REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Welcome to our REGENXBIO Virtual Investor Day event. I am 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 present 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 3 external experts who are leaders in the fields of Duchenne research and retinal disease. Professor Dickson and Dr. Kaiser and Sheth will enjoy, 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, Peter and Veeral to join us today. [Operator Instructions] 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 the 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 5 x 25 strategy is on track for advancing 5 AAV therapeutics from our internal pipeline and license 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. And 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 3 areas: retinal, neuromuscular and neurodegenerative diseases. Across all of our pipeline, we have over 12 active clinical trials. And in 2023, our team is executing on 2 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 3 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 onetime therapeutic option in major retinovascular 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. But 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 U.S. and AbbVie will pay REGENXBIO tiered royalties on net sales of RGX-314 products outside of the U.S. In addition, REGENXBIO will lead manufacturing for clinical development and U.S. commercial supply, and AbbVie will lead manufacturing outside of the U.S. Our pipeline in neuromuscular disease consists of a lead program called RGX-202. RGX-202 is our potential onetime 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. But 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. And lastly, I want to touch on our pipeline for neurodegenerative diseases. We have 3 treatments in development for severe inherited pediatric conditions called mucopolysaccharidosis and Batten disease. Our pipeline programs, RGX-121 and 111 are investigational onetime AAV therapeutics designed to treat 2 different forms of mucopolysaccharidosis, and 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. And according to sources, today the global market for MPS in Batten disease treatments is expected to grow to $3 billion by the end of this decade. But despite this treatment spending, over 70% of MPS in Batten disease patients combine suffered from neuronopathic forms of the disease that either remain untreatable, have standard of care alternatives with high risk of mortality or in one 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, REGENX management will present on the 314 eye care program, including some new safety data from our recent cohorts, will 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 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'm 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 onetime 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 onetime option to treat major retinal diseases. Recently, we announced the expansion of the largest Phase III 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 U.S. are surgically trained and perform approximately 400,000 vitrectomies annually. It is important to recognize, we are leveraging the same surgical technique to deliver 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 the diabetes. That 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 1/4 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 2 lines of vision within 5 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 4 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 patient 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. Hence, 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. Hence, we believe that there is a multibillion-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, yet 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 onetime treatment with 314 that can provide long-lasting treatment outcomes in wet AMD and DR are ideal. Now I turn this over to my friend, Dr. Stephen 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 AAVIATE 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 2 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 2 ongoing pivotal studies. This slide shows the design of these 2 pivotal studies, Atmosphere and Ascent, which will enroll in total, 1,200 patients. We are targeting completion of these trials in time for U.S. 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 2 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 onetime in-office 314 administration for the treatment of wet AMD. And as previously presented across all 3 dose levels, we see dramatic reduction in anti-VEGF injection burden ranging from 64% to 85% including a majority of patients actually needing no anti-VEGF injections. Now 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 onetime 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 and importantly, none of the 314 treated patients develop clinically meaningful disease worsening. And 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 noncompartmentalized vitreal 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. Additionally, 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, and then Cohort 6 split by route of prophylaxis. That is either onetime periocular steroid or short course topical steroid taper. Of particular note, short-course prophylaxis achieves a dramatic reduction in intraocular inflammation, including in patients prophylaxis with topical steroids where there were 0 cases of IOI. Switching to ALTITUDE in which all subjects receive 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 2 lone subjects that had IOI who were in the subtenon steroid prophylaxis arm had trace to 1-plus or mild AC cells with no vitreous involvement. And then importantly, both cases resolve by the next week. And in ALTITUDE, cohorts 4 and 5 with topical steroid drops, there were likewise were no cases of intraocular inflammation. So in summary, initial safety results demonstrate successful reduction of IOI risk, including with short course topical prophylaxis regimen, 0 cases of intraocular inflammation. And 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. Next, 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. Veeral Sheth. Peter is a Professor of Ophthalmology at the Cleveland Clinic, and Veeral is an experienced vitreoretinal surgeon and partner at the University Retina and Macula Associates in Chicago. So welcome, Peter and Veeral.

So 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.

So 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, but 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. And 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. And 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. Then you flip it around and look at the efficacy and we see a reduction in the treatment burden in patients with macular degeneration. And 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. And to a diabetic patient, this is a very important finding. So to date, the data has been very encouraging.

Thanks, Peter. Veeral, what are your thoughts?

Yes. No, I think Peter hit it on the head. I think we're -- 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. And 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 the short course of topical steroids. I think that's really what we're looking at here. And so 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.

And 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. When you look at gene therapy, as I mentioned just a moment ago, there are sort of 2 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 an 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. But certainly that requires surgery. And 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 as well as on the physicians. But even though both are delivered in the office, there is slight differences between intravitreal and suprachoroidal. So 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. And because of that, there's been shown, at least in the past, some high rates of intraocular inflammation and having a considerable immune response. And 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 dexamethasone polymer implant and that would deliver a very high amount of steroid for anywhere from 4 to 6 months after injecting the dexamethasone implant. So 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, they've -- you've tried both the -- no steroids. And even with no steroids, the patients actually did pretty well. There was some IOI, but it's all mild-to-moderate and resolved. But really what's important about what was shown today is if you look at some of the steroid regimens in the later cohorts, it wasn't like they had this long-term kind of intraocular inflammation over time, these were specific time points that very minimal amount of intraocular information was seen. And to me, that's not -- that's just sort of normal inflammation. You remember, this is a virus, your body would want to kind of get rid of the virus. But 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. And Veeral, you mentioned earlier your actual direct experience with suprachoroidal and specifically 314 suprachoroidal delivery and 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?

Yes. So to your point, we've had experiences with kind of multiple platforms. And I think Peter brings up an interesting point, which is we're trying not just therapeutically different approaches, but also with the steroid mitigations, different approaches, right? And so I think, again, 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 somewhat easy and approachable for us as clinicians, what we do right after the treatment matters as well, right? And so I think having patients on topical for a shorter course of time is something, again, that kind of reduces the hurdles for these patients. And so from my standpoint, I think when you talk about the ease of giving this treatment, very short learning curve for this type of a procedure. And I think it works as far as theoretically, the space that we're injecting in makes a lot of sense. And then look, the other thing about safety that I think about as a clinician and I talk to my patients about specifically in these trials is, when I'm not injecting intravitreally 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. So Ram, I'm sure you have a couple of questions for our experts.

Thanks, Steve. Peter, Veeral, 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. But 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. We all know and retina specialists are fully aware that there are 2 FDA-approved products for the treatment of diabetic retinopathy in the absence of macular edema. But as you correctly pointed out, very few of us use it. I would love to hear what Veeral 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 1 or 2 around some laser treatment, et cetera. However, serial anti-VEGF injections in a patient with say nonproliferative disease just is not something I do in my clinical practice, as you talked about. And the main reason is this. 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. And my practice is incredibly busy as Veeral's probably is also, and you're going to wait a long time. You got to probably take at least a half day off to get an injection in the eye. And so there's burnout, patients don't want to do that for an extended period of time. And 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 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. And that to me is the biggest reason why I don't do it because most will eventually fail and not come in for their injections and then the retinopathy goes right back to where it was. So why bother starting from the -- in the first place. So I think your number really reflects both patient dissatisfaction with the treatment as well as physicians.

Yes, I think I'll add one more thing. Peter really talks about the burden on the patient and these patients being working age. And I think the burden also is on our clinics as well. I mean I think as we see our volumes start to grow, we see kind of expansion of the need for injections for patients with now dry AMD, right? So we're trying to figure out where to put all these patients and then on top of that to bring 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. And I think it's a combination of those 2 things, the burden on the patient and the burden on the system itself. And so that's, I think, the 2 biggest hurdles that we see.

Thanks, Veeral. I think that brings me to my next question. You guys have seen the data we presented 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. And I think Steve kind of pointed that out today again as part of his presentation. And he also brought forward new safety data that is single injection of 314 in these patients is well tolerated, especially with the topical steroid drops as a prophylaxis. And we saw pretty much 0% of patients experiencing any type of IOI even as they come off of the tapering schedule in the protocol. So from your perspective, can you describe maybe the clinical value of something like 314 as a onetime 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 a perspective on 314 being a single injection and being able to manage these patients on a lifelong basis. Veeral, let's start with you this time.

Yes. So whenever I think about questions like this, I think about what my actual conversation with the patient is going to be, right? So in this scenario, what you're saying is, Mrs. Smith, I'm going to 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 going to give you a number of injections and you're going to 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 1 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?

Yes, I agree. When I said earlier, I don't use anti-VEGF for patients with diabetic retinopathy. That's simply because the patients aren't going to do it, and they're just not going to come back. We know for a fact it works. I'm not saying anti-VEGF doesn't work, in the diabetic retinopathy data that's been shown from ALTITUDE has been very good. First of all, patients are not losing any diabetic retinopathies, they're not getting worse, and the majority of patients are actually getting better with a single treatment in office. So that's the type of thing that patients can understand and then get on board with. So to me, the diabetic retinopathy data is incredibly exciting. We're seeing good safety. We're not seeing intraocular inflammation, and 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. And 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. And to me, the data to date has been very promising.

Thanks, Peter. I think I'm going to 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 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, that you would have access to where you'll have to take the patients into the operating room. Veeral, I'll start with you again and then shift to Peter.

Yes. So we're -- 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? So we have patients that were previously getting treated often, multiple intravitreal injections over the course of time, and who are now doing incredibly well and asking for this treatment and their fellow eye, right? So I think that speaks volumes to how I think it will roll out for me personally in reality, right, which is -- 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. So 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. It's a surgery. So we do kind of have to have that conversation with patients and talk about risk and things like that. But again, telling you from experience with patients that have signed up for this treatment, it's not an incredibly difficult hurdle by any means. And so to your final kind of question, which is where do I see this in my practice, I think, one, we're very excited for this to actually kind of hit us in reality and in the real world. And 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 and then determine which patient this is right for moving forward.

Peter?

Yes, I agree. I don't want people to think that this is going to be used in 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. And that's been shown in multiple clinical studies even with the anti-VEGF drugs. But the -- what people fail to understand is there's about 15% to 20% of patients even in the clinical studies who need very frequent injections either every month or every 6 weeks. These are patients who have, again, burnout. And 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% to 20%, they are the anchor that pulls down the patients who have wet AMD. And this is a type of treatment that is ideal for that type of patient, right? So first of all, I agree with Veeral. This is not a difficult procedure. This is something any retina specialist could easily do. We do the vitrectomy surgery weekly, if not more frequently even than that. And a subretinal injection is something even my residents do when they're in the OR with me. This is not a difficult procedure at all. And to allow you to have the dramatic reduction in injection burden that you've shown with the subretinal delivery, this is very exciting. So I agree. This is -- the patients in our practice that are in the study are very happy. And I would anticipate that the results will hopefully mirror the Phase II results and we'll have another arrow in our quiver, so to speak, to treat patients with wet AMD. It's that high need patient population that this treatment is perfect for.

Great. Thank you, Peter, Veeral, always a pleasure speaking to you both. I'm going to shift my mic back to Steve to give some concluding comments here.

Great. Thanks, Peter. Thanks, Veeral. Really helpful insights from your extensive experience and context of all the programs on the data we've just presented. And now we discuss our RGX-202 program for treatment of Duchenne.

Thanks, Steve and also to Ram, Peter and Veeral, 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 was responsible for making dystrophin, a protein of central importance for muscle cell structure and function. We have 2 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 AAVIATE 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, and 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 REGENX bioscientists. Our first candidate is designed for expression of 3 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 50x 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 AAV-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 onetime 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. And I'm pleased to report that as of June 30, 2023, we have 2 patients that have been dosed with RGX-202 and 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 and 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 to 42 days after dosing with gene therapy. So we're encouraged that by reaching at least 45 days post dosing, the 2 patients enrolled to date in AFFINITY DUCHENNE, a follow-up that has passed 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 3 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 and today, I'd like to tell you about our 2 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, sciences 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? So it is possible to build truncated dystrophins that are still active. And 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 will tell you a bit more about that. But before that, just define what's RGX-202. It's an AAVIATE vector, which is an efficient vector for skeletal and heart muscle. We have a construct package 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. CT146 is a piece of the original protein that contains important function that we wanted to retain in the vector. And through special design, we've been able to do that. If I come back on this CT domain itself, here is the [ low ] 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 functions -- 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. But we believe and we 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 proteins that also attracts other proteins there, and they are important for physiology. And neuronal nitric oxide synthase is also a very important protein in the physiology of muscle. So to give you an example, this is a short list of proteins that bind Syntrophin. So if you leave out the C terminal domain in a microdystrophin, these proteins will not aggregate properly around dystrophin and causing less functionality. So in a few words, we've assembled our RGX-202 microdystrophin. We've tested it in animal models, essentially in the mdx mouse and we've demonstrated evidence of enhanced expression and stability of this microdystrophin in mdx mouse. The RGX-202 has been demonstrated to have widespread biodistribution, microdystrophin expression, restoration of the complex that associated to traditional thing that I was telling you about. And also this -- all this together leads to significant improvements in muscle pathology. So this set of preclinical studies has led us to an IND and then to the RGX to the AFFINITY -- Duchenne AFFINITY trial that Ken told you about. So 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. So 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. And 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 nonfunctional mRNA, you can eventually restore a reading frame that will give you a proper translation of a protein. So 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 create this -- provoke this skipping of the exon. As you see here on this drawing when there is a deletion of exon 52, 51 into 53 is nonproductive, this is a nonfunctional mRNA. If you exclude 53, you then merge 51 into 54, which restores the open reading frame. So 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 U.S. Those drugs are small RNAs, small oligonucleotides that are being injected about biweekly to patient, and they lead to the production of some dystrophy. Unfortunately, the levels that are being made in patients are quite low. They are rarely above 5% of the original level of protein. And this obviously limits the efficacy. So our approach is to basically perform -- do the same thing that is send into the cell oligonucleotides that will skip exons on the dystrophin mRNA, but the way we bring this 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 3 different oligonucleotides that will exclude exon 53 from the mutated transcript and restore a functional one. So this is the principle that we've now tested. We've built our vector that we call scAAV3X53AS and 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 nonfunctional transcript in which you can restore functionality by skipping exon 53. So in this model, it's possible to test compounds or vectors in our case that will achieve that. So 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 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 mark contrast with what is seen with oligonucleotides in the clinic. And if we translate that into a patient, obviously, we have a serious advantage. The middle panel shows you re-expression of dystrophin in the tissue at the proper location in a muscle and heart, and the right-hand panel shows you normalized skeletal muscle architecture in the treated animals. So 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. But 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. And then if you want to add minor exons that can also be skipped altogether, the population of DMD patients that would be actionable with exon skipping goes close to 50%. So in summary, we've shown you here that RGX-202 is a highly differentiated clinical candidate. It's designed to deliver a transgene that includes the functional element of the C-terminal domain. Our safety data today is in the first cohort of AFFINITY DUCHENNE, indicates that our product is well tolerated. And the additional interim data that will include longer-term and initial microdystrophin 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 be skewed high and sustained level of full length dystrophin in DUCHENNE patients with relevant mutations. And the new program targeting DMD Exon 53, is now started, and our IND filing is now planned for the first half of 2025. Thank you very much. And I will now transition to a fireside chat with Professor George Dixon of University of London.

Happy to be joined here by George Dickson, who is the 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. So 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?

Thank you very much for the introduction, and I enjoyed very much listening to your presentation.

Okay. Great. So I have a few questions for you, and I'll start with microdystrophin, which was the topic of most of what I talked about. And -- what I'd like to get your perspective, as someone who was behind one of the first designs of microdystrophin, where does it come from? And what is important to have in a microdystrophin? I would start with that.

Well, as you presented, with microdystrophins are from catered versions of native protein. Most of them are approximately 1/3 the size of the normal dystrophin protein and there's an attempt to incorporate the main functional domains in that microdystrophin. But I think it's worth being aware that there are some important functional domains that are lacking in the earlier microdystrophins, including this globular [indiscernible] domain of dystrophy, which has now been incorporated into -- yes, so we can expect to [indiscernible].

So not all dystrophies are equal, right? There are different designs. And I guess the reasons are not necessarily always scientistic, it's also historical, right? So what we see today is the result of, what, 25 years of research on microdystrophin, right?

Yes, and an understanding of functional demands in the dystrophin molecule and phenotypes of patients with DUCHENNE and with Becker muscular dystrophy with the outcome of that work and a lot of transgenic animal work study in these proteins as well.

So 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 not a total replacement of dystrophin, but good enough to bring back essential functions, right?

Well, that's correct. And many of the microdystrophins have been showing 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, and as surprising way of then showing expectedly limited clinical outcomes, I would say, despite good expression levels and despite effectiveness in these animal models. And of course, the real question is why is this? And how does the microdystrophin that REGENX has developed -- play into that situation. My view on this is that earlier microdystrophin may align particular domains and this globular [indiscernible] domain dystrophin is when and such, and it's involved in the formation of complex molecular assemblies. In muscle we know this. In heart its down to muscle and blood vessels. And these assemblies involve diverse range of molecular -- signaling molecules, ion channels, structural proteins. So I think one of the keys here is that the RGX-202 is engineered to restore some of those key elements, both the dystrophin and [ hypothalamus ] .

Exactly, that's the idea. Yes.

Yes. And hopefully, this will restore the -- is knowing to restore this crucial binding sites for a number of the DAPs, the dystrophin-associated proteins.

Okay. So that's for microdystrophin and 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?

Yes. I can -- there's really 2 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. That's one question. And the other one is what is the advantages of a way remediated exon-skipping as opposed to nucleotide-mediated exon-skipping. Actually, there's something I thought was kind of important to say here, it's a little bit forward-looking, but I think you would probably agree that these 2 approaches aren't mutually exclusive. There's a future scenario somewhere out there where we could be used in tandem or in combination perhaps even with the synergistic outcomes. Its worth bearing that in mind. They're not wholly competitive. They may be additive or combinatorial therapies based there. But yes, so at the moment, the current generation of oligonucleotide drugs that are developed mainly by Sarepta, 1 or 2 other companies now coming through. For example, for Exon 53 there's is VYONDYS as the Sarepta product and [indiscernible]. But in reality, even at their maximum dose level, they do only produce low levels of skipped dystrophin, something less than 5% normal. And of course, the clinical improvement is quite limited if at all really in certain patients. And the other issue with those reagents, I think an quite important one actually is that they must be delivered on a regular monthly basis, or so by an IV administration. So these are complex drugs. The outcomes are not so good. But they're still producing some effects, and therefore, they're licensed for use in the U.S.

So in this context, how do you see an AAV-mediated exon-skipping, I mean 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. And from the data that you presented and some other data that is out there, certainly in the animal studies, the AAV exon 53 reagent that Janux has developed, for example, is producing close to, I think, around about 90% RNA skipping levels and maybe nearly [ 50% ] of the actual skip dystrophin protein with much improved [ gross ] pathology and sustained effectiveness. So 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 oligonucleotide drugs for exon-skipping.

Yes. Yes. So 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 and we can hope for it to be much more functional, right? I mean, you know it will be much more functional.

Well, I think that's true. The exon-skipping -- generally speaking, we've allowed much larger and presumably more functional dystrophin variance to be reexpressed. That's going to be, I would think, an advantage given the complexity of the dystrophin molecule. So yes, 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 RNA is coming from the vector. It's believed to have the ability to diffuse laterally through the muscle fiber and therefore, there's a thinking that with the AAV mediated approach, not every muscle nucleus needs to be [indiscernible] but there will be a sort of a bystander effect. Where neighboring [indiscernible] dystrophin RNA is corrected. And...

The pharmacology here could be advantageous, right? It could be actually an interesting point for exon-skipping [indiscernible] exon-skipping.

I think it could hopefully improve the dose effectiveness, the dose ranging and so on of the AAV vectors may be improved efficacy and make them safer to a certain extent, those dependent case of the efficacy should be improved. So yes, I think that's a really important issue there. And of course, there's always a prospect of combining the microdystrophin and the exon-skipping in some form or another, it's a complicated question. I understand that -- feasible option. Well, there's also the issue by distribution and how that would be affected. 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 an AAV delivered gene can end up over in many tissues and that needs to be carefully controlled [indiscernible].

Yes. And that's definitely the kind of work that we embark on doing in our IND enabling studies controlling for potential toxicities or anything that could happen from the exon skipping device that we put in the cell. Anyway, I think 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 when a gene therapy is coming in the market and obviously, this is not the end of it because there's a lot of room for doing much more around D&D. But I suppose that there is some level of excitement for someone like you, yes.

Very exciting. I mean it's exciting even to see the drugs that are being authorized at the moment, but 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. Both the treatments are currently being used in patients. I think there's a long way to go. I mean, that's -- it's exciting, but it's also interesting to hope that we can really make advances in the [indiscernible] now that we have these breakthrough medicines that are beginning to come to market to be quite [indiscernible] .

Exactly. Well, George, thank you so much for taking the time to talk with us. And like, again, you are someone, we always appreciate talking to and I hope we'll talk some more very soon...

Thank you very much.

Okay. And so 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. And 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 have installed, the facility can supply up to 350,000 doses for the AbbVie 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 hyperstat 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 product 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 in parallel development. In the last 2 to 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. And two, 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 and 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 5x25 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. [Presentation]

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 5x25 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 2 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 the C terminus domain of a full functioning dystrophin protein. We reported safety updates from the initial dosing 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 and 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. And our RGX-202 program leverages the quality and purity of our NAVXpress manufacturing process. But 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 and 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, and 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 Association of Ophthalmology in November and the AVA 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 who will also participate in our question-and-answer session.

And 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. [Operator Instructions]

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's on extending the interval of treatment for what AMD patients?

Thanks, Shiva. Veeral, 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.