Welcome to our REGENXBIO Virtual Investor Day event. I'm Ken Mills, CEO of REGENXBIO. I'm pleased to introduce our agenda and make some opening remarks. For this event, we have a program to provide an update on the company's pipeline, with a focus on programs with expected interim clinical trial data to be presented in the second half of 2023. Among other things today, we'll introduce some new interim safety data from our AAVIATE and ALTITUDE clinical trials, a new pipeline program for the treatment of Duchenne, and some specific guidance about additional interim trial updates later this year. We're also pleased to be introduced by three external experts who are leaders in the fields of Duchenne research and retinal disease.
Professor Dickson and Doctor Kaiser and Sheth will engage with management in a discussion, each program review, and participate in our live Q&A session at the end of the program. I'm grateful for George Dickson, Peter Kaiser, and Viral Sheth to join us today. If you'd like to ask a question, please submit it via the Ask a Question tab on the top right corner of your video player. You may do this at any point during the presentation, and we'll do our best to answer your question during the Q&A portion at the end of the event. If we're unable to get to your question during the event, we'll follow up with you separately. Today's event will include forward-looking statements. Please see here our full slide of our forward-looking statements that can be reviewed at any time. Please be advised that today's call is being recorded and webcast.
There's been meaningful progress in AAV gene therapy recently, including a growing understanding of gene therapy pricing models and the FDA's validation of surrogate markers as clinical endpoints to support approval. I'm pleased how REGENXBIO remains a leader in the gene therapy space, as our five by twenty-five strategy is on track for advancing 5 AAV therapeutics from our internal pipeline and licensed programs into pivotal stage or commercial products by 2025. Our end-to-end capabilities continue to set us apart as a leader with our manufacturing innovation center running scalable commercial ready batches of our AAV therapeutics, our research and early development team continues to advance what's possible in gene therapy. We'll provide examples of these capabilities today as we present data on our manufacturing innovation center performance and introduce plans for a new IND from our research pipeline.
All of our investigational gene therapies use adeno-associated viral vectors from our proprietary gene delivery platform, which we call our NAV Technology Platform. AAV vectors are non-replicating viral delivery vehicles that are not known to cause disease. Our NAV Technology Platform consists of exclusive rights to a large portfolio of AAV vectors. We believe this platform forms a strong foundation for our current clinical stage programs and with our ongoing research and development, we refer to commercial and investigational AAV vector-based gene therapies as AAV therapeutics. There are thousands of patients who have been dosed with AAV therapeutics from our NAV Technology Platform and hundreds more that are being receiving treatment every quarter. We believe we have a strong pipeline of AAV therapeutics with the potential to deliver one-time treatments to address significant unmet need in patients living with common and rare diseases.
We're currently focusing on an internal development pipeline shown here in three areas: retinal, neuromuscular, and neurodegenerative diseases. Across all of our pipeline, we have over 12 active clinical trials. In 2023, our team is executing on two pivotal phase programs that include over 1,000 subjects to support a goal that we have to file our first BLAs in 2024 and 2025. Let me briefly reacquaint everyone with our three pipeline therapeutic areas. First, our work in retinal disease primarily centers around the strategic partnership we entered into with AbbVie at the end of 2021 to develop and commercialize ABBV-RGX-314 or 314, an investigational gene therapy for wet age-related macular degeneration and other chronic retinal conditions. AbbVie is a strong complementary partner for REGENXBIO.
We're leveraging AbbVie's global development and commercial infrastructure within eye care, with our expertise in AAV gene therapy, clinical development, and deep in-house manufacturing knowledge. Together with AbbVie, we're developing 314 to be a one-time therapeutic option in major retinal vascular diseases to address significant unmet need in patients. This is a worldwide opportunity with the potential to reach over 30 million patients with high unmet need in what is already considered a $14 billion global market for standard of care anti-VEGF treatment. Soon, Ram and Steve will spend more time on the emerging opportunity for 314 in the treatment of retinal disease.
As a reminder, under the terms of our partnership, AbbVie made to REGENXBIO a $370 million upfront payment, with the potential for REGENXBIO to receive an additional up to $1.38 billion of additional development, regulatory, and commercial milestones. REGENXBIO and AbbVie share equally in profits from net sales in the US, and AbbVie will pay REGENXBIO tiered royalties on net sales of RGX-314 products outside of the US In addition, REGENXBIO will lead manufacturing for clinical development and US commercial supply, and AbbVie will lead manufacturing outside of the US Our pipeline in neuromuscular disease consists of a lead program called RGX-202. RGX-202 is our potential one-time gene therapy for the treatment of Duchenne.
being developed as a highly differentiated product designed to deliver a transgene of a novel microdystrophin that includes functional elements of the C terminal or the CT domain that's found in naturally occurring dystrophin. Today, we will also introduce you to a new program with exon-skipping science. This announcement expands on our commitment to Duchenne and is an alternative to the use of existing standard of care antisense oligonucleotide therapy, where short half-life requires frequent injection and results in limited protein expression of near full-length microdystrophin. Olivier will describe this work in more detail during his section. According to sources, with the introduction of new microdystrophin-based AAV gene therapies, the global market for Duchenne treatments is expected to grow to nearly $7 billion over the next several years. Lastly, I want to touch on our pipeline for neurodegenerative diseases.
We have three treatments in development for severe inherited pediatric conditions called mucopolysaccharidosis and Batten disease. Our pipeline programs, RGX-121 and 111, are investigational one-time AAV therapeutics designed to treat two different forms of mucopolysaccharidosis. We are also developing RGX-181 to treat neurodegenerative disease in CLN2 Batten and RGX-381 to treat loss of vision in CLN2 Batten children. All of our treatment candidates are designed to deliver human genes to the cells in the brain and throughout the central nervous system. According to sources today, the global market for MPS and Batten disease treatments is expected to grow to $3 billion by the end of this decade.
Despite this treatment spending, over 70% of MPS and Batten disease patients combined suffered from neuronopathic forms of the disease that either remain untreatable, have standard of care alternatives with high risk of mortality, or in 1 case, involve an invasive biweekly infusion of medicine into the skull of young children. The delivery of gene therapy and the expression of an enzyme that can replace what's missing in brain cells could provide a permanent solution for the brain aspects of MPS and CLN2 form of Batten, allowing for long-term correction of the disease. We believe this strategy could potentially prevent the progression of cognitive deficits or other loss of function that results in death of these children.
We have plans for more updates for our neurodegenerative programs throughout this year, and importantly, we remain on track to support our first BLA filing for RGX-121 using the accelerated approval pathway. That completes a short summary of the current pipeline. As you can see, we have a strong pipeline of AAV therapeutic candidates addressing high unmet need for millions of patients and diseases that represent current market opportunities of over $20 billion. For the remainder of this program, REGENXBIO's management will present on the 314 eye care program, including some new safety data from our recent cohorts. We'll provide details and updates about our plan for additional interim updates from the phase II AAVIATE and ALTITUDE suprachoroidal studies.
We'll also discuss the science and the design of RGX-202, our microdystrophin-based gene therapy candidate, share some of our early experience with safety data from our AFFINITY DUCHENNE trial, and update on our plans for interim data later this year, which we expect will include initial microdystrophin expression results from patients in cohort 1. As I mentioned, we'll also introduce continuing innovation that our scientists have made with an exon-skipping platform in the treatment of Duchenne. We want to thank you again for joining us for our virtual investor day, and we'll now move on to our program, and I'll hand the mic over to Ram to begin the ocular program review.
Thank you, Ken. Steve and I will be reviewing the ocular program today. I am Ram Palanki, EVP of Commercial Strategy and Operations. 314 is our lead candidate in the ophthalmology portfolio and represents the largest market opportunity in the field of gene therapy. It is a one-time platform, anti-VEGF treatment, intended to target over 30 million patients worldwide impacted by AMD, diabetic retinopathy, and other chronic retinal diseases that respond to anti-VEGF therapy. The goal being sustained long-term vision gain and stability in wet AMD and prevention of blindness in diabetic patients with a single treatment administered via the subretinal and in-office suprachoroidal routes. Together with AbbVie, we are developing 314 to be the first one-time option to treat major retinal diseases. Recently, we announced the expansion of the largest phase 3 gene therapy program ever into the major geographies of the globe.
With this expansion, we are in a great position to accelerate access to 314 to the millions of patients suffering with wet AMD worldwide as quickly as possible. Meanwhile, we continue to assess the suprachoroidal approach in the clinic to expand access to 314 patients in an in-office setting for patients suffering with both wet AMD and diabetic retinopathy. As we transition to the next set of slides, I want to remind the audience that the anti-VEGF market opportunity is poised to grow significantly as the population ages, with AMD still being the leading cause of vision loss in people over 60. In 2028, the global wet AMD market is expected to surpass $10 billion.
North America alone is expected to hold the largest revenue share in the AMD market, amounting to more than $5 billion within 5 years, almost 50% of the global market size. Most retina specialists in the US are surgically trained and perform approximately 400,000 vitrectomies annually. It is important to recognize we are leveraging the same surgical technique to deliver RGX-314 efficiently into the subretinal space. With approximately 2,500 retina specialists performing 4 million injections, caring for 800,000 wet AMD patients, there is a relative shortage of retina specialists that can provide sustainable chronic medical care to the exploding baby boomer senior population and population with diabetes. Brings us to the problem that we see in the real world today in the management of wet AMD, a chronic, lifelong, sight-threatening disease.
Today, only a quarter of patients are estimated to receive approved intravitreal injections frequently enough to sustain vision improvements, which leads to patients losing vision over time. Published real-world data suggests patients lose, on average, almost two lines of vision within five years of initiating current intravitreal anti-VEGF treatment. We believe a single treatment with 314 can provide a sustainable platform anti-VEGF therapy to improve long-term vision gain and stability. Long-term follow-up in our subretinal studies has shown durability over four years, with stable to improved vision and a meaningful reduction in anti-VEGF burden, with the majority of patients staying injection-free. Finally, I'm going to shift gears to the potential blockbuster opportunity in diabetic retinopathy. DR is a blinding ocular complication of diabetes that is approaching epidemic proportions and is a global health problem. It affects working-age adults.
Untreated, early diabetic retinopathy could significantly increase the risk of vision-threatening complications, vision loss, and ultimately blindness over time. Though intravitreal anti-VEGF therapies are approved and reimbursed for the treatment of early diabetic retinopathy, the utilization is very low due to the high treatment burden. Today, less than 1% of patients with early disease are treated with intravitreal injections. In this slide, I want to highlight the complexities of sustaining frequent therapies in diabetic retinopathy. In initial stages, the ocular complication is mostly unnoticed by the patients till it progresses to severe levels, leading to visual distortion. It is recommended that patients with diabetic retinopathy monitor their eye health at least 6 times a year on top of the 9 CDC-recommended annual doctor visits to care for their diabetes. Yet, 50% of DR patients never show up for their annual exam.
When patients do get diagnosed and/or initiated on treatment, almost half of them are lost to follow-up. Providers today hesitate to initiate frequent treatment that requires long-term commitment from patients to visit the retina specialist office for their intravitreal injections on a very frequent basis. We believe that there is a multi-billion dollar potential for 314 as a single in-office injection to become a new standard of care to treat and prevent progression of vision-threatening diabetic retinopathy. With that, I'd like to conclude my portion of the presentation today, reminding the audience that frequent intravitreal anti-VEGF treatment has been shown to reduce the risk of blindness in randomized clinical trials. Real-world evidence shows patients lose vision over time due to an unsustainable burden of current anti-VEGF injections. The societal cost of blindness is significant.
Treatment strategies that mitigate the social and economic impact of blindness are urgently needed. Sustained treatment strategies, such as one-time treatment with 314, that can provide long-lasting treatment outcomes in wet AMD and DR are ideal. I turn this over to my friend, Dr. Steven Pakola, to share the latest and greatest with 314 data.
Thank you, Ram. My name is Steve Pakola, Chief Medical Officer at REGENXBIO. I will now dig deeper into the 314 program for treatment of wet AMD and diabetic retinopathy. 314 utilizes an AAV8 vector that encodes for an anti-VEGF monoclonal antibody fragment with the goal of sustained protein production by the patient's own retinal cells. 314 is being explored in clinical development via two separate routes of administration: subretinal delivery and suprachoroidal delivery. We selected the subretinal route because it's the most clinically validated approach to safely and effectively deliver gene therapy to the retina target tissue, and we selected suprachoroidal delivery as an additional route, given the ability to, in the office, deliver 314 to a compartmentalized space close to the target tissue and thereby limit exposure to other ocular tissues, including anterior eye structures.
The main studies across our 314 program are shown on this slide. Our most advanced platform is our subretinal delivery program for treatment of wet AMD, which is in pivotal development with two ongoing pivotal studies. This slide shows the design of these two pivotal studies, ATMOSPHERE and ASCENT, which will enroll, in total, 1,200 patients. We are targeting completion of these trials in time for US and European regulatory submissions in late 2025 through the first half of 2026. In addition to the pivotal stage program for subretinal delivery, there are two phase II studies ongoing, assessing in-office suprachoroidal delivery of 314 for treatment of wet AMD and diabetic retinopathy, respectively. AAVIATE is an active controlled dose escalation trial evaluating one time in-office 314 administration for the treatment of wet AMD.
As previously presented, across all 3 dose levels, we see dramatic reduction in anti-VEGF injection burden, ranging from 64%-85%, including a majority of patients actually needing no anti-VEGF injections. Switching to ALTITUDE, our phase II trial of in-office 314 suprachoroidal delivery for treatment of diabetic retinopathy. We have enrolled patients with DR severity ranging from moderately severe NPDR up to moderately severe proliferative DR. This is an observation-controlled dose escalation study evaluating one-time in-office 314 administration, that has now completed dosing across 3 dose levels, including completion of dose level 3, with short course prophylactic steroids announced earlier this year. This slide shows previously released efficacy results for dose levels 1 and 2, showing, as expected, in observation control, patients generally do not improve, but rather develop worsening disease, while patients treated with 314 at either dose generally improve.
Importantly, none of the 314-treated patients develop clinically meaningful disease worsening. Now I'm pleased to present initial interim safety results from the dose level 3 cohorts with short-course prophylactic steroids from both suprachoroidal delivery studies. As background, this slide shows the steroid regimens used in our trials, as well as those used in other gene therapy programs for treatment of wet AMD. Such regimens are used with the goal of mitigating inflammation and in particular, intraocular inflammation or IOI. Given that the suprachoroidal space is compartmentalized, unlike the non-compartmentalized vitreous space, we chose to employ a much less burdensome prophylactic steroid regimen than what is being used for intravitreal-based gene therapy programs. For example, we use only ocular steroids, not systemic, and we employ a relatively short course. For example, 7 weeks topical steroid taper regimen.
Starting with the AAVIATE study, as observed in prior cohorts treated without prophylactic steroids, 314 with prophylactic steroids continues to be well tolerated. As intended, short-course prophylactic ocular steroids successfully mitigate the risk of inflammation. This side-by-side table of all dose level 3 cohorts compares without prophylaxis in the left column to with short course prophylaxis in cohort 6 overall in the next column, cohort 6 split by route of prophylaxis. That is either one-time periocular steroid or short-course topical steroid tapering. Of particular note, short-course prophylaxis achieves a dramatic reduction in intraocular inflammation, including in patients prophylaxed with topical steroids, where there were 0 cases of IOI. Switching to ALTITUDE, in which all subjects received prophylaxis via the topical route, we again see with this prophylaxis regimen, 0 cases of intraocular inflammation.
By looking at all visits of all patients in prophylaxis steroid cohorts in AAVIATE first, we see that the two lone subjects that had IOI, who were in the sub-Tenon's steroid prophylaxis arm, had traced to 1 plus or mild AC cells with no vitreous involvement. Importantly, both cases resolved by the next week. In ALTITUDE, cohorts four and five with topical steroid drops, there likewise were no cases of intraocular inflammation. In summary, initial safety results demonstrate successful reduction of IOI risk, including with short-course topical prophylaxis regimen, 0 cases of intraocular inflammation. With these encouraging initial findings, we look forward to presenting interim 6-month results in cohorts with prophylactic ocular steroids for ALTITUDE at AAO later this year and thereafter for AAVIATE at Hawaiian Eye.
We are pleased to have our 2 guest thought leaders join me and Ram for a fireside chat. We're pleased to have 2 thought leaders in the retina space to join us to discuss the 314 program, Dr. Peter Kaiser and Dr. Viral Shah. Peter is professor of Ophthalmology at the Cleveland Clinic, and Viral is an experienced vitreoretinal surgeon and partner at the University Retina and Macular Associates in Chicago. Welcome, Peter and Viral. To start, based on the data presented today, what are your clinical impressions on 314, administered via the in-office suprachoroidal route? Peter, let's start with you.
The data presented so far is very compelling. We know that there are several ways to deliver gene therapy, and the beauty of the suprachoroidal space is this is an in-office procedure, and that's very comparable, say, to an intravitreal delivery. We've seen cases of inflammation in patients who are when it's delivered intravitreally, and so that's one of the things we look at very closely when we talk about the suprachoroidal delivery. The data presented to date shows that the patients are doing very well in many cases without any prophylactic steroids and then in some cases, with prophylactic steroids. With that type of regimen, the amount of intraocular inflammation that I saw in both the AAVIATE and ALTITUDE data releases to date, have been very promising.
You flip it around and look at the efficacy, and we see a reduction in the treatment burden in patients with macular degeneration. In the patients with diabetic retinopathy, we're seeing either stable or improvements in the diabetic retinopathy severity scores, but more importantly, we're not seeing any worsening. To a diabetic patient, this is a very important finding. To date, the data has been very encouraging.
Thanks, Peter. Viral, what are your thoughts?
Yeah, no, I think, you know, Peter hit it on the head. I think, you know, for those of us that have a lot of experience with gene therapy, we're really looking to find that balance between efficacy and safety. I think the data you presented today is very reassuring from the standpoint of you were able to achieve really this kind of, this balance between the efficacy and safety with a short course of topical steroids. I think that's really what we're looking at here. I think Peter's point on delivery, ease of delivery, right? Suprachoroidal injections for again, for those of us that have been using this procedure know that it's easy to accomplish in the clinic, and I think that bodes well for our patients and access for those patients as well.
Turning back to you, Peter, you're certainly one of the top experts and a go-to expert when it comes to considering anything about drug development landscape and all the different programs that exist within the retina space. Could you compare for us what you see as the clinically important differences in the prophylactic steroid regimen that we use, as well as all of the different steroid regimens that are used across the different gene therapy programs?
Sure. You know, when you look at gene therapy, as I mentioned just a moment ago, there's sort of two ways to deliver it. One is in the operating room, and the second is in the office. In the operating room with the subretinal delivery, this is a immune-privileged space. The transfection rates are excellent, so there's very low risk of an immune response. There's a very low risk of inflammation, and to date, the data with subretinal delivery has been excellent. Certainly, that requires surgery, so to look at in-office delivery, either through intravitreal or suprachoroidal delivery, is appealing, right? This is something that would obviously be easier on the patients and as well as on the physicians.
You know, even though both are delivered in the office, there is slight differences between intravitreal and suprachoroidal. Intravitreal, of course, you have to worry about the gene product getting across the internal limiting membrane. You worry about the virus being a large molecule, getting across the internal limiting membrane. Because of that, there's been shown, at least in the past, some high rates of intraocular inflammation and having a considerable immune response. Because of that, the companies in this space are smart in that they're using steroids for an extended period of time to really mitigate the risk of intraocular inflammation, in some cases, even using a dexamethasone polymer implant. That would deliver a very high amount of steroid for anywhere from 4-6 months after injecting the dexamethasone implant.
That's probably the highest we can give in terms of local delivery, but in many cases, they're combining this also with oral steroids to really tamp down the inflammation you see with an intravitreal injection. Others are using just very long-term topical steroids, which is also a very reasonable way to tamp down the inflammation. In the case of 314, with the suprachoroidal delivery, you've tried both the no steroids, and even with no steroids, the patients actually did pretty well. There was some IOI, but it was all mild to moderate and resolved. Really, what's important about what was shown today is if you look at some of the steroid regimens in the later cohorts, you know, it wasn't like they had this long-term kind of intraocular inflammation over time.
You know, these were specific time points that very minimal amount of intraocular inflammation was seen. And to me, that's just sort of normal inflammation. You remember, this is a virus. Your body would wanna kind of get rid of the virus. The fact that there's minimal to no, in my opinion, inflammation with the steroid prophylaxis used in both AAVIATE and ALTITUDE, this is very encouraging.
That's great. Thanks, Peter. Viral, you mentioned earlier your actual direct experience with suprachoroidal, and specifically 314 suprachoroidal delivery. As an experienced investigator, you've had your hands on a lot of the different programs. How do Peter's takeaway comments resonate with your own actual experience?
Yeah, you know, to your point, we've had experiences with kind of multiple platforms. I think, you know, Peter Kaiser brings up an interesting point, which is we're trying not just therapeutically different approaches, but also with these steroid mitigations, different approaches, right? I think, again, you know, when I'm talking about access for patients and this ease of rolling this out in the real world, not only does the treatment and the mode of treatment have to be, you know, somewhat easy and approachable for us as clinicians, you know, what we do right after the treatment matters as well, right? I think, you know, having patients on topical for a shorter course of time is something, again, that kind of reduces the hurdles for these patients.
You know, from my standpoint, I think, you know, when you talk about the ease of giving this treatment, very short learning curve for this type of a procedure. You know, I think it works, you know, as far as theoretically, the space that we're injecting in makes a lot of sense. Look, the other thing about safety that I think about as a clinician and I talk to my patients about, specifically in these, in these trials, is, you know, when I'm not injecting intravitrally, and I'm injecting in the suprachoroidal space, I'm not worried about endophthalmitis and things that we might worry about with that intravitreal approach as well.
Great. Thanks, guys. I want to make sure not to monopolize the Q&A because we have the benefit of my colleague, Ram Palanki, on the line. Ram, I'm sure you have a couple questions for our experts.
Thanks, Steve. Peter, Viral, good to see you both. Transitioning from what Steve was speaking to about wet AMD and just what we presented as data today. As you've seen, Steve brought forward the safety data on DR. I have a couple of questions around the topic. As you both know, there's a wealth of evidence that points to treating early diabetic retinopathy with anti-VEGF therapy, which has shown to prevent progression of vision-threatening DR, that significantly reduces the risk of complications such as proliferative diabetic retinopathy, diabetic macular edema, and things like anterior segment glaucoma. Still, in the clinic today, you and your colleagues only treat less than 1% of patients. Can you both share your thoughts on why that's the case today, when there is overwhelming data to show that anti-VEGF therapy could prevent the progression of the disease?
Maybe we'll start with you, Peter.
Sure. You know, we all know, and retina specialists are fully aware that there are two FDA-approved products for the treatment of diabetic retinopathy in the absence of macular edema. As you correctly pointed out, very few of us use it. I would love to hear what Viral says, but I personally, in the absence of diabetic macular edema, very rarely would use serial anti-VEGF injections. There are certainly situations where we'll give maybe one or two around some laser treatment, et cetera. However, serial anti-VEGF injections in a patient with, say, non-proliferative disease, just is not something I do in my clinical practice, as you, as you talked about. The main reason is this: you know, these patients are working-age patients.
Imagine having to go to your doctor's office every 2 to 3 months to get an intravitreal injection. My practice is incredibly busy, as Viral's probably is also, you're going to wait a long time. You're going to have to probably take at least a half day off to get an injection in the eye. There's burnout. Patients don't want to do that for an extended period of time. Remember, they're getting these shots, but they're not really seeing a visual benefit, right? To them, they're just getting a shot in the eye for reasons that they don't really contemplate and understand. From a physician standpoint, I also know that if they decide they're not going to continue it, the retinopathy is going to go right back to where it was.
That, to me, is the biggest reason why I don't do it, because, you know, most will eventually fail and not come in for their injections, and then the retinopathy goes right back to where it was. Why, why bother starting from the in the first place? I think your number really reflects both patient dissatisfaction with the treatment as well as physician.
I think I'll add one more thing. You know, Peter really talks about the burden on the patient and these patients being working age. I think the burden also is on our clinics as well. I mean, I think as we see our volume start to grow, we see kind of expansion of the need for injections for patients with now dry AMD, right? We're trying to figure out where to put all these patients. On top of that, to bring, you know, NPDR patients in or diabetic retinopathy patients, as Peter mentioned, that may not be symptomatic at all, to bring them in for regular treatments. Even though we know it works and the data is strong that we can really stabilize this disease, we don't do it. I think, it's a combination of those two things, the burden on the patient and the burden on the system itself. So, you know, that's, I think, the two biggest hurdles that we see.
Thanks, Viral. I think that brings me to my next question. You guys have seen the data. We presented this this year, bringing forward a lot of the potential of 314 as a single in-office injection. To be able to stop the progression of early diabetic retinopathy in a majority of patients. I think Steve kind of pointed it out today again as part of his presentation, he also brought forward new safety data. That a single injection of 314 in these patients is well tolerated, especially with the topical steroid drops as a prophylaxis. We saw pretty much 0% of patients experiencing any type of IOI even as they come off of the tapering schedule in the protocol.
From your perspective, can you describe maybe the clinical value of something like 314 as a one-time treatment option that will help you prevent the progression of the disease in your patients on a long-term basis? I think it would be really good for our audience to hear from both of you, the perspective on 314 being a single injection and being able to manage these patients on a lifelong basis. Viral, let's start with you this time.
Whenever I think about questions like this, I think about what my actual conversation with a patient is going to be, right? In this scenario, what you're saying is, you know, "Mrs. Smith, I'm gonna be able to potentially change the trajectory of your disease with one treatment in the office," right? I think about that conversation that I have today, where I have to say, "Hey, look, I'm gonna give you a number of injections, and you're gonna come back often for these injections in order for me to achieve this goal."
Whereas potentially in the future with 314 and suprachoroidal, we may be able to do that with one treatment in the office. For me, it's from a value proposition standpoint, it makes a lot of sense as a clinician, but I think equally as a patient to say, "Well, I might be able to stabilize this and change the course of my own future and potential vision loss down the road." I think it makes a lot more sense, and it's an easier treatment to approach that way.
Peter?
I agree. You know, when I, when I said earlier, I don't use anti-VEGF for patients with diabetic retinopathy, that's simply because the patients aren't gonna do it and they're just not gonna come back. We know for a fact it works. You know, I'm not saying anti-VEGF doesn't work. In the diabetic retinopathy data that's been shown from ALTITUDE has been very good. You know, first of all, patients are not losing any diabetic retinopathy. They're not getting worse, and the majority of patients are actually getting better with a single treatment in office. That's the type of thing that patients can understand and then get on board with. To me, the diabetic retinopathy data is incredibly exciting. You know, we're seeing good safety.
We're not seeing intraocular inflammation. We're seeing exactly what I'd want in my patients with this disease, which is stabilization or improvement in their diabetic retinopathy. That's something that's very easy for them to understand. I would hope that in the future, your company will show us additional data that's just as important, which is the reduction in vision-threatening complications, reduction in progression to neovascularization, things that our patients really care about. To me, the data to date has been, you know, very promising.
Thanks, Peter. I think I'm gonna shift back to our subretinal program, as we try to close this session out. The main question here being, both of you are participating in our pivotal program today, for the treatment of wet macular degeneration. Recently, with our partner, AbbVie, we have announced the expansion of our program on a worldwide basis, and the intent there is to accelerate the access to 314 on a global basis as quickly as possible. What are your perspectives on the potential value of 314 being administered in the OR setting, for the treatment of wet AMD?
I would love to hear some perspectives from both of you on, you know, how many patients do you think are eligible in your patients, and how do you plan to use it once, potentially it gets approved in the next few years? Just to kind of provide a perspective on a treatment that you would have access to, where you'll have to take the patients into the operating room. Viral, I'll start with you again and then shift to Peter.
As you mentioned, we're part of the programs that are delivering subretinal for wet AMD, and we're excited. We have a number of patients in these programs receiving this treatment, and I can tell you the satisfaction is very high with these treatments, right? We have patients that were previously getting treated often, multiple intravitreal injections over the course of time, and who are, you know, now doing incredibly well and asking for this treatment in their fellow eye, right? I think that speaks volumes to how I think it'll roll out for me personally in reality, right? Which is, you know, to your first point, the procedure itself. We do vitrectomies all the time. We've been doing subretinal delivery of things like TPA for decades now.
The procedure itself is not incredibly difficult, and I think the majority of retina specialists will be able to perform that, so not a concern of mine. You know, it's a surgery, so we do kind of have to have that conversation with patients and talk about risk and things like that. Again, telling you know, from experience with patients that have signed up for this treatment, it's not an incredibly difficult hurdle by any means. You know, to your final kind of question, which is where do I see this in my practice? I think, you know, one, we're very excited for this to actually kind of hit us in reality and in the real world. Once it does become available, I think it's something that I certainly will have a conversation with the majority of my patients requiring frequent injections. Determine which patient this is right for moving forward.
... Peter?
I agree. You know, I don't want people to think that this is, this is gonna be used on 100% of patients with wet macular degeneration. It certainly won't. There's plenty of patients who do very good on anti-VEGF injections, and can extend to very long intervals. That's been shown in multiple clinical studies, even with the anti-VEGF drugs. What people fail to understand is, you know, there's about 15%-20% of patients, even in the clinical studies, who need very frequent injections, you know, either every month or every 6 weeks. These are patients who have, again, burnout. If you look at the real-world studies in those type of patients, their visual outcomes are actually very poor.
On average, we do great in wet AMD, but if you look at that 15%-20%, they're the anchor that pulls down the patients who have wet AMD. This is a type of treatment that is ideal for that type of patient, right? First of all, I agree with Viral. This is not a difficult procedure. This is something any retina specialist can easily do. We do the vitrectomy surgery weekly, if not more frequently even than that. A subretinal injection is something, you know, even my residents do when they're in the OR with me. This is not a difficult procedure at all. To allow you to have the dramatic reduction in injection burden that you've shown with the subretinal delivery, you know, this is very exciting.
I agree. This is. In the patients in our practice that are in the study, are very happy, I would anticipate that the results will hopefully mirror the Phase II results, we'll have another arrow in our quiver, so to speak, to treat patients with wet AMD. You know, it's that, it's that high-need patient population that this treatment is perfect for.
Great. Thank you, Peter. Viral, always a pleasure speaking to you both. I'm gonna shift my mic back to Steve to give some concluding comments here.
Great. Thanks, Peter. Thanks, Viral. really helpful insights from your extensive experience and context of all the programs on the data we've just presented. Now we discuss our RGX-202 program for treatment of Duchenne.
Thanks, Steve, and also to Ram, Peter, and Viral for their insights. Now we'll move on to discuss our pipeline of AAV therapeutics that are designed for the treatment of Duchenne, a rare disease caused by mutations in the DMD gene, which is responsible for making dystrophin, a protein of central importance for muscle cell structure and function. We have two updates today. First, we're reporting our first-ever safety results from initial patients dosed with RGX-202 from our AFFINITY DUCHENNE study. RGX-202 is our novel, highly differentiated treatment candidate, designed to deliver a transgene for novel microdystrophin that includes functional elements of the C-terminal or CT domain found in naturally occurring dystrophin. FDA has just supported the accelerated approval of the first microdystrophin gene therapy, providing clarity on regulatory pathway.
With this in mind, RGX-202 has several distinct potential advantages over alternative microdystrophin gene therapy candidates. With RGX-202 achieving the same levels of expression as other gene therapies, our C-terminal design has the potential to improve outcomes in boys with more biologically potent and stronger microdystrophin. Our AAV8 capsid design also provides an alternative for boys who may not be eligible for alternative capsids, which may be anywhere from 15% to 30% of boys. Finally, we make RGX-202 with a commercial-ready, high-quality process with high yields and purity to support the potential for rapid development and commercialization. Our second update today is about the expansion of our commitment to Duchenne. We're announcing a new AAV therapeutic program with exon-skipping science, which is a new approach to reawaken the DMD gene in boys to produce a near full-length dystrophin.
Depicted here on the right, the design of our new exon-skipping transgene is based on innovative vector engineering by REGENXBIO bioscientists. Our first candidate is designed for expression of three short antisense oligonucleotides targeting exon 53. Our results demonstrate the robustness, durability, and safety of exon 53 skipping with a high degree of skipping efficiency to support meaningful levels up to 50%, which is 10 to 50 times greater than what is observed with oligomers that are part of approved standard of care of near full-length dystrophin in large animal models. Our AAVs-based exon-skipping platform is an alternative for boys with certain mutations and may help them produce near full-length dystrophin. While further studies are needed to confirm, it's plausible that treatments can achieve highly effective production of near-term, full-length dystrophin may have advantages and improved outcomes compared to microdystrophin gene therapy because they're more similarly reproducing natural biology.
Investigational new drug application-enabling studies are being initiated, and we expect to submit an IND to the FDA in the first half of 2025 based on our exon 53 skipping candidate. All of our treatment candidates are intended as a potential one-time gene therapy for the treatment of Duchenne. While in principle, all types of DMD mutations are addressable by the microdystrophin platform. Clinical evidence from a number of sponsors of microdystrophin gene therapy trials suggest that certain mutations might be excluded. Therefore, having a microdystrophin and an exon-skipping platform is an approach that supports the potential to enable treatment for boys with many different DMD mutations.
This slide illustrates the inclusion criteria and endpoints for our AFFINITY Duchenne trial. I'm pleased to report that as of June 30th, 2023, we have 2 patients that have been dosed with RGX-202. It has been well tolerated with no drug-related serious adverse events. The time of post-administration follow-up ranges from 45 days to over 3 months. Patients enrolled in AFFINITY Duchenne are 4 and 10 years old. As we take a look at the additional features of the study design, I'd like to highlight that we recently joined other sponsors currently running AAV gene therapy trials to deliver microdystrophin in Duchenne to pre-competitively collaborate as part of a working group. This group is chaired by academic investigators and with engagement of experts with diverse backgrounds.
The working group has presented findings of shared safety events that predated the start of our AFFINITY DUCHENNE trial, including through a published New England Journal of Medicine correspondence. This correspondence describes serious adverse events whose timing is consistent with transgene expression, and laboratory findings indicate immune response against epitopes of dystrophin recognized as non-self by certain patients. In the cases of these SAEs reported by the working group, the age of the boys were between 7 and 9 years old, and the symptom onset was at the 24-42 days after dosing with gene therapy. We're encouraged that by reaching at least 45 days post-dosing, the two patients enrolled to date in AFFINITY DUCHENNE have follow-up that is past the window of symptom onset reported by the working group in these studies and by other sponsors.
The next interim update for AFFINITY DUCHENNE is expected to include additional patients, longer follow-up on safety from existing patients enrolled, and the first measures of microdystrophin expression from patient biopsies that are collected at three months. This interim update is planned to be presented at the World Muscle Society Congress in October. Olivier will now describe the features and benefits of our novel and differentiated RGX-202 candidate, as well as the new science behind our exon-skipping platform.
Thank you, Ken. My name is Olivier Danos. I'm the chief scientific officer. Today, I'd like to tell you about our two programs in gene therapy for Duchenne muscular dystrophy. First one is RGX-202 that Ken already told you about. I just want to get back on the principle of RGX-202, which is a microdystrophin gene therapy. Microdystrophin is a short version of dystrophin that has been designed to fit into AAV vectors. Basically, in doing that, scientists have been guided for many years by the nature of mutations found in an attenuated form of Duchenne muscular dystrophy, which is called Becker muscular dystrophy, where patients with very large deletions in the protein still have some function left, right? It is possible to build truncated dystrophins that are still active.
A lot of effort has been going through the design of microdystrophins that fit into AAV. We have designed our own brand, based on everything that was known in the field, again, more than 25 years of research, on how to reduce the size of dystrophin. I'll tell you a bit more about that, but before that, just define what's RGX-202. It's an AAV8 vector, which is an efficient vector for skeletal and heart muscle. We have a construct packaged in this vector that encodes our microdystrophin, and this is under the control of a muscle and cardiac, cell-specific promoter. Our microdystrophin is different from others, chiefly because it contains an added domain at the C-terminal.
That is, on the right-hand side of it, you see an added green box here called CT-146. CT-146 is a piece of the original protein that contains important function that we wanted to retain in the vector. Through special design, we've been able to do that. If I come back on this CT domain itself, here is the little square in green that you see at the tip of the protein, of the dystrophin. This domain is involved in recruiting and building a very complex set of proteins around dystrophin.
Dystrophin really acts as a hub in the muscle and cardiac cell, attracting other proteins that serves all kinds of physiological functions for the cell. The C-terminal domain can be left out of some microdystrophin construct, and that's what's been done before, because it's not absolutely required for essential function of dystrophin. We believe, and we've actually shown, that adding the C-terminal domain brings back more functionality in terms of getting together more proteins that are essential, and those proteins are indicated in this slide. Protein like dystrobrevin has an important role. Syntrophin is a group of protein that also attract other proteins there, and they are important for physiology. Neuronal nitric oxide synthase is also a very important protein in the physiology of muscle.
To give you an example, this is a short list of proteins that bind syntrophin. If you leave out the C-terminal domain in a microdystrophin, these proteins will not aggregate properly around dystrophin and causing less functionality. In a few words, we've assembled our RGX-202 microdystrophin. We've tested it in animal models, essentially in the MDX mouse. We've demonstrated evidence of enhanced expression and stability of this microdystrophin in MDX mouse. The RegeneX-dwo2 has been demonstrated to have widespread biodistribution, microdystrophin expression, restoration of the complex that are associated to the dystrophin that I was telling you about. Also, all this together leads to significant improvements in muscle pathology.
This set of preclinical studies has led us to an IND and then to the RGX-202, to the AFFINITY DUCHENNE trial that Ken told you about. This is now in the clinic, and let me now move to our second approach for restoring dystrophin, and this is through exon skipping, still using AAV vectors. Exon skipping, I need to go back on exon skipping briefly here. This is based on the fact that there's a group of large mutations, deletions, in the chromosome of many Duchenne patients, that delete, exclude, whole exons in the protein. This is illustrated here. All the blue boxes that you see are exons on the dystrophin gene.
When one of those is missing, the mRNA that will be transcribed from this gene will not be functional anymore, because information will be missing and in a way that cannot be repaired. It's been known for a while that in certain situations, if you're able to delete more material, exclude more exons from this non-functional mRNA, you can eventually restore a reading frame that will give you a proper translation of a protein. This is the principle behind exon skipping, and the way you can do that is by sending short antisense sequences that will modify the process of mRNA splicing and provoke this skipping of the exon.
As you see here on this drawing, when a deletion, when there is a deletion of exons 52, 51 into 53 is non-productive, this is a non-functional mRNA. If you exclude 53, you merge 51 into 54, which restores the open reading frame. Again, this has been demonstrated and it's also been developed into drugs which are available for patients. Four of them have been approved in the US Those drugs are small RNAs, small oligonucleotides that are being injected about bi-weekly to patients, and they lead to the production of some dystrophin. Unfortunately, the levels that are being made in patients are quite low. They're rarely above 5% of the original level of protein, and this obviously limits the efficacy.
Our approach is to basically do the same thing, send into the cell oligonucleotides that will skip exons on the dystrophin mRNA. The way we bring these oligonucleotides is using an AAV, and we do it permanently, once by having an AAV genome that brings oligonucleotides. In our case, we're targeting exon 53 also, and we send three different oligonucleotides that will exclude exon 53 from the mutated transcript and restore a functional one. This is the principle that we've now tested. We've built our vector, that we call scAAV3-EX53AS.
It, and we've tested that in a model where this is a murine model that contains a mutated human Duchenne gene that has a non-functional transcript, in which you can restore functionality by skipping exon 53. In this model, it's possible to test compounds or vectors, you know, that in our case, that will achieve that. What you see here is a summary of our data so far. On the left-hand panel, we show the level of skipping that we get into in the mutated mRNA, in those in the muscle cells and in the heart, and also the level of protein.
Remarkably, the level of skipping that we see are often close to 100%, and that results in levels of protein here at 3 months that are close to 50% of the normal levels. That is really in marked contrast with what is seen with oligonucleotides in the clinic, if we translate that into a patient, obviously we have a serious advantage. The middle panel shows you reexpression of dystrophin in the tissue at the proper location, in the muscle and the heart. The right hand panel shows you normalized skeletal muscle architecture in the treated animals. That's the data that we're now amplifying and developing for an IND.
What I've shown you is about exon 53, and if you look at what proportion of patients would benefit from a skipping of exon 53, you count about 10% of the population, which is there. Now if you develop other exon skipping AAVs that are able to skip exon 45 and exon 51, which is something we're actually currently doing, you can add another 20% of patients. If you want to add minor exons that can also be skipped, altogether, the population of the DMD patient that would be actionable with exon skipping goes close to 50%. In summary, we've shown you here that RGX-202 is a highly differentiated clinical candidate. It's designed to deliver a transgene with a.
That includes the functional element of the C-terminal domain. Our safety data to date, in the first cohort of AFFINITY DUCHENNE, indicates that our product is well tolerated. The additional interim data that will include longer-term and initial micro dystrophin expression results will be reported at the World Muscle Society Congress in October of this year. In addition, we have initiated a new program of AAV-mediated exon skipping, where we express antisense sequences with the potential to rescue high and sustained level of near full-length dystrophin in Duchenne patients with the relevant mutations. The new program targeting DMD exon 53 is now started, and our IND filing is now planned for the 1st half of 2025.
Thank you very much, and I will now transition to a fireside chat with Professor George Dickson of University of London. Happy to be joined here by George Dickson, who's a professor of molecular and cell biology at the Royal Holloway, University of London. George has spent most of his career studying neuromuscular diseases and muscle cell biology, including the first cloning of an intact dystrophin gene, and he also discovered the role of adhesion molecules in stem cell fusion. He identified utrophin, and also he interestingly did the first description of exon skipping in Duchenne muscular dystrophy. George is really a great expert, someone we like to talk to, and I'm particularly happy to have you with us today, George. How are you doing?
Great, Olivier. Thank you very much for the introduction, and I enjoyed very much listening to your presentation.
Okay, great. I have a few questions for you, and I'll start with micro dystrophin, which was the topic of most of what I talked about. And I'd like to get your perspective as someone who was behind one of the first designs of micro dystrophin on where does it come from, and what is important to have in a micro dystrophin? I would start with that.
you know, as you presented, Olivier, the micro dystrophins are truncated versions of the native protein. Most of them are approximately a third the size of the normal dystrophin protein, and there's an attempt to incorporate the main functional domains in that micro dystrophin. I think it's worth being aware that there are some important functional domains that are lacking in the earlier micro dystrophins, including this globular carboxy-terminal domain of dystrophin, which has now been incorporated into...
Yes.
We can expect the 202.
Not all dystrophins are equal, right? There are different designs, and I guess the reasons are not necessarily always scientific. It's also historical, right? What we see today is the result of what? 25 years of research on micro dystrophin, right?
Yeah, an understanding of the functional domains in a dystrophin molecule and the phenotypes of patients with Duchenne and with Becker muscular dystrophies. It's the outcome of that work and a lot of transgenic animal work studying these proteins as well.
What would you expect to see in patients treated with microdystrophin gene therapy? I mean, I guess that will depend on the microdystrophin itself, but in general, this is something that will be a not a total replacement of dystrophin, but good enough to bring back essential functions, right?
Well, that's correct, Olivier. Many of the microdystrophins have been shown to be very active, certainly in animal models of the disease, in reversing the pathology and the pathophysiology in these illnesses. I mean, of course, I think it would be fair to say that some of the earlier microdystrophins, in a surprising way, often show unexpectedly limited clinical outcomes, I would say, despite good expression levels and despite effectiveness in these animal models. Of course, the real question is: Why is this, and how does the microdystrophin that REGENXBIO has developed play into that situation. My view on this is that the area of microdystrophin may lack particular domains, and this globular carboxy-terminal domain dystrophin is one such, and it's involved in the formation of a complex molecular assemblies in muscle. We know this in heart, in skeletal muscle and blood vessels.
Mm-hmm.
These assemblies involve a diverse range of molecules: signaling molecules, ion channels, structural proteins.
Right.
I think one of the keys here is that RGX-202 is engineered to restore some of those key elements of the dystrophin carboxy-terminus.
Exactly.
That's the idea.
Yeah. Yeah. Hopefully this will restore those, or is known to restore those crucial binding sites for a number of the DAPs, the Dystrophin-associated proteins.
Okay. That's for microdystrophin. I also, I'd like now to maybe switch and get your ideas on exon skipping. Exon skipping is something that people have heard about because there are small oligonucleotide drugs that are actually on the market and taken by patients that trigger exon skipping and restore some level of dystrophin. Can you comment on what's available to patients today and maybe some of the limitations?
Yeah, I can do. There's really two questions in this area, Olivier, in a sense. One of them is to ask the question: What are the advantages of exon skipping compared with microdystrophin gene therapy?
Right.
That's one question. The other one is: What is the advantages of AAV-mediated exon skipping as opposed to oligonucleotide-mediated, exon skipping?
Mm-hmm.
Actually, there's something I felt was quite important to say here. It's a little bit forward-looking, I think you would probably agree that these two approaches aren't mutually exclusive. There's a future scenario somewhere out there where they could be used in tandem or in combination, perhaps even with a synergistic outcome.
Mm-hmm.
It's worth bearing that in mind. They're not wholly competitive. They may be additive or combinatorial therapies based there. At the moment, the current generation of oligonucleotide drugs that are developed mainly by Sarepta, but one or two other companies now coming through. For example, for exon 53, there's Vyondys, that's a Sarepta product, and eteplirsen. In reality, even at their maximum dose levels, they do only produce low levels of skipped dystrophin, something less than 5% normal. Of course, the clinical improvement is quite limited, if at all, really in certain patients. The other issue with those reagents, I think a quite important one actually, is that they must be delivered on a regular monthly basis or so by an IV administration.
These are complex drugs, and the outcomes are not so good, but they're still producing some effects, and therefore they're licensed for use, certainly in the US
In this context, how do you see an AAV-mediated exon skipping?
Yeah.
What should we be able to do for this to make a difference, basically?
Well, what are the advantages of an AAV-mediated exon skipping? Well, first of all, it would be single, hopefully a single IV treatment, like most of the AAV gene therapies, with long-term effectiveness. From the data that you've presented and some other data that is out there, certainly in the animal studies. The AAVX 151, 53 reagent that Regenx has developed, for example, is producing close to, I think, around about 90% RNA-
Yeah.
RNA skipping levels and maybe nearly 50% of the actual skipped dystrophin protein, with much improved muscle pathology and sustained effectiveness. This would be a great step forward, I think, in my, in my view. The AAV-mediated system looks to be much more effective than using certainly simple antisense oligonucleotide drugs for exon skipping.
Yeah. Yeah. That's actually exciting. The other point of view, obviously, is that we're making a dystrophin, which is much more complete, much larger than any micro dystrophin. You know, we can hope for it to be much more functional, right? I mean, we actually know it will be much more functional.
Well, I think that's true. The exon skipping, generally speaking, will allow much larger and presumably more functional dystrophin variants to be re-expressed. That's going to be, I would think, an advantage given the complexity of the dystrophin molecule. Yeah, I think that's certainly an advantage. I think one of the other areas that's not discussed so much, as you know, the antisense RNAs coming from the vector is believed to have the ability to diffuse laterally through the muscle fiber. Therefore, there's a thinking that with the AAV-mediated approach, not every muscle nucleus needs to be transduced.
Okay.
There will be a sort of bystander effect, where neighboring myonuclei will also have their dystrophin RNAs corrected.
The pharmacology here could be advantageous, right? It could be actually an interesting point for exon skipping, AAV-mediated exon skipping.
I think it could hopefully improve the dose effectiveness, the dose ranging, and so on, of the AAV vectors, maybe improve efficacy and make them safer to a certain extent. Those dependent phase and efficacy should be improved. Yeah, I think that's a really important issue there. Of course, there's always the prospect of combining the microdystrophin and the exon skipping in some form or another. It's just a complicated question, I understand that.
Yeah. Yeah.
Feasible, feasible option.
Right. Right. Okay.
There's always.
No, go ahead, please.
Well, there's also the issue of biodistribution and how that will be affected. You know, the whole point with the exon skipping strategy as opposed to microdystrophin, as you know, is that the therapeutic product will only be expressed or produced in tissues that are naturally producing dystrophin. Whereas.
Yes.
you know, an AAV-delivered gene can end up all over, in many tissues, and that needs to be carefully controlled.
Right.
Since it could produce some negative effects.
That's definitely the kind of work that we embark on doing in our, you know, IND-enabling studies. Controlling for, you know, potential toxicities or anything that could happen from the exon skipping device that we put in the cell. Anyway, I think, you know, for someone like you who's been involved with all kind of dystrophin things for I don't know how many decades, but since the beginning, basically since the discovery of the gene, must be terribly exciting to be here today and, you know, when a gene therapy is coming on the market. Obviously, this is not the end of it because there's a lot of room for doing much more around DMD. I, you know, I suppose that there is some level of excitement for someone like you. Yes?
Very, very exciting. I mean, it's exciting even to see the drugs that are being authorized at the moment. There's a lot of optimism that improvements will come along the lines that we've had described today, improved microdystrophins and improved approaches to exon skipping. That can really increase the therapeutic efficacy of the treatments that are currently being used in patients. I think there's a long way to go. I mean, it's exciting, but it's also interesting to hope that we can really make advances in the field now that we have these breakthrough medicines that are beginning to come to market, to be quite honest. Yeah.
Exactly. Well, George, thank you so much for taking the time to talk with us and, you know, like, you again, you're someone we always appreciate talking to, and I hope we'll talk some more very soon.
Yes.
Okay.
I love to be involved, Olivier. Thank you very much.
Okay, now I will hand it over to Curran to discuss our manufacturing capability.
Thank you, Olivier. I'm Curran Simpson, Chief Operating Officer at REGENXBIO. Today I'm pleased to present to you the manufacturing capabilities review for the company. REGENXBIO has built a new world-class gene therapy manufacturing facility located in our corporate headquarters in Rockville, Maryland. The facility ensures that we have full control of GMP manufacturing in an end-to-end supply chain that ensures seamless clinical and future commercial supply. Given the maximum 2,000 liter scale we've installed, the facility can supply up to 350,000 doses for the ABBV-RGX-314 program for wet AMD and diabetic retinopathy, and up to 1,600 doses for RGX-202, our Duchenne program, in addition to preserving capacity for other programs. The co-location with our process development and R&D teams allows for the potential to progress from clinical candidate to clinical supply in 12 months.
The foundation of REGENXBIO's NAVXpress platform is the long-term investment in process development and state-of-the-art analytical capability. Through the years, investment in cell line development, upstream, downstream process development, and other aspects of development have led to significant advances in both vector yield and purity. REGENXBIO uses a platform process which is highly similar across all of our programs. This enables to manage our supply chain in a robust manner while enhancing the speed of development with a plug-and-play approach for new programs. We are able to leverage our deep understanding of vector production for new programs, reducing the need for implementing significant changes during clinical development. At REGENXBIO, we have now successfully transferred all of our legacy programs from the previous adherent cell-based HYPERStack forum to a suspension-based bioreactor platform process. The NAVXpress process technology enables production at the appropriate scale to best serve the indication requirements.
We have recently demonstrated comparability and scalability at the 2,000 liter scale, which is highly desirable for products delivered systemically or for a broad patient population. In 2023, we have initiated production of our first process performance and qualification lots in the Rockville Manufacturing Innovation Center, which are the production lots that will be submitted as part of our future BLA applications and could become our first commercial production lots, if approved. As stated earlier, our investment in process development and scale-up has resulted in dramatic increases in vector yield and overall batch productivity, as depicted by the chart on the left. Through improvements in cell line productivity, yield optimization in the bioreactor, coupled with purification enhancement and scale-up to 2,000 liters, vector titers per batch have increased almost 800-fold since 2015.
In this case study, you can see how technology advances, such as improvements to the transfection process, purification, yield improvement, and scale increases, have dramatically increased the number of patients that can be treated with a single production batch. In addition to the productivity enhancements, improvements to the product profile and reduced levels of process and product impurities have resulted. Overall, we can now develop a commercial-ready process at the earliest stages of clinical development, reducing the need for future bridging studies and parallel development. In the last 2-3 years, increased focus by regulatory agencies has been applied to the ratio of full to empty capsids in the final drug product, particularly those administered at high doses systemically.
While there is no set regulatory requirement for percent full capsid, it is generally viewed that the percent full capsid should be above 50% for a particular drug product. As you can see from the graph, we have utilized the NAVXpress process to increase the percent full capsid above 50% in every program. 2, for new programs, we have eliminated the need to update the process and platform to reach acceptable results. We're able to do so without a dramatic reduction in purification yield via proprietary downstream methods, which we employ in the purification process. In summary, the NAVXpress process has been proven to be robust across programs, utilizes a highly similar process across programs, and has a strong history of consistent performance in a GMP setting.
We have dosed over 250 patients successfully with materials derived from the NAVXpress process platform. On average, we are dosing a new patient every day across our clinical programs. We utilize state-of-the-art analytical characterization to monitor and ensure consistent product quality. The most significant bottleneck in our industry is experienced, capable people.
It's not all brick and mortar. We've been very successful in creating a positive, healthy work culture, hiring experienced people, and retaining those people. With the key attributes of our manufacturing capability in mind, we built a team and a culture that supports our vision, our purpose, our mission, our core values of trust, accountability, perseverance, and innovation underpin who we are as a team. Integration of our NAVXpress process platform with state-of-the-art manufacturing capability and people, provides REGENXBIO with an industry-leading competitive advantage. From early-stage development to late-stage commercial supply and supply chain, we are poised to deliver on the Five by 2025 strategy that Ken outlined. Now, please watch the video of our team and process in action, and thank you for listening. That will be followed by Ken's closing comments. Thank you very much.
REGENXBIO is a cutting-edge gene therapy company focused on multiple indications that are in clinical development. All of this is supported by the NAVXpress process platform, which not only includes the process, but our in-house process development capability that are all contained within the Rockville site. One of the main goals of the NAVXpress process platform has been to consistently produce high-quality product and actually product profile. Product profile is the analytical view of a product to make sure it's consistent, every batch being the same, and patients receiving the same consistent product with each dose. The NAVXpress process platform has allowed us to go from an academic manufacturing capability to now an industrialized manufacturing capabilities, allows us now to potentially serve hundreds and thousands of patients, as opposed to tens or hundreds of patients.
It's really significant to make gene therapy manufacturing robust, predictable, and safe for patients. The Manufacturing Innovation Center encompasses the entire floor, so all the components of manufacturing, quality control, and our new fill finish line all reside in that facility. One of the most exciting things about the Manufacturing Innovation Center is the co-location with our corporate headquarters, our process development team, quality team, regulatory team. Having that all in one site is a real differentiator from other companies. Allows us to move quickly, move processes, and transfer processes into manufacturing seamlessly, and represents an end-to-end approach to our supply chain.
With the steps we've taken in building our process development team, building manufacturing, building our 2,000 liter capability and our fill finish site, we're in great position to potentially serve markets commercially, to serve patients globally, and to be at the forefront of gene therapy. I'm super proud of the team. You have a group of people at REGENXBIO that are committed to patients.
Thanks, Curran, for that great update and video of the capabilities of the REGENXBIO Manufacturing Innovation Center here in Rockville. Our facility is cutting-edge, focuses on product quality and purity, which supports accelerating the development of our AAV therapeutics. We want to thank all of you for joining our Virtual Investor Day today. We continue to perform at a high level as we execute on our mission of improving lives through the curative potential of gene therapy. I believe we have a clear and definable path to achieve our 5x 2025 vision and continue to lead what's possible in AAV therapeutics. Today, introduced some new clinical trial data from our retina programs using suprachoroidal delivery and our Duchenne microdystrophin product candidate. We also introduced a new program for the treatment of Duchenne that extends on our commitment to novel treatments for Duchenne with important scientific advances.
We also provided specific guidance about upcoming trial updates later this year on an interim basis, and I will again, just quickly summarize some of these updates that we shared today. For our AAVIATE and ALTITUDE trials, we reported that the mild to moderate intraocular inflammation previously observed with suprachoroidal delivery is mitigated with a short course of steroid eye drops. With a much less burdensome prophylactic steroid regimen than what's being used for other gene therapy programs, short course prophylaxis achieves a dramatic reduction in intraocular inflammation in patients enrolled in AAVIATE and ALTITUDE, including the fact that patients enrolled with topical steroids, there were no cases of intraocular inflammation reported. In addition, we now have two promising approaches for the treatment of Duchenne based on the replacement of a functional version of dystrophin.
RGX-202 is our novel microdystrophin candidate that expresses a truncated form of microdystrophin, but includes a C-terminus domain of a full-functioning dystrophin protein. We reported safety updates from the initial dosings in cohort 1 of the AFFINITY DUCHENNE study to support well-tolerated profile to date. We're confident that RGX-202 will address unmet needs for Duchenne boys. It is the only clinical candidate that expresses a functional microdystrophin with the C-terminal domain of full-length dystrophin, an essential part of dystrophin's function, structurally and biologically. Our RGX-202 program leverages the quality and purity of our NAVXpress manufacturing process. To expand our commitment to Duchenne with a new approach to reawaken the DMD gene in boys to produce near full-length dystrophin, today, we also announced a new program with exon-skipping science.
The design of the new exon-skipping transgene is based on innovative vector engineering by REGENXBIO scientists. It's based on the expression of 3 short oligonucleotide sequences focused on exon 53. Our results demonstrate the robustness, durability, and safety of the exon-skipping process and approach, with a high degree of exon-skipping efficiency to support meaningful levels of near full-length dystrophin in large animal models. We have plans for an investigational new drug application, enabling studies that are being initiated. We expect to submit an IND to the FDA in the first half of 2025 based on our exon 53 skipping candidate.
Finally, we also presented on the features and performance of our REGENXBIO Manufacturing Innovation Center and announced our plans for updates in the next 6 months that will include interim trial updates from AFFINITY DUCHENNE trial, including first measures of microdystrophin expression at World Muscle Society Congress in October, the ALTITUDE trial interim update for diabetic retinopathy at the American Academy of Ophthalmology in November, and the AAVIATE trial interim update for wet age-related macular degeneration at the Hawaiian Eye Conference in early January 2024. We're looking forward to the remainder of 2023 with a number of important updates on our research and clinical stage programs. We have an amazing team of scientists and engineers dedicated to expanding the understanding and applications of AAV vectors and applying these capabilities to innovate AAV therapeutics that have the potential to significantly impact patient lives.
I want to say thank you again to our experts who joined for our team today in a discussion, and will also participate in our question and answer session. With that, we'll now transition to the question and answer portion of the event. We'll take a minute to gather the questions and then begin. As a reminder, if you'd like to ask a question, please submit it via the Ask the Question tab on the right corner of the video player. If we're unable to get to your question during the event, we'll follow up with you separately.
Okay, good morning. To start our Q&A session, our first question is related to our wet AMD program. What is happening in the market, and how concerned are you about the impact of new products like faricimab on extending the interval of treatment for wet AMD patients?
Thanks, Shiva. Viral, would you mind if I put you on the spot to maybe contextualize some of these new products and how it might relate to what's in development here at REGENXBIO?
Yeah. No, absolutely. You know, I think you're referencing recent approval of faricimab and a potential approval for high-dose EYLEA. As a clinician, you know, these are exciting kind of milestones for us because they are steps in the right direction for our patients. I'll reference a slide that Ron presented earlier this morning, which is, you know, he showed that clinical trial data and real-world data don't often match up, and in fact, there's a gap between what we see in the real world and what we see in clinical trials. We've got lots of really good clinical trials with lots of really good data, but we know, Peter knows this, in reality, we see that gap. That gap exists because these treatments are still frequent injections.
You know, yes, faricimab is a step in the right direction in terms of durability, we still have to administer that as a frequent intravitreal injection. We know in the real world, there's lots of reasons why that may not be sustainable. I think, you know, what you're developing here with 314, we've got data looking at subretinal delivery 4 years out now, showing that these patients can have sustainable vision gains, 2 lines of vision gains, 4 years out, right? Whereas in the real world, we're seeing those same patients that are being treated with intravitreal injections are, in fact, losing all those gains we get in the first 2 years of intravitreal therapy. I think that the excitement is genuine if I...
You know, when we talk about sustainable, durable treatments, that are potentially given to a patient once, and we see those vision gains over the course of many years. Just to tack on to that, you know, when we talk about diabetic retinopathy, for example, we're not treating those patients. I think Peter and I mentioned that earlier, because these are patients that are seeing okay. They don't necessarily see the need for treatment, but we know that they're potentially on this downward spiral with their diabetic retinopathy. The trade-off is they have to come in frequently for these injections, and it's, again, just not sustainable for these patients. To be able to offer them a treatment, you know, 1 time in the office, potentially, and changing the course of their disease for the better, I think is gonna have real meaningful outcomes for these patients.
Thanks, Shiva. Looks like we had another question.
We do. We have a multilayered question for diabetic retinopathy. "Regular anti-VEGF injections are pretty underutilized in diabetic retinopathy. What sort of data would you need to see for a suprachoroidal gene therapy to meaningfully utilize this in practice? Do you need a substantial number of patients to achieve a two-step DRSS improvement?... Do all patients need to see stability or benefit?
That's a great question. I think Peter, maybe as a clinician and a clinical trialist, stepping off of what Viral was alluding to, can you frame out what kind of outcomes we want to see in DR and what the benefits are in the real world?
You know, to a patient with diabetes and diabetic retinopathy, the main thing that they're going to be concerned about is worsening of their disease. You know, over time, what we worry about and what we follow patients for is to make sure they don't worsen and develop vision-threatening complications. It's one of the reasons why once you're diagnosed with diabetes, you see us at least once a year, because we're following for things that you may not actually notice. You may have perfect vision. When you look at the data, 2-step improvement is something that historically has been used for registration, but the FDA requires a 2-step in either direction. You can either prevent a 2-step worsening or allow a 2-step improvement.
From a patient's standpoint, what they're more concerned about and understand is preventing that worsening. Sort of what Viral said about age-related macular degeneration, the reason we don't do this with anti-VEGF injections currently is, it works. You know, we could do it. It would prevent that worsening with anti-VEGF, but require very frequent injections. If you stop those injections, that's when patients oftentimes do very poorly. In contrast with 314, with this single in-office procedure, you'd be able to have that long-term maintenance of prevention of worsening without requiring all these injections. For patients, currently, we don't use it, but if this were available, we would use it actually quite frequently.
Thank you. Shiva, looks like we're gonna shift a little bit in our third question.
Yes. Our next question is a RGX-202 question. If it is so important, why have you been the only one to include the C-terminus?
George, can I introduce you to the Q&A here and talk about why are we the only ones doing the C-Terminal domain approach in microdystrophin gene therapy right now? Maybe a little context about the science and the history here. You're muted, George. George, still muted. Sorry. There you go.
Yeah, sorry, Ken. Yeah, some of these things are historical. The issue with the microdystrophin was always trying to develop a gene which would be compatible with the AAV gene delivery system, and some of the earlier designs, trying to incorporate C-terminal domain, the size was just above that limit for efficient packaging and efficient handling. We tried to do this for many years. I have to say that REGENXBIO have, in a sense, solved that problem. They reengineered the whole gene. They reduced the size to be compatible with the AAV vector system, and they improved production and purification methods make it a viable therapeutic clinical option. The reason is not that people wanted to include the C-terminal domain.
Again, the reason was that it was the lesser of two evils, as it were, to try and have a functional high titer vector as opposed to including the domain and having more titer and more functionality in terms of transduction. Really, that's a historical issue, which is great to see that, in that sense, REGENXBIO seem to have solved that problem, and they're now taking that product into clinical trial.
Thank you. What's next, Shiva?
Next question is on our exon skipping candidate. Can you elaborate on how the exon skipping candidate works without synthetic alterations to avoid degrading the dystrophin mRNA? Do the antisense mRNA, the 3 antisense mRNA, form a complex with each other?
Wow, Olivier. We're suddenly deep in the weeds on science here, which is good. People are understanding. Can you talk a bit to what's happening with the 3 ASO approach?
Yes. exon skipping works by basically masking very important sequences on the mRNA that allows for splicing factors to work and to, you know, normally include exon in the mRNA. by masking these factors, you can prevent these exons from being included and, you know, exclude them, right? Now, if you do this with... You can do this with one target and prevent the binding of one of these factors, or you can choose to try to be more efficient and use several targets, and that's what we've done.
We've actually made a great number of different constructs using different combination of different targets, and shown that some of them, you know, work very poorly, actually, and you get very low levels of exon skipping, whereas by adding, for instance, the three that we ended up picking up, we get very, very high levels. There is an empirical level of things there where, you know, you screen a large number of constructs, and you get a good one. Now, do they act together? We assume that they act together on the same molecule, although this needs to be maybe researched a bit more. They probably don't form complex between each other. They are independent complexes that binds on the mRNA.
Great. Thank you. What's next, Shiva?
Another exon skipping question. For the new exon skipping program, do you expect the full-length expression you're seeing pre-clinically to translate to the clinic? What benefit do you think this would have relative to the microdystrophin expression?
George, how good are the models here for assessing the exon skipping and its translatability, you think, into humans?
There's a number of issues. There's a number of issues there, Ken. The dystrophins or the microdystrophins, or this partly truncated dystrophins, the Becker dystrophins, they are biological activities based on functionality and level of expression. Exon skipping, in a sense, can only restore a dystrophin molecule as a function of the mutation patients have. In some cases, it will restore a virtual full length. In other cases, it will restore a slightly reduced dystrophin molecule. By and large, these are much bigger, more complete molecules than the microdystrophins per se. These are, in a sense, Becker-type dystrophins.
They won't produce a complete cure or a complete restoration of 100% dystrophin function, but they will have many more functional aspects than the microdystrophins, and therefore, will hopefully be more active and produce better clinical outcomes. I mean, the only other point I would add here is that with exon skipping, the outcome is dependent upon the native gene, and therefore, expression is restricted to those tissues only that normally express the dystrophin. That's unlike microdystrophins, which are being potentially distributed in an off-target way, perhaps to other tissues.
Olivier, we have a MDX mouse model here that has the specific mutation that we're focused on targeting. Is that right? The translatability of this model is compelling?
Yes. Yes, we're looking at our candidates in a model that expresses the human gene, right? This mouse has the whole dystrophin locus with a mutation that is amenable to exon skipping. It expresses a mutated human mRNA, and we fix the mRNA by exon skipping. We look at the real situation that we would be facing in patient cells. Complementary to that, we also have several models, cells from patients, where we can look at the efficiency of exon skipping. The two together give us a good idea of the efficiency and the translatability to the patients.
Thank you. Next?
Okay, next question, RGX-202 question: What's your expectation for dose level 1 versus dose level 2 in terms of microdystrophin expression? What are you looking for from 202 compared to what was seen with Sarepta? When could we get functional imaging data from 202?
Maybe I'll take this one. I think we've, you know, presented that we're at 1E14 GCs per kg dose with our cohort one data. I think we have Pfizer at that same dose level in pivotal phase, Sarepta's approved candidate is at a dose that is just slightly above that, accounting for, you know, differences perhaps in titering. We've said all along that at that dose level, expect to get the same level of expression of microdystrophin that others have observed. What we're looking for is more potency per molecule of microdystrophin expressed in humans, and that picks up on the second part of that question.
You know, we would expect to achieve similar levels of expression as where others are, but on a longer-term basis, taking into account MRI, NSAA, just general mobility function and long-term cardiac function, maybe not certainly at three months or six months, but I think we could start to see separation at a year or beyond a year in terms of the clinical functional outcomes. I think that's been represented very well in preclinical data we've presented, as well as the origin of work that George in his lab demonstrated in terms of the potential for separation of the C-terminus inclusion in a microdystrophin. You know, we'll expect to have data like that as we transition into 2024 with respect to first patients dosed in this trial currently. Next question.
Okay, Ken, it looks like we have another 314 question. Looks like the steroid regimen has removed IOI risk. Subject to data later this year, do you now have enough confidence to advance 314 suprachoroidal into pivotal trials? What sort of clinical evidence do you think is required to make the decision to advance?
... Steve, maybe I can direct this your way.
Sure. We're certainly excited about the results that we've seen, that we've presented this morning from not only interim data from ALTITUDE, but also AAVIATE. As usual, our goal is, first things first, see good safety and tolerability. As you mentioned, with topical steroid, short course taper steroids, we've seen no intraocular inflammation. We and AbbVie look forward to future data that we'll see. I think an important point is we already were seeing what we'd want to see, so really hitting our target. The opportunity to have longer-term follow-up is certainly valuable, and we look forward to presenting more data later this year.
Peter, Viral, maybe I can tease something out from you with your experience as a clinical trialist involved in a lot of programs. Are we getting close with what we're seeing from suprachoroidal? I mean, you know, you've both experienced that we've got subretinal in pivotals already. You know, what's your assessment of, you know, where this is from, you know, your practicing perspective?
I mean, from my perspective, the DRSS, the prevention of worsening, as I mentioned, both in the fireside chat as well as just a few seconds ago, to me, is clinically relevant as well as an approvable endpoint. The fact that none of the patients in the study to date have had a two-step or more worsening, they're basically staying the same or improving. That, to me, is enough clinical evidence to move this forward.
As Steve said, it's all about safety, and the use of the topical steroid regimen has shown to be very effective with really no IOI, no inflammation to be concerned about, no adverse events that would preclude moving this forward to phase 3. Of course, that from a clinical standpoint, I would like that because this is something our patients really, really want. There's nothing about the data so far that would, in my opinion, preclude it, of course. I'm not the one with the purse strings. I have to pay for that big study.
I'll just add one thing, you know. I think that this... You know, the data is definitely reassuring, and I think it bridges the gap that we have. You know, we, in the clinic today, talk to patients about the current treatments, and they routinely decline these intravitreal injections. From my standpoint, the way I look at this is: Do we have a treatment that solves the problem that we actually have today? Which is, you know, we need to be able to give these treatments to these patients in order to achieve these outcomes that we know we can achieve.
The second part of it is, you know, you mentioned that we're part of a number of different programs, and I think we've seen, and I talked about this earlier, we've seen steroids being given in different ways. For me, again, giving a short course of topicals is an approachable way of mitigating inflammation, in a way that we can actually get this treatment to patients, and make it relevant.
Thanks, both. Next question?
Okay, next question. Any additional color on episcleritis?
Steve, what's the answer?
Sure. I think right off the bat, I think an important point is nothing we've presented today is unanticipated, since we previously presented cases of transient episcleritis. Actually, what we've presented today is an actual decrease in cases of transient episcleritis. The cases that have been presented and that we've seen in the trials are mild, moderate, and really just picked up on slit lamp examination and resolved really quickly already by the next few visits after applying short course steroid eye drops. I think the other important point is that this is not intraocular inflammation, and intraocular inflammation is the location that's really most important to minimize. Likewise, to the prior question, we have the benefit of Peter and Viral, very experienced clinicians. What's your view on episcleritis versus IOI, for example, from your own clinical experience? Start with you, Peter.
You know, episcleritis, especially when you're doing a suprachoroidal injection, and we use this currently with the Clearside Biomedical XIPERE injection. You get some injection site reaction just by putting a needle into the suprachoroidal space. And the reason we don't see that with intravitreal is because it's a less, I'm not going to call it invasive, but there's more to a suprachoroidal injection than an intravitreal injection. We don't see episcleritis around an intravitreal injection site, but we see it in both the XIPERE as well as other programs that use the suprachoroidal needles. This is a injection site reaction. It's different from IOI. IOI is a very different bear altogether. This is an inflammatory response to something, and we see it in many of the gene therapy programs. The fact that it was ameliorated with topical steroids in this program makes me very confident that we can move this forward.
Thanks, Peter. Viral, anything to add?
I think I'll add that, you know, it all boils down to how much of a clinical concern these things are, right? I think episcleritis, to Peter's point, is something we expect as a localized injection site type of reaction. Steve, you mentioned it, these are transient cases, they resolve completely. Again, clinically, not a concern of mine. I am much more in tune with IOIs and just intraocular types of inflammation. Again, here we've seen with a short course of topicals, that risk is mitigated as well.
Great. More questions. Keep them coming.
Okay, Ken. Next question. On manufacturing, any color on how the shift to NAVXpress could influence the way either you or the FDA cuts the data from the pivotal studies? How will the expanded enrollment help address this possibility in terms of statistical powering?
Great, we have a manufacturing question. You know, we're in pivotal phase of development with a couple programs, certainly a large one for subretinal, to reviews here on FDA requirements and where we are.
I think we're in good shape. The commercial-ready process was developed actually a couple of years back for 314. In terms of exposures in the clinic, especially with the expansion, I would expect a positive review in the BLA. In terms of, Yeah, I don't see any concerns, especially when you look at the comparability data that's already been established.
Great. Glad we started up that facility. What's next?
Okay. We have a set of questions related to the Duchenne franchise. How do you guys see your DMD franchise evolving with the extended C-terminal and now exon skipping? How do these assets hedge your chances in the DMD versus competitors? Are your two Duchenne programs complementary, or is it a life cycle management strategy?
Olivier, what do you think? Are these complementary, or how... Maybe you and George can talk about...
Well-
some approaches.
I think that, so exon skipping, it only applies to about half of the patients with Duchenne. For the rest of the patients with, in which you find mutations that, you know, cannot be corrected with exon skipping, you need something like myodystrophy. Myodystrophy is on and will stay on. In the myodystrophy field, we hope is a better option because of the new structure that we have, the C-terminal, the higher functionality, probably the higher half-life, therefore, the, a different, you know, pharmacological properties as well. That's kind of our edge with the myodystrophy approach.
With exon skipping, exon skipping actually offers eventually a better option to patients that have the relevant mutations because it would be reexpressing dystrophin at physiological levels and dystrophin proteins that would be almost full length, almost very close to the wild-type ones, and therefore, most likely, much more functional than any myodystrophy, even the best myodystrophy that you can find and that we can think of designing. That's the way we're looking at it, and we're looking at the two approaches as complementary and as giving us the most chances and opportunities to give very good treatment options to patients.
If I can add something. Go ahead.
Oh, no, sorry, please. I was going to throw it over to you, George.
Yeah, if I can add something to what Olivier has said, is correct, that there are some groups of Duchenne patients for whom exon skipping will never be a solution. They will require some alternative approach to replace the gene. It may be the case that exon skipping, where it's appropriate, offers a better solution than the myodystrophy gene therapy. These are issues that will be resolved eventually in the clinical trial data. I think you agree, Olivier.
The only other thing I'd add is that the point I made in the fireside chat discussion, certainly experimentally, these approaches can be very complementary if used together. In other words, induced exon skipping can lead to more efficient gene therapy with a myodystrophy, that's been shown in a number of animal studies. Looking somewhat into the future, there is this prospect of a synergistic outcome in some of the patients with these two reagents, if an administration protocol can be designed where they can be given either simultaneously or consecutively.
Yeah, those are the kind of things that we'll be looking at at the experimental research level, and make decisions, of course, but there is a potential for synergies, so we'll be looking into that. For now, we're developing those two independently, for sure, and we have a platform, and if, you know, if elements of this platform are complementary, that's even better.
I think the overall point we take away is still a lot of unmet need for Duchenne boys, Duchenne patients, microdystrophins as a class, even with improvements of the C-terminus addition, are, you know, still showing signs of positive signals in the clinic, but we need more things as well. Exon skipping with high efficiency could be a real solution there. Really proud of the team and the collaboration we have also. Shiva, we're getting close on time, but I see a number of questions. Maybe we can try to get some answered in rapid-fire form.
Okay, yeah, we have a few more. Another Duchenne question: Should Sarepta show positive results later on this year, leading to expansion of the age of patients eligible for gene therapy, how would this influence the practical challenges of enrolling in your clinical trials in Duchenne?
Yeah, I mean, I can feel that. I think, we've seen a great regulatory precedent here with respect to the use of the accelerated approval pathway. While there's, you know, currently a narrowing of the label, I think that could change, and it'll obviously be a function of additional data that comes forward. I don't think that we view much of an impact in general.
I mean, the number of boys and families that are looking for different types of solutions, that the notion that some boys may not be eligible for treatment for a variety of reasons, including preexisting immunity and the fact that we're using a different vector, could contribute to not just our ability to enroll, but our ability to provide meaningful solutions clinically and commercially as we continue the development of RGX-202. I think, if anything, for me, the recent occurrences and of the milestone of the approval and what happens next are all gonna be wind behind the sails of what we're doing, both with microdystrophin C-terminus development and even with the exon skipping program.
Okay, next question is, can you clarify if AAO and Hawaiian Eye are 6-month updates, or will you have 12 months of outcomes follow-up?
Steve?
Sure. Sticking with the rapid fire, first comment is, these are ongoing studies, as you're all aware. There's always a dynamic aspect as far as what specifics, what availability we'll have in time for particular podium presentations. There's also the agreement with our global partner, AbbVie. We're available, as one example, ALTITUDE, in treatment of DOR. You've heard the excitement from Peter and Viral to the results we already see at six months. Availability and agreement on what we could present, certainly the ability to present one-year data and see if we can have confirmation of effect and durability, will be one of the key things that we hope to have available.
Thanks.
Okay, since we're out of time, we'll take this one last question. On suprachoroidal, should we be expecting updates on efficacy metrics as well as safety from the higher dose cohorts, including BCVA or DRSS, from their respective studies at the upcoming conferences we've guided to?
Yeah, I'd revert to the prior question and answer. It's dynamic. What we have available, we look forward to presenting. You know, I won't repeat what I said last question in terms of the excitement that we see. Certainly, if we can have one year available data, that would be great.
Thanks, Steve. Shiva, looks like we borrowed another five minutes from our colleagues here, I appreciate it, but I think we are going to wrap up at this point. As we said, we'll be able to follow up with people individually if there were any outstanding questions. Just want to say again, thank you to Peter, Viral, George, for being really generous with your time today and sharing your thoughts and providing perspectives. Always grateful for the partnership and objectivity that you bring. Thanks to our team, thanks to everyone for participating today. I think that's a wrap, unless I'm missing something?