screening patients to enroll, can you add any color on the proportion of patients which are being screened out due to neutralizing antibodies to AAV8? And on MPS II, just wondering if you can add more color on how the route of administration, either intracisternal or intracerebroventricular, is chosen for patients. Thank you.
Sure. Certainly let the second question go to Paul and Ray. On the first point, you know, I mean, we're very interested in the phenomena of preexisting immunology, as we've talked about, Lisa, and as a group that, you know, we continue to believe that RGX-202 is differentiated, that there are just certain boys who may only be able to access that, access that based on preexisting immunology, and antibodies to existing therapies that are approved or other therapies that may come. And I think we continue to view that at least 15% of the market could be preserved just for AAV8 alone. And in that, we have not seen really a significant rate of screen fails as we've been progressing through development.
Now, you know, we've enrolled 5 patients, so I don't think that there has been, you know, a significant funnel to have worked through in a way. And I think also we may be seeing that there are, you know, choices being made from, you know, patients that have previously screen failed in other studies that are coming to RGX-202 right now as well. So that may contribute to that. But, you know, otherwise, I can say that we haven't seen anything that, you know, would affect our understanding of, you know, general phenomena of preexisting immunology based on what's in the literature or, you know, our thesis that, you know, there's a minimum number of patients that should be able to access 202 uniquely either. So, that's all been good.
Paul or Ray, I guess, you know, it's Lisa's bringing up an interesting question. You know, we, we've got a couple different ways here to deliver RGX-121 to boys, you know, the intracisternal approach has been the primary, but, as a fallback, intracerebroventricular has been used as well. What's the decision process there for, clinicians?
I think that when you look at the procedure, the intracisternal is a newer, more technically sophisticated method, probably a little less invasive. You're not doing an operation. There's no healing or wounds. You don't have to place a burr hole in the skull. It takes a neuroradiologist, interventional neuroradiologist, or interventional radiologist, or a neurosurgeon who does a lot of imaging work as part of their practice to tackle. They probably become comfortable after five, for sure, very comfortable after 10 administrations. But it's a. There are variations in anatomy and vascular structures to look out for and approaches that vary from patient to patient. So it is more sophisticated. The intraventricular is a very standard procedure that they do a lot whenever they're placing ventriculoperitoneal shunts.
They use exactly the same equipment. It's image guided as well. Both are... One is real-time image guiding. The intraventricular, they rely on the MRI before to provide landmarks, and the machinery and software guide them into the ventricles. So, the ventricles are usually very easy to hit. There tends to be a mild increase in intraventricular pressure and, or some brain atrophy that makes the ventricles larger. So it's usually not a difficult procedure. How do we make a decision? It's really a group decision. REGENXBIO has been incredibly well organized with it, collecting the MRI, MR venogram, MR angiogram. All of those are collected a couple of weeks, a week to two weeks ahead of the planned procedure. Then the images are distributed to a team, including Dr.
Pukenas at University of Pennsylvania, who put together the technique. We have a group meeting, and they've all looked at the films ahead of time, and they try to assess whether they think this is a reasonable case to pursue with the IC injection. If people don't agree and they think that, yes, maybe I can get it, but it'll be 50/50, it's really great to have a backup. You may not need the backup for other disease that we are using this procedure, but MPS, there's thickening of the lining materials. There's hypoplasia of the bone structures over the cisterna magna. So it may be a much more complicated and needing a backup procedure than these other diseases. So hope that... Does that answer your question?
Yes. Thank you so much, and thank you for all the detail. Thank you.
Thank you. I would now like to turn the call back over to Ken Mills for any closing remarks.
We've gone a little bit over our planned time, but I'm so grateful, Paul and Ray, for your time and insights. I mean, this has been an amazing day for us, you know, from morning to almost evening here on the East Coast. And, you know, just your insights into the effect that gene therapy can have on patients and families with diseases like MPS II, I think has been profound. I think, look, as an investment community, I think you understand our plans this year are intended to generate significant value for our shareholders. And, you know, we think we've got the resources and the sort of allocation focused in the right places here.
It is absolutely about being laser-focused on the filing of this BLA for RGX-121, for getting RGX-202 into pivotal phase. You know, even jumping back to my earlier remarks, I mean, initiating pivotal trials for suprachoroidal, completing enrollment of our pivotal trials for subretinal when it comes to wet AMD and diabetic retinopathy. I mean, this year, I mean, by the end of this year, our entire pipeline should be initiating pivotal stage, fully enrolled in pivotal or under a filed BLA. And, and these are the types of milestones that we announced today that we believe make REGENXBIO incredibly well positioned to create value, value for shareholders. Thanks, everyone. Thanks again to Drs. Harmatz and Wang for having us. And, thanks, everyone, for the questions and the conversation. Have a good rest of the day.
Thank you for your participation. You may now disconnect.