Okay. I have got the thumbs up from the back, so we are ready to go. This is a really special day. I have been thrilled to be working in something new, which 11 years ago started out on a program at UPenn, starting with RGX-314, and here we are in the vicinity of top-line data. I am really thrilled that today is more or less an exposé of the program, rethinking where we are, thinking about the commercial opportunity, looking at the clinical data, and the unmet need. We are just thrilled to have you all join us today. Just a note that I will be making forward-looking statements today, as well as some of the panelists. I will not read this entire slide to you, so there is that.
Those of you that are maybe a little less familiar with REGENXBIO, this is a really transformational, not year, but even quarter in terms of upcoming events. We have been at this for roughly 15 years. Started out in the first five years out-licensing our technology primarily. Then in the last 10 years, beginning internal development of the program, some of which you will see today. We have over 20 licensees developing in the field. I use the example of Zolgensma as one of the success stories from the NAV technology in terms of showing what gene therapy can deliver. In particular, today, we will talk a little bit about the sura-vec program, which has partnered with AbbVie in a broad spectrum of retinal disease areas.
In particular today, we will talk about the wet AMD program, which is delivered subretinally, where we expect to show top-line results in Q4 of this year. We have been able to show over the last few months, long-term data supporting that top-line data release that will come soon. Not too far behind it, we have excitement around the rare disease programs with our Duchenne program in which we are anticipating a pre-BLA meeting by the end of this year and then filing a BLA for that program in Q1 of next year. We are really turning the corner in terms of setting up 2027 to be a year where we move substantially towards commercialization. Because I came out of operations, I always get to throw a manufacturing slide in, and this one will be no different.
One of the unique features of us as a gene therapy company is our in-house manufacturing, and some of our panelists have been gracious enough to come visit and see this in action. We have the capability in the Rockville plant to produce close to 350,000 doses per year of sura-vec. So a substantial capacity on ocular, and then in the rare disease for Duchenne, which is a very high vector requirement, up to 2,500 doses per year. The facility was inspected last year as part of our RGX-121 program, and it is really rare for a new facility to go through an inspection with no observations. We are pointing that forward to sura-vec and to the Duchenne program as something that we feel really strong. Being positioned for commercial readiness on the manufacturing side is really critical.
Being able to make vector, which is highly purified, is also a key tenet of that. As well, being able to produce product at a low cost of goods. I think another asset of us as an organization is, as I mentioned, our key partnerships. Today you'll hear about our partnership with AbbVie, and then also in rare disease, our partnership with NS Pharma. We've developed a strong alliance management capability and the ability to manage a program with a large partner like AbbVie, we think in a way that provides robustness to our program and the potential to develop commercially in a very successful way. Today's highlight, I won't go through our entire pipeline, but certainly the highlight today and the focus of the conversation will be around our subretinal wet AMD program.
We are excited, as I mentioned, to bring top-line data this quarter, for both pivotal programs. They happen to enroll and land roughly on top of each other so we can announce the results of both programs simultaneously in what's anticipated to be a joint release with AbbVie. That will point us towards regulatory submission in 2027. As a reminder, AbbVie has ownership of the IND and will actually be doing the BLA filing process. Again, going back to the early development, I remembered the early proof of concept studies that were done in Jim Wilson's lab. The design of the program was intentional to support a design with the potential to serve a spectrum of wet AMD patients.
So an anti-VEGF fab as the gene of interest, AAV8, which is well understood as a vector in retina that has a strong safety profile, and a subretinal route of administration. These were design elements that were built into the program from the beginning and haven't really changed at all during the course of development. The biological mechanism is well understood. I think the key here was could we produce durable protein expression by going through the subretinal route? I think our recent data, five-year data, that you'll see later in more depth, shows that the necessary durability is present and a key element of the value proposition for patients. I think the other piece of this is targeted delivery.
You're in an immune privileged section of the eye at delivery, and therefore, we feel the safety database that we've built over time in this program is exceptional and comprehensive. The program moved from— There was a significant period of time at the beginning of the program on dose escalation. I believe one of the things that really strikes me on this program is the careful and methodical method at which we selected the doses that went into the pivotal study. In 2021, as we started the program, we signed the collaboration agreement with AbbVie. Very quickly, AbbVie said, "Well, U.S. only isn't going to work for us. We want this to be a global program." We began expanding the programs dramatically to not only enroll patients in the U.S. but to expand into Europe as well to support our planned global submissions.
Around that time as well, we began building our case for bilateral evidence. I think the number you will see later is roughly 50% of patients that have wet AMD also have that in fellow eye. One of the things that really differentiates, we think, our program is the potential to be able to dose the fellow eye for these patients. Some of our patients, as you will see later, have come in readily to those that are met the inclusion criteria readily come in for fellow eye treatment. The enrollment for the study completed in 2025, and we are at near or at the point of last patient last visit, and that will lead us into the top line results that we expect to show later in the quarter.
One of the things that you have seen recently as well for both our subretinal indication and also recently in diabetic retinopathy is an update on long-term durability and in particular for subretinal, again, reported five-year data, which is exceptional. So we are well positioned, we believe, to transform wet AMD care. We think we have the right treatment paradigm, a one-time administration of a gene therapy. We think there is a significant unmet need out there for patients. We will talk about that today in terms of how our development data supports the commercial thesis that we are bringing forward. We think the design of the program in terms of durability matched with safety and efficacy. All three pillars will come together nicely in the designs of our studies and what we will show versus appropriate comparators. Then the evidence that we will be able to bring to regulatory agencies.
We have had a great relationship recently with FDA in several meetings around this program, making sure that what we expect to submit with the upcoming BLA submission is what FDA is expecting. So alignment with regulatory authorities has been a primary motivation here in the last year, and we feel that we are in great shape with the agency. Then, as you will hear a little bit more about today, and a lot of the theories you will hear now about gene therapy is we know it works, but is there a market for it? Are patients interested in this new therapy? Is there a commercially feasible methodology that is available to us? We will talk in depth today about how we see that for sura-vec and how confident we are that that is an opportunity, a significant opportunity, to move this program forward.
Questions that we will try to answer today, and you are welcome later in the mission today to bring your own up. Why does wet AMD need a new treatment paradigm? Why is sura-vec uniquely positioned to address unmet need? How broad is the potential commercial opportunity for sura-vec? What is it in the clinical profile that gives us confidence? What will drive commercial adoption and global success or access? So these are elements that in the presentation we are trying to address as we now hopefully turn the page to top-line data and then the value proposition post that. We have a really strong panel of experts that we brought with us, many of which, or all of which have been part of our program over the years. Absolutely would not be standing here without this team and others beyond them that have been supporters of us.
We have Gaurav Shah, Dr. Gaurav Shah attending today, Dr. Lejla Vajzovic. Thank you for being here. Dr. Arshad Khanani, Dr. Rahul Khurana, and Dr. Ramanath Bhandari. Thank you for being here. From our agenda, you'll see that several of them will be giving presentations or in a Q&A with Ram Palanki, again, talking about the commercial prospects for the program. With that, I'll bring Lejla up to start us off.
Thank you, Curran. That was fantastic. Thank you so much. As mentioned, I'm Lejla Vajzovic. I'm a retina specialist practicing at Duke University, and it's been a true pleasure to be part of all these gene therapy programs, including sura-vec program. I am a retina surgeon, so I routinely perform surgeries, not only adults, but pediatric patients as well. I'd love to just start by all of us know that today's treatment paradigm for wet AMD has definitely changed and will hopefully change in the future as well. We know that as we had diagnosed patients in the past with wet AMD, we knew those patients will lead to central visual acuity loss. With the invent of anti-VEGF, we all were very excited to provide patients with therapy that would help them preserve that vision.
I can tell you, as I meet my brand new patient diagnosed with wet AMD, I will tell them, we very much are going to be friends. We're going to be friends for life and very frequently visit at friends for certain. I hope that I will shape with you a little bit of a paradigm that potentially having a treatment that would, yes, maintain that friendship, but really allow them to spend more time outside my office. What are we talking about when we talk about AMD in general? We know that it's a very large global health challenge that we have. 200 million patients worldwide have diagnosis of AMD, and we know it's the number one cause of severe vision loss in patients greater than 60 years of age.
We know that these numbers are only going to increase because we are projecting 47% growth over the next several years. By 2040, we anticipate 288 million patients diagnosed with AMD. Focusing on wet AMD patient population, particularly in the lower, we know that 20 million worldwide are diagnosed with dry AMD. We know based on those visual acuity losses, primarily patients with wet AMD are contributing to that, 90% of that. We know that those patients, unfortunately, about 60%, 59% to be exact, will very much lose 10 or greater letters on visual acuity. Clearly a large treatment burden for certain. As I see that patient in my clinic, I know every single retina specialist in this room and outside will ask themselves three very critical questions. Disease activity being one.
We know that the disease is very heterogeneous, variable, and when we diagnose the patients, we're trying to understand what category this patient may fall into. We want to see that anti-VEGF response, and we want to see that they're responding well. But that response is guiding how frequently are we going to follow that patient and potentially re-treat them. The treatment adherence is our biggest problem. Really the biggest challenge that we face is while we want to provide the best outcomes for our patients, I can tell you the number one question I get from my patients, "Doc, when is my next injection? Can we stretch that out at all?" The problem is here. I think this is a really nice illustration. If you take 775,000 patients diagnosed with wet AMD in the U.S., and you plot them on this diagram.
While it's not a perfectly bell-shaped curve, we very much, I think, illustrate the point that patients will fall into various category in terms of their disease activity. Those who are going to be needing less than eight-week interval injection or greater than eight-week. If we talk about low disease activity into moderate disease activity, those are those patients that are needing fewer than every eight-week injection, so greater than eight-week interval stretched out. Those who need more frequently than eight-week interval are going to be those highest disease activity, those really that we very much need help with in highest unmet need. That's about 40% of those patients diagnosed in the U.S.
Well, when we look at the left side of that graph, you'll notice very much that treatment-naive patients will clearly, as we diagnose them, they're going to declare themselves in which category they're going to fall. As we look on the other side of the diagram, you'll notice the bilateral disease. 50% of wet AMD patients will have bilateral disease and talk about treatment burden for those patients. Clearly, we have unmet need among high disease activity, bilateral disease, most certainly. Why is this important? Well, we do very much know that while when I diagnose that patient very first visit in my office, they're all very much going to be adherent to their treatment initially.
But as we look at year one and stretch out to year four, you'll notice in year one alone, about 56% of patients will be on that on-label treatment and really treating their disease activity. 14% illustrated here in the light blue will be a little bit of underdosed, higher frequency, or stretching out those visits further, and about 30% will be lost to follow up. So in first year alone, we're losing 30% of patients. Year three, that translates to about 50% of patients are lost to follow-up. A year beyond that, year seven's almost three-quarters, so 75%. But I also want to point out year nine. Yes, high loss to follow-up, but only 6%, so only 6% of patients are continuing on that on-label treatment dosing. How does this translate to outcomes?
Well, I think this graph will nicely help us understand that a little bit from the pool data from clinical trials. Now we know when we give intravitreal injection with anti-VEGF, we are creating really a bolus treatment, and we know we immediately get a very good drying effect of the retina. As we follow the patient, the fluid recurs and then goes away as we give the bolus injections. So we always have asked ourself, what is this challenge of recurrent fluid appearance and disappearance, this swinging, so to speak, effect? What kind of outcomes does that have in terms of visual acuity and long-term outcome for our patients? Well, from pooled clinical trial data, we've put patients into four categories, four quartiles here, based on that fluid fluctuations.
The quartile one is going to be your very dry patients that do not have much fluctuations, and your quartile four is going to be your really high fluctuation, higher change in that fluid, very much. So quartile four is the one we want to emphasize here and focus on. Why? Because in that quartile particularly, we can see that there are poor visual acuity outcomes, close to 10 letter loss in that category, increased subretinal fibrosis risk, which also leads to poor visual acuity outcomes, and increased risk of geographic atrophy, most certainly. So all of those very much tell us that fluid recurrence, the swinging, do matter, and they do lead to poor visual outcomes in the long term.
And when we look at the real-world data in terms of visual acuity alone, while we know that in clinical trials we get really amazing outcomes with recurrent injections, when we see these patients in the real world, yes, the first year we'll have three letter gains on average, year two less, and then as we follow the patient further, unfortunately, we have decline of that visual acuity and really contributing to almost eight letter loss from initial treatment gains to the really follow-up in year six. So outcomes, yet again, illustrated that they are poor in the real world. And yes, we are super excited to have second-generation therapies. I think their durability is definitely there. But you'll see that in clinical trial, that durability was 45% and 77% in terms of 16-week interval and greater.
But when you translate that to real world, it's no longer 16, it's actually 13-week interval that we're comparing, have the data for. And you'll notice those percentages shrink to 16% across. When you ask a retina specialist, what is really that we are excited about? Well, we are excited potentially having a solution for treatment burden that we have currently among these patients. And when the PAT survey, the American Society of Retina Specialists survey results come out year- after- year, and the latest one being here, you'll notice that gene therapy is the answer. 50% of us voted for that as the number one excitement thing that we are there out for. And then internationally, we see very much that percent very replicated, 44% too.
Now, we talked about these bolus injections and swings and potentially the outcomes we see in terms of visual acuity, subretinal fibrosis, and geographic atrophy. What if we had a therapy that we deliver and then maintains that steady supply of protein and treatment all across the board? We would hope that what we see in visual acuity gains in the clinical trial world, such as one illustrated below, that now no longer in the real world that dips down to below the entrance visual acuities in clinical trials, but is hopefully maintained in terms of duration, but also very much for that patient in the real-world setting. This is really the paradigm we're talking about, providing, so to speak, a steady production of protein to help us really maintain that disease control. sura-vec therapy has been very much differentiated, the program itself, from other programs.
I do stand here with having experience really in all of these programs. I will say what really excites me about sura-vec, we have amazing data that is long data in terms of follow-up. We're talking about one-time delivery in the OR. We're talking about no steroid prophylaxis for those patients that receive this therapy. I think that's a huge differentiator here. We're talking about over 13,000 patients that have been treated across two study programs in pivotals, and we are talking about comparing it to standard of care, ranibizumab versus aflibercept, what we're routinely using clinic. As I mentioned, we very much have followed these patients now long term and have outcomes in the long-term data that's going to be shared with you shortly. I do want to point out one very important differentiated factor for sura-vec and design of the clinical trials.
As we saw the patients, enrolled patients in sura-vec programs, we provided anti-VEGF as a treatment entrance, so to speak, for the clinical trial. If the patient had a response at week one, so at week one alone, had a response to anti-VEGF, they were potentially enrolled in trial. If you compare to other programs, that assessment happens at week four. That is much later in the disease course. Yes, some patients will, at that time point, already have fluid recurrence and potentially will not be further enrolled in a trial based on that. So very important factor to differentiate that if you're enrolling patients after week one, you are not only enrolling those that may have recurrence of the fluid a little later, but also those who responded.
Really highlighting that we included in this clinical trial not only high disease activity patients, but low disease activity patients as well. That help really mimic and help me understand how I may apply this in the real world in the future. Bringing it back to this bell-shaped curve, which I think is a wonderful illustration of really where our patients may fall on this disease activity trajectory. But I want to point out while we have emphasized that patients with high disease activity would very much benefit from longer duration and potentially one-time treatment approach, but I will point out that actually any patient from low disease, moderate to high disease, and even more so bilateral disease patients. I hope I shared with you really the magnitude of the treatment burden that we currently have in the real world.
I hope I shared with you some of the outcomes we see in the real world in terms of visual acuity and long-term outcomes. I hope that you have seen a little bit of insight in clinical trial designs and how sura-vec may position us to help address this treatment burden for the patients. I am going to pass it out to my colleague and friend, Gaurav Shah, who is going to give us a little bit of an overview of sura-vec and surgical aspect to it. Thank you so much.
It is always a tough act to follow Lejla, and I have done that for many careers. It has never worked, so hopefully this will be better this time. First of all, to the team and for all of you, thanks for attending on a beautiful day in New York. I am going to just tell you the three hats that, I wear multiple hats, but the three hats that I wear is one is I lead the organization for the American Society of Retina Specialists. That is hat number one. Number two, I am part of West Coast Retina Medical Group, which is a private practice group. The third hat is leading the Sutter Health systems for the Chair of Ophthalmology. All of these organizations are really one thing, providing the best care for our patients and access to our patients in terms of care.
As I go through that presentation, I think that will be evident of what we are talking about. As Lejla nicely mentioned, I started this journey, I do not know, maybe I feel old now, in 1997, when we were just doing lasers and intravitreal injections were coming on. A lot has changed in retina. A lot of things have changed. Again, we have to adapt to new technologies and new therapies. Currently, we treat, we observe, we treat and extend, we adjust, we re-treat. There is a lot of guesswork there. What Lejla really talked about is this sort of therapeutic approach as a one-time gene therapy. It gives durability to patients, and it also gives durability to doctors. It is really two different approaches, both for patients and doctors.
It is a way for gene therapy to either be given by the subretinal or the intravitreal route. Lejla nicely showed this, and I will show again. Some of the advantage that I see of getting the product to where it is needed, I think that is, as you correctly said, targeted therapy. What about subretinal gene therapy? Well, it is well-tolerated. We know from the data we have from the safety, because anytime you have any new product, we are looking for safety, is it efficacious, and can we do it? Those are the three questions I ask irrespective of whatever product I am going to use. When we look at subretinal therapy of this approach, one of the things is that there is no steroid burden here. It is not an inflammatory component as with intravitreal therapy.
Very important, this was mentioned by Steve, but this was also mentioned by Lejla, is the bilateral nature of the disease. Our patients have two eyes. They are going to have disease in both of their eyes. That is critical to remember, that bilateral disease is prevalent and prominent in these patients. When we lose patients to follow-up, we miss the bilateral disease. That is another important point to remember. If you look at, well, a lot of people, I guess, take steroids for different things, but not a lot of people take steroids for six months. That is very different than if you were to do steroids post-operatively. One of the issues as you will see is when you deliver drugs or products where they are needed, it is much more targeted and the side effects are also significantly less, not needing steroid usage in these patients, except in the typical post-operative period.
What can steroids do? They can cause problems with pressure. Pressure problems can lead to vision loss, and that is the very real deal that we want to try to avoid in these patients. How about this approach in terms of, I think Lejla sort of mentioned this is a surgical approach. All three organizations I deal with and lead, is the infrastructure there? Answer is yes. Is it compatible with what we do now? The answer is yes. Do we know how to do this? The answer is yes. Really, if you look at all the things that this sort of approach allows us to do, in the program itself, there is probably over 500 surgeons who have been trained to actually do this. It is not something that people are not familiar with doing.
Currently, Lejla and I, we train fellows, and this is something that the fellows are getting more and more familiar in their training program to do these things. There is a pipeline of people who know what to do now and who will for the future. As we look at new therapies, this is going to be the approach of putting stuff under the retina where it is needed. You guys have all, I am sure, have heard about vitrectomy surgery. Everybody has heard about injections. We put these injections in the vitreous cavity and hope it gets to where it needs to be. The standard vitrectomy surgery is we remove the posterior hyaloid, which is a vitreous. Then we use instrumentation that is readily available currently with all three of the machines. This is something we can do and we are doing tomorrow or the next day.
This is available right now with all the machines. A couple of machines have actually special subretinal injectors that are currently there. The surgical companies are already thinking for the future, just like we are, okay? Just like this therapy is. This is available now and ready to go. It is very important. There is not a lag time of learning the procedure or doing those things, okay? This is surgery that we do. Again, outpatient surgery. There are places that we do this. If we look at about 3,300 surgeons who do this, about 500 estimate annual procedures, right? The standard of care, this surgery is performed by us, and we perform it at an ASC, we perform it at a hospital or a combination thereof. The facilities are there to do this. That is not an issue.
For the ASRS, access to the operating room is really critical for our surgeons. As we have more and more therapies like this will only open up access to other surgical procedures as we go along. Again, as we talk about new therapies, we talk about safety, we talk about efficacy, we talk about can we do this, where can we do this? We also have to talk about, I don't need to tell you guys about finances. You guys know finances way better than I do, okay? Is the procedure paid? The answer is there's a code, CPT code. This code is in addition to your vitrectomy codes. There's two codes. One is to do the vitrectomy surgery, the second is to put the product under the retina. These are two additive codes.
It's not one or the other, it's one and the other. What about the place of where you're going to do the surgery? It's at the ASC or the hospital. There are codes for that as well. How is the product paid for? The product is paid for by Medicare and commercial carriers. It's an ASP that we all sort of know. It's + 6% or 8% or 9%. This won't be assigned day one, but it'll be four to six months after the product is approved. Is the procedure paid for? Yes. Is the site of care covered? Yes. How is the product paid for? Again, all of these things exist currently right now. How have other therapies helped this therapy? We all know about Luxturna, right? Luxturna is used for RP, RPE65.
Lejla's quite familiar with this disease because she deals with pediatric patients. It is one of those therapies that got us into thinking that this approach and these types of approaches have helped therapies like this. How about Encelto for MacTel? Same issue, right? There are established codes and facility payments that exist right now that allows us to do this therapy, hopefully as soon as we have our hands on it, quite frankly. Okay? I don't see any downtime to figure all of those things out. This is an important slide. Lejla showed part of this. For those of you not familiar, our society sends out the survey to our members, and this is a big number. This survey is really looked upon by many in industry, many in the community, and many retina specialists of where do we think things are going.
Lejla showed, quite honestly, that it's great excitement about these types of therapies. The question that was asked is, at what point is it worth it for a patient to have surgery? Is the durability, what's that number? Our members, the vast majority, said six, nine, or 12 month. That's the window they would tell and have that conversation, which all of us will have, is when do we go to that route? Yes, surgery can have risks, but surgery has real benefits. I think we have to weigh all those things, but vitrectomy surgery is very different than when I started. I don't want to do the math. It was many years ago. Okay? The advantages of this approach, Lejla quite nicely mentioned, this is targeted. This is immune-privileged compared to the intravitreal approach.
There is no need for steroids, and the issue of bilateral treatment can easily be done here versus other therapies. There are many advantages to this approach versus putting a product in the vitreous cavity versus a subretinal space. I hope I've given you this overview of what this therapy means to three different organizations, both in terms of access to the medicine, where do we do it, and the finances of it. Thank you.
Thank you, Gaurav, and welcome, everyone. My name is Steve Pakola. I'm the Chief Medical Officer at REGENXBIO, and it's my pleasure to present on the overall development program of sura-vec for treatment of wet AMD. You've already heard some great lectures and presentations, discussions on how big the unmet need is for treatment of wet AMD, and particularly the opportunity for a one-time treatment like gene therapy that can provide a foundational anti-VEGF activity. It's really that opportunity that gives the potential for a real shift in the treatment paradigm for treatment of these patients. When you're in that situation, what do you do? I think go big or go home. What we've done is we've gone big and we've gone broad.
Our goal with this program and what we set out to do was certainly provide treatment that can preserve vision and dramatically reduce the treatment burden of the disease. Critically, we wanted to provide the most clinically relevant data that we could. Lejla referred to, what was it? The frequent visiting friends. These are the patients that it makes sense that if you have a sustained anti-VEGF drug, that these are the patients that you potentially could really help, and even in some patients, prevent the need for any injection. That was very important for us to really look at a broad spectrum of patients. Another really clinically relevant situation is bilateral disease. Both of the talks that you heard discussed, a lot of these patients do have bilateral disease. You'd really like the opportunity to treat both eyes.
What's nice about subretinal delivery, as Gaurav reviewed, is we know that that's the most immune privileged space that you can inject compared to the other available injection sites. It's really an ideal site to limit the risk of immune response to a second eye treated. Lastly, an important goal was to be able to provide, potentially, sura-vec around the globe and really do the studies that would be needed to provide the data that would allow access. Certainly with our global partner, AbbVie, that's what we endeavored to do. This slide shows where we've come in the program, and I think it's important to note that this is actually the largest gene therapy program and the most comprehensive gene therapy program that's ever been performed. That's not just for wet AMD, that's also for any indication.
Over 1,400 patients enrolled across our trials. That includes over 100 patients who have been dosed. This has been across over 500 specialists who have been trained to deliver sura-vec, and that includes over 300 specialists in the U.S. who have been trained. This again, has been across a broad population of patients, including high disease activity, several cohorts of bilateral treatment patients. Also, we have advanced into evaluating how our data stacks up against real-world data. Here is a schematic that shows the different studies that we have performed, both completed and ongoing. We also include the doses that have been looked at in the study based on these little squares with colors. The important point here is that we did do dose ranging, and we are able to pick a low dose and a high dose to carry forward into the pivotal program.
Another important note is that we did look at the low dose and high dose in several settings. We really have the confidence from the results that we have already seen with the low dose and the high dose as we have advanced into pivotal. Okay, so let us address an important aspect of the sura-vec program, consistent inclusion of patients with high disease activity. We have referred to that several times before. This slide shows that in table format, where you can see in both the phase I, II study and also the pharmacodynamic study that included the pivotal doses, that we have chronic patients with a high treatment burden. Again, that is what gave us the confidence to enroll a clinically relevant, broad spectrum of wet AMD patients in the pivotal program.
Now that we have addressed some of the aspects that allowed us to get to late-stage development, let us start talking about the actual pivotal studies themselves. We have two pivotal studies that we completed enrollment last year. Of course, that is what puts us in a position to have top-line results later this year. These were treatment-experienced patients, up to four years of treatment allowed, and again, the low dose and the high dose. So we have the ATMOSPHERE study and the ASCENT study. This slide shows the basic design of the ATMOSPHERE study in which patients to be eligible for enrollment had an initial ranibizumab screening injection, and as Lejla mentioned, a week later, assessment for anatomic response to that injection before these patients could be enrolled in the study.
The patients enrolled in the study were enrolled one to one to one to either low dose sura-vec, high dose sura-vec, or on-label anti-VEGF treatment. In the case of ATMOSPHERE, that is monthly ranibizumab. I think a key aspect is you can see the inclusion criteria in the lower left-hand corner, and these all support the aspect of really trying to have a broad spectrum of patients enrolled in the trial. Here is the second pivotal study that is very similar to the first study. The main difference is really that active control arm. Instead of ranibizumab monthly, it is on-label Eylea or aflibercept Q8 week dosing. Both studies, the primary endpoint is the well-established regulatory accepted primary endpoint of change in best corrected visual acuity at one year or trials, it is actually right at 54 weeks, and non-inferiority compared to that active control arm.
The ATMOSPHERE study was performed in the U.S., and the ASCENT study was global. We were very glad with AbbVie's support to be able to expand globally in that trial. This is just a nice visual representation of how much of a global footprint we were able to achieve with this program. In summary, the design elements we've just reviewed were very intentional, very strategic, with the goal to make the data that comes out of this trial as clinically relevant as possible to our panelists here and all of their colleagues in the retina space. I think the question then is, we often get, what does success mean in these pivotal programs? Not surprisingly, of course, you have to hit on the primary endpoint. Also you have to have a meaningful effect in terms of treatment burden.
A key aspect we've seen in the trials we've done so far and what we hope to see in the pivotal studies is actually a meaningful proportion of patients who don't need any supplemental injections in the trial when we have the readout, and certainly over 50% reduction in the treatment burden as well. With that, I'm excited to invite up to the stage Rahul Khurana to actually present some of the phase II results that we have to date. Thank you.
Thank you, Steve. My name is Rahul Khurana. I'm a practicing retina specialist in the San Francisco Bay Area. I'm part of a seven-person retina group, and we mainly see patients. We operate and take care of patients in the clinic, and we're also heavily involved in clinical trials. As we are very excited to hear the phase III data readout that comes in December, I wanted to really share with you that across three pivotal clinical trials, we see very consistent outcomes with sura-vec. We see that sura-vec delivers on three levels. One, stable, improved vision. Two, stable and improved retinal anatomy, and three, reduced treatment burden in patients with high disease activity, high treatment burden, and fellow eye. The data that we have so far, which involves a phase I study, a phase II pharmacodynamic study, and a fellow eye study.
These three studies give us a very consistent picture on the efficacy of sura-vec. The first thing we want to look at is visual acuity. One of the goals for any retina specialist is to maintain visual acuity. You can see here on this graph after sura-vec injection, in the phase I study, patients gained 3.9 letters in the high dose and 3.3 letters in the second dose that's here. When we looked in the phase II study, again, we see a maintenance of vision of 2.7 letters in the high dose and 1.1 letters in the low dose. Finally, in the fellow eye study, you can see again, the visual acuity is maintained at 0.4 letters. When you look at these curves, you see a very consistent theme.
The vision stays the same, and that's one of the real goals in our treatment of neovascular AMD. We see initially in normal clinical practice, we get visual gains, but unfortunately, we lose the vision. So to maintain vision is really the goal, and you can see a very consistent theme among three different studies. As important as vision is, and to our patients, vision is the most important thing, but to retina specialists, a biomarker of disease activity is a retinal anatomy or the OCT. So for retina specialists, the OCTs are very important. Again, when you look at the retinal anatomy, you can see that there's no worsening of the retinal thickness, but rather an improvement, a decrease of 35 microns and 40 microns in the phase I study.
Again, in the phase II study, you can see an increase of 4.7 microns and a decrease of 16 microns in the low dose. Finally, in the fellow eye, you can see the retinal anatomy is maintained of 0.1 microns. Again, when you look at these curves, the things to see at is the consistent stability of the retinal anatomy. If you remember when Lejla presented the data, that when we have problems in our management of neovascular AMD is when we get fluctuations. When that number goes positive, when there's thickening of the retina, increased fluctuations leads to geographic atrophy, subretinal fibrosis, and ultimately vision loss. So really the goal for any type of treatment for neovascular AMD is to have retinal anatomy to be maintained and no increase or thickening of the retina, and you can see by this a very consistent theme.
Finally, when we look at the treatment burden, we can see that there's a meaningful reduction across studies. In the phase I study, which looked at patients with a high treatment disease, these were the very challenging treatment of patients who needed seven injections or 10 injections in the previous year. This reduction went down nearly 68% and 61% to nearly two and 4.1 after sura-vec treatment. In the phase II study, you can see this reduction went down from nearly eight treatments needed in the previous year, down to only 1.1 and 1.4, a reduction of nearly over 75% treatment reduction. Finally, in the fellow eye study, you can see that there was a reduction from nearly nine injections before sura-vec injection to 0.7 or a 93% reduction. Clearly a dramatic and meaningful reduction in the treatment burden.
Well, another way of looking at the treatment burden is to look at it a little bit more granular. I know this is a busy slide, but you can see on the left, these are the number of treatments these patients received before sura-vec injection. You can see they received quite a few treatments, and they received everything from aflibercept to ranibizumab to second-generation faricimab and brolucizumab. Despite these injections, you can see how often these treatments are given. After sura-vec injection, you can see on the right a dramatic decrease. The injections are the colored dots, and you can see after sura-vec injection, the number of injections went down dramatically. In the phase II study, you can see there was a 53% of patients were injection free. That means they needed no injections after sura-vec, 60% in the low dose arm.
In the fellow eye, patients had 60% were injection free as well. You are seeing among both the low dose and the high dose, this very impressive injection-free interval and a dramatic reduction in the number of injections needed. The phase I data gave us a great opportunity to look at the long-term results because we have five-year data, and I think this is where it is most powerful. You can see in the original study, the patients maintained their vision through years five and the cohort three gained nearly nine letters, while cohort four lost only one letter. This is a huge success in our management of neovascular AMD. You can recall from the natural history studies and from the real-world outcomes, people usually lose between four to eight letters.
The curve is all the negative, so if you can maintain the vision, that is a great success for our patients. Furthermore, to maintain these great visual outcomes, you can see in the very bottom, very few injections were needed. When you look at this phase I study, you can see the injection annual rate went down from nearly seven injections before down to two to three, a 65% reduction in cohort three and a 64% reduction in cohort four. It is important to remember that this phase I study looked at specifically high treatment injection burdens, patients who needed injections very often. We can look at a couple case studies that I think this will really bring home the treatment burden and the injection-free intervals.
You can see in this patient, this patient received 25 injections before and eight injections in the year before, which meant they had to get an injection every six years. After sura-vec was given, you can see here in the blue line here, the patient received a few injections afterwards, but then was injection free over the entire time. Most importantly, the patient gained nearly five letters after five years. When we look at the retinal anatomy, you can see by the OCT images on the bottom left at baseline, you can see the presence of subretinal fluid. But when we looked at the OCTs at years one, two, three, four, and five, you can see dry anatomy there. No fluid and sustained disease control. Here is another case that shows a very dramatic reduction in the injection burden.
This patient also received about 50 anti-VEGF injections before, in the previous year received eight, which average about an injection every five to six weeks. After sura-vec, the patient was injection free for the entire five years. More importantly, the patient was able to maintain their vision gains with dry retinal anatomy throughout the time, as illustrated on the OCT. Finally, I wanted to talk about the fellow eye case. We have talked a lot about bilateral disease, and I think this really highlights the human element on it. We are not just treating the eye, we are actually treating a person and a patient. You can see this patient also was involved in the study and received nearly 10 injections in the prior year, got sura-vec and did phenomenal. Required zero injections afterwards. However, the fellow eye unfortunately developed neovascular AMD.
Even though in the sura-vec treated eye, they were doing amazing, did not receive any injections, in the fellow eye, they still had to come in every month and essentially received an injection every one month. When they got sura-vec in the fellow eye, they have been essentially injection free, requiring only one injection afterwards. We are not just treating the eye here, we are treating the patient. Bilateral disease is a heavy burden. I think it is important to realize that, and it really shows the power of this potentially transformative therapy. Here is another fellow case, which shows a patient, again, in the first eye, you can see on the bottom left, received nine injections in the prior year, had fluid, was given sura-vec, did extremely well, gained six letters, and did very well in the period afterwards.
The fellow eye developed neovascular AMD, also received seven injections in the prior year, but then was transitioned to sura-vec and has done extremely well and has maintained their excellent visual acuity outcomes. As important as efficacy is, and efficacy is very important as we look at it, safety is really important. I am excited to have my fellow colleague, Dr. Arshad Khanani, share some safety data about sura-vec. Thank you.
Thank you, Rahul. That was a great talk. Before I get started, I want to spend one minute to highlight the perspective I have been thinking about before this event. I am Arshad Khanani. I am in private practice, multi-specialty group, involved in many trials. I tell you, over the last 10 years, I have talked to many of you, and it has been like not too much excitement about gene therapy, not too much excitement about gene therapy. Now, I think we are at a stage that we are going to read multiple pivotal programs in the next 12 months. What I see myself is a disconnect between patients, physicians, and the Wall Street. I hope, after today and tomorrow, we see this excitement in all of you.
Because when I talk to Rahul, I talk to Ram, I talk to Lejla, Gaurav, when we deal with these patients in clinical trials, we see that excitement. Here you heard today about sura-vec. It is the largest and the longest going program. From that program, we have actually learned a lot about gene therapy. Was I scared when I dosed my first patient six or seven years ago? Yes, I was, because it is a new modality. But now we have generated so much data on efficacy, so much data on safety that now we have used what we have learned from sura-vec in multiple other programs for wet AMD, for geographic atrophy and others. I think I just want to highlight that please take the opportunity today as you talk to us.
I think that piece of excitement from the patients and from physician is super important when you look at the efficacy and safety, because one day you or your family member can have the same disease and having this potential to be injection-free 50% of the time or reduce the number of injections in 50%-75% of the time, in terms of treatment burden reduction, that's huge as a practitioner. I just wanted to reframe because I know many of you have talked and spoken to me over the last several years about it. But I think we are at a very monumental time in our field, where we are actually shifting the treatment paradigm for patients, and we are closest than ever, and it's been great to be part of journey with all my friends and colleagues. Rahul excellently presented the benefit we saw with sura-vec.
We saw maintenance of visual acuity, maintenance of disease control, significant reduction in treatment burden, and a large subset of patients going injection-free. But none of that is important if we don't have good safety. This is a surgical procedure, and we have had learnings about sura-vec over the last five to seven years. So when you look at the pivotal doses across the programs that Rahul presented very nicely, we have not seen any drug-related serious adverse events. I think it's important. In a world of treatments, this is not a disease where we don't have treatments. We have excellent treatments. Obviously, we don't keep up with the injection burden. So the question is, we need to have treatments that don't cause serious adverse events to patients who have other options.
In terms of pigmentary changes, we have not seen any central macular pigmentary changes at pivotal doses, and I'll go a little bit more into that on the next slide. But what have we seen? We have seen routine post-procedure related inflammation. We do a lot of vitrectomies, as Gaurav said so nicely. And we are used to mild inflammation. We start the steroids. We finish them usually four, three, two, one taper within a month, and it goes away. We have seen conjunctival hemorrhage. That's just the red eye you get from making incisions in the eye. Again, that also goes away. Now, this peripheral retinal pigmentary changes, that's a finding that we learn in subretinal gene therapy programs, and it's not just this program. It's actually common in every subretinal gene therapy program. So let's go through that journey a little bit. What has that led to?
That led to the dose and bleb optimization and what does that mean? So in the phase I, II study, we were putting blebs. So these blebs are these areas where you do the subretinal injections, superiorly or inferiorly. And then what we learned was if you do an inferior bleb because of gravity, there's a chance that the gene therapy material can actually go into the macula, and you can have pigmentary changes there. So that learning from phase I, II led to the placement of blebs inferiorly in the far periphery. And that has worked really, really well. And this is not just for this program. I said this learning was taken to all the other programs we are part of, whether it's another neovascular AMD program or geographic atrophy program.
When we look at the larger cohort of patients in the phase II study, we saw no patients with central pigmentary changes, and this was actually by the Reading Center or CRC. What we have seen is that these pigmentary changes are localized in the peripheral retina. They stabilize over time, and they do not have any impact on best-corrected visual acuity. This optimized procedure, obviously, is the one that is being used in ATMOSPHERE and ASCENT. So, great learnings for the field in terms of how we can safely deliver gene therapy without having any impact on visual acuity for patients from adverse event side. On the same side, we are able to help them control disease and maintain long-term vision. The other question comes about bilateral disease.
For subretinal gene therapy, I presented the Fellow Eye data, I think several years ago at AAO, is just a reminder that subretinal is targeted, it is compartmentalized, and it is immune privilege. So I think when you are not exposing the immune system to the vector, then there is less chance of inflammation. I think that is what we have seen, the safety in the Fellow Eye study is comparable to what we have seen in the other programs. We have not seen any drug-related SAEs. We have not seen any cases of vasculitis, hypotony, or chorioretinitis, and we have not seen anything new. The AEs are similar. So I think the main thing I want to highlight and summarize is gene therapy to me was I was fearful five, seven, eight years ago. We had some programs that had adverse events, whether there is high dose, whether there is wrong prophylaxis.
Subretinal continues to be safe, and this idea that, oh, we are suddenly going to have some event happening is not true now because we have had experience for a long time. This is not new. So I think to summarize that sura-vec has been well tolerated at pivotal doses in all the programs that we have seen. There have been no drug-related serious adverse events. As you recall from the discussions and talks earlier, no prophylactic steroids are required. We are using four, three, two, one , the usual post-vitrectomy taper. The clinical experience, as a field we learn, and we have optimized this procedure.
This also supports the delivery of subretinal gene therapy in both eyes for the patients. Thank you very much for your attention. So now we will have Ram Palanki and Ram Bhandari for the next session.
We wanted to break things up a bit with the Ram show here. This is our preview for potentially going on Fox. I have known Ram for a very long time, and I have actually spent a lot of time in his clinic just to learn how retina works in a community setting. He is a special human because he operates in the world of research and everyday life, just in terms of seeing his patients. What I will try to do here is really bring his community perspective from a standpoint of his learnings from all the clinical trials he has done and how he uses his treatments, where the burden is today, and what he is trying to solve. Trust me, I have not told him to say any of this.
I think it is really important to know that when we go through this process here, we are really trying to bring components of the experience that the physicians in our clinical trials has had with our program on how they see the product from a standpoint of fitting into the clinic. With that, Ram, maybe you can tell the entire audience here on how your day looks like when you actually wake up at 4:30 in the morning and walk into the clinic.
Well, actually, Ram, thank you. I think, from my practice perspective, typically on a typical day, I may do one or two vitrectomies actually before I get to my clinic. I will actually start OR 6:00 A.M., do two cases, and be in the clinic by 8:00. That is how common vitrectomies are here, and we typically do five to 10 vitrectomies on a weekly basis in my practice for each surgeon. Then it is off to seeing patients. In terms of patients, I think you have all heard the stories about how overburdened we are with the injection frequencies we have in our clinic at present. My practice is not any different. We see anywhere between 60 and 80 patients in a day. Multiple intravitreal therapies, multiple intravitreal injections.
I am sure my experience, although I work in a semi-rural or suburban location, is not that different from the retina specialists that are treating the multitudes of patients across the country.
That's great. I mean, you live in a small town with 120,000-
Small city.
Okay. Right. Small city in the Midwest, which has about 120,000 people in population. You also serve your larger area of population that you draw on. So, describe the type of patients you get and what you're trying to solve, and who takes up most of your chair time today in the clinic, and what's the unmet need from a real-world perspective that you're looking to solve for?
Yeah. Out of those 60 - 80 patients we see in any given day, I would say 2/3s of them are wet macular degeneration patients in my practice. The practice where our catchment area, our town is 120,000, but the catchment area is 500,000. The practice takes care of about 370,000 lives. In terms of the patients we're seeing, they're the people coming in from an hour or two hours away, to see us in central Illinois. The reason for that is, there's not that many retinal specialists outside of the main metropolitan areas in the area. The practice consists of majority, which is wet macular degeneration, but then we also take care of diabetic retinopathy, diabetic retinal disease, and other retinal conditions like retinal detachments, which we take care of in the OR.
That's great. How do you as a practicing retina specialist in a community setting think about the clinical trial data and how it fits into your practice? I mean, we have a lot of discussions today about the inclusiveness of the clinical trials that we have at sura-vec versus the exclusiveness of some of the other pivotal programs out there. You take the totality of the data and evidence into account. How do you think about solving your unmet need in your practice? From a practical standpoint, how would you apply these therapies?
Yeah. That slide that Lejla actually brought up earlier today really takes it home. What's unique is that I've had the perspective of participating in multiple gene therapy trials across different sponsors. The unique thing about ATMOSPHERE and ASCENT specifically is the overall inclusiveness, in terms of screening patients into the trial. Low-burden and high-burden disease patients were taken into this trial, which cannot be said for every other gene therapy on the market. That's a key point of distinction when you think about ATMOSPHERE and ASCENT. Partially, this was because they were the first. They were the first group going into the clinic, and they basically took all comers that had any kind of response to ranibizumab into the trial.
That's something to be really, when we come to the real world, it gives me confidence to be able to treat both my low-burden and high-burden patients. High-burden patient, obviously, they're going to be the ones who want to come into the patients. In the real world, they may be the ones that we treat first. The low-burden patients who can't get into the clinic on a regular basis, there's also a need there, and we have confidence treating those patients as well.
That's great. You also have a unique setting in terms of an archetype of a practice. You go into your operating room, which is owned by you, and you operate in the clinic. How does this look like? I think Gaurav very elegantly framed around the pathways that exist already for the procedure you do, and you have the ability to buy and bill for the drugs that you'll have to administer to these patients. How do you see that fitting into your life, potentially, if sura-vec gets approved? Do you see that as all being seamless, or do you have to put any new things in place given what you do today?
Really, there's not anything new that we would have to put in place. There's really two components. One is the actual surgical component, which we're all very familiar with. As retinal surgeons, a vitrectomy is very common in our practice pattern. All of us on the panel do vitrectomies weekly, I'm sure multiple. The second aspect for our practice is not unique, or at least my practice is not unique. Retina has moved towards the world of pharmacology in the last 10 years. We're very familiar with buy and bill. That's how it would work in my practice because I'm one of the owners of the practice, and our practice also owns the ASC. So we're very familiar with net cost recovery and how to run the margins from distributors, and how to actually create access for patients in terms of allowing patients to be treated with novel agents.
Okay. I'm going to ask you one last question and then step into how the commercial world looks like potentially when sura-vec potentially gets approved. I think Gaurav framed the advantages of subretinal therapy when it comes to gene therapy, right? Because we all talk about intravitreal therapies, and it's a different way of looking at life when you're actually moving a patient from versus making a decision on what type of foundational therapy you want to actually put into a patient, right? Because that's a long-term decision you're making for the patient. How do you see the advantages that Gaurav described as helping you with your decision making when you want to administer the concept of gene therapy to a patient?
Yeah. I think the primary thing, as Arshad was saying, is actually, for me, is safety. I think safety trumps all else when we're doing something. When we have the standard of care is so safe, we already know that. If we're going to change the modality of treatment, safety is going to be the number one priority. The second is durability of treatment. When we look at that, when we think about gene therapies in general or other forms or modalities, untargeted gene therapies, we're threading the needle between safety and efficacy. With sura-vec, we really don't have to make that compromise. We both get efficacious treatment for our patients and also a safe treatment modality.
How I see it is, I see it as a treatment that I could potentially use in both my high-burden and low-burden patients as a cornerstone of therapy, which will either meaningfully reduce the number of injections or make the patient injection free.
That is great. I am going to have the full panel come back and talk about how this fits into their life later on. Thank you for answering these questions. That was useful to just take a break on a didactic basis and come back to how we view life at REGENXBIO in terms of gene therapy getting into the practice. A little bit of background about myself. Hold on a second. I started my life in the early days of Lucentis development. In fact, I had the opportunity to contribute to the ANCHOR protocol, which was the second phase III protocol for Lucentis. I also had the opportunity to contribute to the first OCT protocol ever written. I think the first time we actually decided to install the protocol, we were talking about 150 microns to be the retreatment criteria. This was in 2006, 2007.
That is just because we did not know what OCTs meant as a biomarker. We have learned over time, and now today, they are the main biomarkers you go to in terms of making the treatment decision. All of that to say, Lucentis started in wet AMD, and then we realized it works across an entire franchise opportunity, from DME to RVO through every retinal vascular disease. That is how today it has become a $15 billion market as a retina franchise. What is very interesting as part of this number for everybody to take home today is that $15 billion represents only the branded market. There is another 40% of the market there that is dominated by bevacizumab today. You have to question why is it still so dominant.
The reasons it is dominant is because no other product has been able to provide the type of benefit to the patient where it warranted to rethink if that patient that is getting bevacizumab should actually get a better treatment. I think I want you guys to take that home because there is actually a whole other opportunity out there in terms of the number of patients that have the same issues as the patients that are on branded drug today. 70% of the branded market across the retinal vascular diseases is actually wet AMD, and that just tells you the magnitude of the size of the market we are dealing with, and there is fundamental validation of durability in the marketplace. You go from Lucentis to Eylea. Eylea to Vabysmo. As you think about second-generation anti-VEGFs, consistently, the market has adopted these incremental therapies.
I want to take you back to one of the slides that Lejla presented. We talked about how many patients discontinue or are lost to follow-up just after the first year. She also talked about the three-letter gain you see in the first year. If you actually compare that to Lucentis phase III trials, where patients get every month injections, that number is at seven to nine letters. So even at a starting point, you are starting the patients at a place where you have a sub-optimized outcome. What does that tell you? The math does not work. Because you go back to Lucentis days, there were 800 physicians treating about less than 100,000 patients that had wet AMD. Because the solution, to Gaurav's point when I met him, was they were going in and doing surgeries on these patients just to slow down the progression of the disease.
All of a sudden, there was a treatment that was transformative, and everybody started trying to figure out, how do I now manage my capacity issues? If you do the pure math today, you have about 2,500 - 3,000 specialists that are just seeing one million wet AMD patients. They also see millions of diabetic patients. They also see millions of dry AMD patients. There is just not enough capacity there. I think you have to really rethink. All these patients are discontinuing and falling off the spectrum. Those patients, if they could have a treatment that solves the problem and sends them home, and they can take new patients into the clinic, it works for everybody. I do not need to get into this too deep because I think Lejla did a really good job of what this means for them in the clinic.
I think the concept of foundational therapy is a paradigm-shifting concept because now you are actually helping the patients to have a therapeutic protein in their eye on a very, very long-term basis. That just gives you a lot of flexibility in how they manage their patients, how they manage their clinic, and that is the concept that we are trying to solve for with sura-vec today. We talked about this whole spectrum of patients, and I do want to talk about this high disease activity and bilateral disease. As Chief Commercial Officer, I think about how is this product potentially adopted in the marketplace? How was Eylea adopted against Lucentis? How is Vabysmo adopted against Eylea? How is Eylea HD adopted against others? The first place physicians go to is that high disease activity patient because that is where they are trying to solve the problem.
When they get comfortable there, when they get confident there that they can solve the problem, it is an easy decision to start adopting the product in patients that have a lower burden. When you think about the clinical trials we have installed that everybody talked about, we have included those patients in the trial. You have seen the data. It has been a very consistent theme. I think what that brings forward is sura-vec is a very efficacious product. Potentially, when you start using the product in the marketplace, you will gain a lot of confidence, and that will translate a broader adoption. That is a concept that is so important to understand why this is a fundamental difference that we think really helps set the TPP for sura-vec. The bilateral disease is a big part of the whole picture.
I think Rahul t alked about we have to think about the patient, not just the eye. Sorry. I had a lot of coffee today. When you think about a bilateral patient, this is not a simple decision you are making as, again, shifting a patient from or switching a patient from Eylea to Vabysmo. The one decision you make is going to stick with that patient. So you have to have the ability to treat the second eye if you are treating the first eye because you are not solving the problem if you are only treating one eye. It is a big part of the picture. I do not think people think about bilateral disease when you talk about biologics that are administered regularly, but this is a very big aspect of the decision-making process.
So all of this is great. We talked about the high-burden patients and potentially we will have the data later this year and hopefully we will be creating access to this product broadly. We actually went out there and did a real-world study taking the inclusion and exclusion criteria of our pivotals. We tested it against what happens in those patients in the real world, taking all of the claims data and the publicly available databases from the EMR datasets that the clinicians have. We looked at what do those patients do over time, and how does our pharmacodynamic data from our phase II that uses the same pivotal doses perform? What we saw just at one year is about a line difference in these patients.
That is a fundamental thesis that really creates the value for this product on the basis of if you carry that one-line difference at one year into what you saw as long-term follow-up over five years, that delta just keeps going up. I think this is the first time anybody has actually done a head-to-head comparison, picking the same type of patients that have been included into a clinical trial to show that potentially this is the value that you are bringing to the market. You did not just do that by doing another incremental therapy, right? It is a one-time treatment with an 83% reduction in the number of injections these patients got. I think that is the biggest value proposition that you are talking about. So I am going to try to wrap some basic concepts for this whole room into one single slide here.
What I am trying to show here is on one side, there is just a lot of patients. The math does not work. There are not enough clinicians to see these patients. You take that concept, and you think about where are these patients? Out of the universe of about 2,000 clinics in the country, they are all concentrated in 150 sites. Those 150 sites are responsible for seeing almost 60% of the patient volume. That is a very important concept. Then you think about how does sura-vec get delivered. We deliver it through the subretinal process, which requires a vitrectomy, which requires the infrastructure of an OR. The number of vitrectomies on a volume basis, I think Gaurav talked about this, about 500,000 are performed annually in the U.S. Where are they performed?
They are performed in the same exact sites as where the patients are today and where the injections are happening. There are a few concepts that come through with this. The volume of the patients is very concentrated in the same place as you do injections and as you do surgeries. What that means is there is an existing competency, and there is an existing infrastructure in the same places where most patients are, and that is where the biggest unmet need is, and that is where sura-vec, in terms of its commercial potential, has the highest return. Why is that? Because, Steve talked about this, we have implemented a pivotal program, and the whole strategy was you want to recruit into a pivotal program where there is highest concentration of patients, where there is highest competency, where there is the best infrastructure.
That's what we have done in the pivotal program. There is almost an 80% overlap of our clinical sites to the same places where the patients are concentrated, where there is competency, where there is infrastructure, all of those that are required for seamless access to patients. As part of that, we have trained over 300 physicians today, which is pretty much saying that any site you walk into, you have a few surgeons that are already familiar with the procedure, that are already experienced with the procedure, and they know what this can do to their patients. Something unique has been happening in retina recently. There's been a lot of consolidation, and the largest consolidation that has happened is Retina Consultants of America.
You can see the numbers there, and I don't want to get into the specific numbers, but the fundamental concept is this concept of concentration of patients and physicians and infrastructure has also been consolidated into a single administrative aspect of the business. So to ensure there is access to these patients in a consolidated setting, you're dealing with a single set of administrators, which creates a lot of efficiency. When you look at our program, broadly, our pivotal strategy established a footprint in all of these sites. Now, I think Gaurav very elegantly talked about all the systems that are in place. Really, you have to think about when I do a procedure, do I get paid? Do I get paid for the time I'm taking from a site of care? Can I bill for this product when I actually buy it? Those are the three fundamental concepts.
I think Gaurav already gave you his perspective as a clinician, but all those exist already. We don't have to come up with new codes. We don't have to create a new pathway. They know how to do all of this in their clinics today with what they do. About 500,000 of them are done every year. I think one of the data points that is really important is when you go back and look at the 2024 Medicare data, pretty much every retina physician in the country has billed for vitrectomies. All this translates into where does sura-vec fit? Because somebody has to buy and bill sura-vec.
As it stands today, in the facility that sura-vec can be potentially administered, the WAC payments for the established gene and cell therapy precedents that are there, which is Luxturna and Encelto, you can see they're all getting paid above the WAC. What that means is on a net cost recovery basis, practices are staying positive. They all have to do business, and they have to sustain as business entities. We, potentially coming into the market, are walking in with precedents that we just have to replicate. So hopefully in my entire presentation, I was able to convey to you that the patient reach is seamless given how we executed our pivotal program and where the patients are, where the competency exists, where the infrastructure exists.
On the other side, can the physicians actually do this in a sustainable fashion and keep the net cost recovery in their clinics, all that already exists today. With that, I will bring the rest of the clinicians onto the panel and ask some specific questions, then you will have an opportunity to ask some questions yourself. First, thank you for being here. I know what it means for you guys to take a day away from your clinic and show up to speak to an audience like this. There is a lot of net cost recovery that you guys have to go through. With that, maybe what we can do is, you all kind of went through the presentations.
I would love for you to give your own introductions from a standpoint of who you are, what you have done, and the archetype of practice that you practice in, which is a very important component because each one of them operate in a different setting. Those, probably the five settings you will see here, is the common distribution of what you will see as a type of practice that exists in the U.S. With that, maybe Gaurav, you can start.
Sure. Thank you, Ram. I would not miss this opportunity to see you, so thank you. I appreciate the invite. A little bit about, as I talked about, the three different organizations. Just as a practice model, we are called West Coast Retina. We are great community partners of these guys. We have an incredible region in the Bay Area that has incredible retina people that we all actually get along. So that is first of all. But we practice it in the Sutter Health systems. So I lead the department, and we are in a hospital and an ASC, so we operate in two different settings. The ASCs, I do not have any financial interest. None of us have a financial interest in the ASC, but we have a kind of a hybrid setup.
Yeah. So my name is Rahul Khurana. I practice in the next door of, in the little bit south of the peninsula in the Bay Area. We live in a great area, and I am part of a seven-person retina group, and we are in a private practice. We have our own clinics. We do a lot of clinical research. We operate at both an ASC and a hospital, which we have no financial interest in and are not really involved with, but just do our surgeries as an outpatient settings in those situations.
Hi, everybody. Lejla Vajzovic. I am a retina specialist at Duke University in Durham, North Carolina. I practice in academic setting, and I do operate in hospital settings, Duke University Hospital System. As you are familiar with academic setting, I as a salaried physician, really have no incentives, so to speak, to really take in what therapies or what potentially outcomes for my patients are there. But I want to highlight that I do operate in hospital setting, and as such, it is the hospital rates that often get charged for any procedure they are done.
Great. I am Arshad Khanani. I am with Sierra Eye Associates. It is a multi-specialty practice in Reno, Nevada, near Lake Tahoe. We have two surgical retina and two medical retina doctors, a glaucoma specialist, and pediatrics. A big focus on research, and I operate out of two hospitals. No financial interest in either of those hospitals, obviously. Our focus is obviously clinical trials. But one thing I want to mention is that I am overloaded, so every time I take a day or two off, Euretina AAO, I get punished in clinic with injections till 8:00 or 9:00. So I get ready before and after because we have patients to take care of. Just like a couple of days off here, I get back home, Thursday I have double the patients, Friday I have double the patients.
From my perspective, I am over capacity, and we have added two new doctors, and they are almost reaching capacity. Even for a small practice, it is something I keep in mind as we look at the future.
Thank you. I am Ram Bhandari. I practice at the Springfield Clinic in Springfield, Illinois. The Springfield Clinic is a multi-specialty practice with specialties including pediatrics, ophthalmology, and neurosurgery. We are about 300 partners strong, and we own our ambulatory surgery center and buy and bill all drugs.
That is great. Hopefully you understand the different archetypes here, and that really represents, on a geographical basis, pretty equal distribution to a certain extent in the country. With that, maybe I will start with the clinical side of things, and then we will get into the net cost recovery and the practice economic side of things. Maybe from your perspective, Gaurav Shah, just because you are first in line, I am just going to go with you.
Story of my life.
Right. Looking into the future, potentially you have two options for gene therapy. You have the subretinal option, you have an intravitreal option. I would like to hear, and I am sure this audience would like to hear, how do you make your choices for those two options in the context of the patients that are sitting in front of you on a decision that is one time, because you cannot switch between therapies. You have to make a choice, and that choice has a permanence for that patient.
Yeah. I think it goes with any discussion about any therapies we have with any one of our patients, that it is a risk-benefit ratio, as you had said. What are their needs? What are their wants? I think Steve, or I do not know if it was Steve or somebody, said, "Go big or go home." I think the issue is that I talk to my patients and say, "There is an option. There is a couple of options," but I prefer an option that gets targeted therapy. As a surgeon, I like to target what I do. I like to fix it once. I call it one and done. Okay? That is my approach to pretty much most everything that I do. If I have that approach to patients, I tell them, "These are the options.
This is what I would recommend." More importantly, not from the also durability and efficacy, but we've talked about safety. Is the issue of being on six to eight months of potential steroid therapy that requires consistently coming into the office. I do think we have a lot of patients. I practice in an urban environment, but patients are mobile, and they have mobile lives, and they would like to have, in my opinion, that one and done approach.
I think one and done is a concept that fits all gene therapies-
Yes.
in some way. You've talked about the-
The safety issue of coming in. Is you have a therapy, but I don't have to consistently keep seeing them month- after- month for the side effect profile that we talked about.
Rahul, how do you see this in the world of two therapies that could potentially coexist? If that's the case, the choices you make and how you make them.
Yeah. I think about this very deeply because we've been involved in a lot of clinical trial programs, and the one thing we haven't really talked a lot about, but gene therapy is amazing. This is science fiction, what we're doing here. We're turning the body's own cells to make a medicine so you don't have to get chronic treatment. It's unbelievable. That also being said, it is extremely potent, and we're still understanding what it does, and we're taking these cells, and we're telling them to do something they're not supposed to be doing. In this case, we think it's for good, that it's making a protein to treat this disease, but it's very potent.
To me, when I think about this, I'm really concerned about safety, and my concern with intravitreal gene therapy is that when you do intravitreal gene therapy, you're not just injecting it into the eye, and it's just going to the retina. You're exposing the entire eye, the entire organ, to this vector that's transforming all these cells. That, to me, is the concern. Even though sura-vec involves a vitrectomy, which is a surgery, which is invasive, which has risks, you are targeting that just to the retina to where you want it. That, to me, is the key differentiator. To me, because I believe that gene therapy is so potent, you really want to have it compartmentalized and targeted and not expose the rest of the eye to gene therapy.
Lejla, what is your view on the totality of the evidence that exists today and going into the clinic? Potentially, these trials will all read out at some point, us being first in class and being there early, but these things could come on and be approved. How do you view life?
Yeah. I think my colleagues here said it really well. Gaurav and Rahul highlighted not only targeted therapy, the safety profile. I think the end result of any large phase trial, and I love the fact that this is the broadest. Lots of patients have been enrolled. Not only lots of patients, lots of surgeons were involved in this, so really broad reaching. I love the fact it's very inclusive patient population. Why do I say inclusive? Because those that needed frequent therapy as well as those that potentially would not need frequent therapy were enrolled in trial. I think this really mimics my real world, for certain, to understand how I may apply, and I would love to see that, really, the safety will be number one besides the efficacy.
I think we all have seen therapies that work very well but did not quite have the safety mark associated, so I think safety will play a part for me. I love the fact that we're not dependent on long therapy of steroids to control that safety.
It's interesting, as I speak to this community a lot, and we hear this concept of intravitreal is easy. It's done in the office, and nobody actually thinks through this whole big picture of bilateral treatment efficacy in types of patients and the steroid treatment burden. I guess, Arshad, you've been part of all the trials. You've been a pioneer in gene therapy. You pretty much started this journey in the clinical community. You've experienced so many things. You recruit patients across the board. You give advice to all of us. What is your view on the components of a subretinal therapy on efficacy and safety and the components of a intravitreal therapy on efficacy and safety?
No, I think, so number one, it's great to have options for patients. I think it's nice that we have multiple shots on goal here. Obviously, if you have intravitreal gene therapy, it's easy. Right? You don't have to go to the OR. It's accessible. Everybody knows how to inject. For the last 10 years, the learnings have been, we have to pay attention to certain things when it comes to gene therapy. Number one is dose. We need to make sure we use low dose. We need to pay attention to the vector. Is the vector going to the front of the eye, or the vector is going to the back of the eye? Then number three is prophylaxis.
I think there's been a lot of learnings for IVT gene therapy. I'll tell you that one program obviously had a lot of issues and the other program has not shown much issues, but obviously the steroid piece is there. For me, that patient's sitting in front of me, let's say they are pseudophakic, so we don't have to worry about cataracts with steroids, and they qualify for sura-vec. My discussion would be, are you able to take 20 week of steroid eye drops or not, and do you want to go through an injection, or do you want to go through a surgery? As Rahul said, surgery is invasive. I think having those two options actually is super important, and we are learning about efficacy and safety of both of the programs.
I think a lot of the decisions are going to depend on what we see in the pivotal trials. Of course, we have long-term data. We have a lot of data. At the same time, we still don't have hundreds of patients that we are going to have from pivotal. I think as a physician who has done tons of subretinal gene therapy, injected dozens of intravitreal gene therapy patients, I would tell you that I think both of those options are work and actually safety is important, but we also have data on safety with IVT gene therapy now long term. I think I'm a little bit different perspective here that seen all the different modalities, I think it's great to have options. At the end of the day, we have to make the decision, as Gaurav said, talking to that patient.
If somebody has glaucoma already, they're not going to be on steroids for 20 weeks. That's the patient that I would consider subretinal gene therapy. Then the lastly is the data from the program in terms of high-need patients. How do they do that? We'll have the data here. I think there's a lot of questions. I wish it was a binary answer, one or the other. I'm actually very excited about both of them.
I'm going to ask you this question in a little bit of a different way here, Ramanath, because you already talked about your views. Busy clinic, walking in and out, totality of patient management. We talk about the net burden of gene therapy in the context of the modalities you pick. How do you view that?
Well, I think when we think about patient selection and we look at the trial design that ATMOSPHERE and ASCENT had, it was truly an all-comers design. Really, the screening visit was really looking at, is ranibizumab effective in this patient, not is ranibizumab effective and durable in this patient. I think that's something that needs to be seen in the context of the results of all gene therapies when we look at this. Because if that's lost, and we just look at the headline or the top-line results without that context, you will end up putting patients into areas where the therapeutic efficacy might not match the patient need. When we look at the inclusiveness of ATMOSPHERE and ASCENT, and we know what kind of patients were brought into the trial, we can have confidence treating those high-need patients. Gene therapy is all about, Arshad mentioned dose.
It's all about dose, right? It's all about getting the right dose where we have safety and efficacy. The reason why the dose for ATMOSPHERE and ASCENT has been safe is really the targeted profile of the injection and the procedure.
That's great. I'm going to switch now from that conversation to a lot of the conversations we'll have about net cost recovery. You're all businesses, you're all different archetypes of businesses. You'll have choices again to make in terms of that background of net cost recovery against the background of patient benefit. I've spent enough time with you guys. I think you all make decisions on patient benefit, and that's a very clear indicator of how this specialty even evolved back from the 2000s. Because when we were developing Lucentis, the biggest complaint that retina specialists had, even including Gaurav back then, is are you going to turn us into injection machines? Which you have become. But I think it's a fundamental concept of changing the behavior without actually having the concept of patient benefit as a real experience for you in the clinic, right?
Once you start going through the process, you change your perspective on it. But I think fundamentally today, Gaurav, you talked about all the existing systems and infrastructure, and that exists. So how do you see this? For the first time, you're getting a high volume vitrectomy procedure potentially into the clinic, right? You never had this opportunity before.
Yeah.
This is a public health priority that you can solve with a surgical solution. This is like even thinking about the cataract aspects, and when people went through the process of now you can actually replace the lens and it became a high volume procedure. How do you see this in the context of what you've talked about as reimbursement and systems being in place, but practically in your practice setting, how will this be looked upon in the concept of the net cost recovery?
Yeah. Before I answer that question, I just want to have an audience. Just a little bit of a take back, because a lot of people, Ram, have talked about this subretinal surgery. I just want to give a little bit of a historical perspective. Subretinal surgery is not new. We did this 20-some years ago, where we not only made blebs, but we actually were taking stuff from under the retina. As my partner Matt Thomas in St. Louis developed this, everybody started doing this. This concept of subretinal, I just want to make sure the audience realizes this is not a new concept.
That, I think, is a very critical thing to realize, that we have been doing this type of procedure, when we didn't have anti-VEGF therapy for CNVM and so on and so forth. That's sort of the part that's important to remember. Going back to your question, is the infrastructure and net cost recovery and all those things. First thing with any therapy is we talk about safety, efficacy, durability, and then, is it fiscally responsible to, number one, to do, to perform, and to have the infrastructure to do it? I think, as I showed, for the physician, there are two components. There's a vitrectomy component and a subretinal component. There's two different codes. Again, those are additive codes as we do from the physician point. The other issue is from a facility fee. We have to do these surgeries at surgery centers or hospitals.
All of those facilities look for procedures or look for volumes of procedures that bring business to that institution. That is there with this procedure. In retina, we really didn't have that high volume type procedures, in terms of where you could do maybe eight of these in a day, or seven, or whatever that might be. Because what that does is that opens that business to doing other things for you, other procedures. OR access is near to my heart because the ASRS and the Academy are dealing with operating room access for our retina physicians. When people talk about, "Well, how am I going to do these procedures, and where am I going to do this?" I think the market will find itself because these facilities are going to want to do these things because of the way the finances work.
The third issue is, how do we do the buy-and-bill and all of those things? That has all been set up by therapies that have come before. I think from a finances standpoint, this is there now, and it will continue to be there, and the facilities are actually going to be wanting you to do this.
How about you, Rahul? You're a different archetype, and you're going into an OR from a different perspective.
Yeah. I think for many in the room, when you talk to your retina specialist on speed dial and ask about this and ask them what they think, there are some practical concerns they're going to have. They're going to be worried about the business side. Just from a practical side, Medicare cuts are real, and they're rough. They've been occurring at a relentless rate. One of the few profitable lines in our business is the buy-and-bill situation. When you take this away, there can be hesitancy, and there can be concern about that. Now look, I'm an optimist. I think as a field, we will adapt, and we will find the things there. As long as this treatment works and it's safe, I think we'll all bend and do the right thing as it goes there. Sometimes it takes some time, sometimes it doesn't.
But at the end of the day, I think all of us went into this to take care of our patients, and we want to get the best outcomes. If this truly is the best outcome, if this can deal with the issues of adherence, give the best control, I think we will move there. It may be slower than some may expect, but ultimately, we bend that way. I remember when Lucentis first came out for diabetic macular edema, and our mainstay at the time was focal laser, and there was a lot of resistance in the community because at the time, that was a procedure that paid well, paid better, and there was resistance. But ultimately, as the data came out and we saw the amazing outcomes that we had in diabetic macular edema, now very few people do focal laser, and the field has moved on.
I think with a lot of these things, ultimately, it's really going to come down to whether this works and whether it meets an unmet need, which I think it does, then I think the field will move in that direction.
Lejla, you talked about your setting and you're a salaried physician in a prominent academic institution. How does this work in your setting?
Yeah. I'm exactly that in terms of what was said before. We all will do what's the right by the patient, and it certainly would be amazing to have these therapies approved to provide to really address the unmet need of having therapy that's going to maintain visual acuity long term. I think the logistics in a real-world setting do come up play. We talk about OR access.
We talk about the treatment burden or potentially hurdles to getting to the OR, but I can tell you that we very well were able to figure this out for other therapies, such as Encelto, cell-based therapy, which I would say is really kind of carving the way for some of the other therapies, hopefully coming down the pipeline to really showcase that there is a, yes, need, but also a business model that can very much be established in a hospital setting with really net financial overall positive results.
Maybe I'll have you both address it from a standpoint of any differences, or you kind of agree with the general statements that you make.
No, I think it's a little bit different for me because we're a small business, and our margins and our revenues are directly related to anti-VEGF branded usage as well as rebates and other things. I think when I think of sura-vec, it's a way for me to optimize outcomes for patients, but also it's a way for me to have room for new patients. So from the net cost recovery perspective, I'm not negative, even though the revenue won't be the same for that patient. That patient leaving my chair, I'm not there till 9:00 or 10:00 P.M. I'm replacing that patient with another injection patient. So for me, it's not a loss, but I think that patient, yes, the revenue will be less. Now, of course, we have to monitor, we have to do supplemental and other things.
I think for me, capacity is a big issue. And my patients come from really, really far away. So giving the best treatment to the patient, optimizing the outcomes, and then replacing that patient with another injection patient so we don't have a net loss.
How do you view this?
My practice is very similar to Arshad's practice, with the exception that we own the ambulatory surgery center. With that ownership stake in the ambulatory surgery center, and this is kind of broadly, there are other practices that have the same setup. You are seeing the variety of practices here and the different setups. For my practice, we would actually benefit both from an access standpoint and a buy and bill standpoint on the actual use of sura-vec.
Ram, this OR access thing, that term is being used a lot. There is OR access and there is profitable OR access. There is no issue if you talk to administrator, if you are profitable as a surgeon, as a practice, to them, him or her will be more than happy to have you in their OR. Any health system, any ASC. There are distinctions between OR access and profitable OR access.
I am going to ask one last question here. I think in the big picture of what you brought forward, it always amazes me. We get into net cost recovery and you look at the math and what is actually happening in the real world. A few things, right? The millions of patients you see in the clinic, and I brought this through my presentation forward a bit, versus the number of physicians that exist, there is a big mismatch. What you see is within the first year, almost 40% of patients discontinue or drop off. In essence, they are not even in your net recovery equation today. They are falling off because they cannot sustain what you have as an option for them, or they cannot get access to you because they just live far away and they have caregivers, or they do not have caregivers.
All these things kind of kick in, but you do not realize the magnitude of how many patients are in that segment of patients that are not even coming into your clinic because they cannot do it. You think about that discontinuation rate and loss to follow-up. What does a gene therapy option mean for all of you? Because these are patients that are not coming into the clinic, right? Then in the context of gene therapy, how do you see, again, an IVT and a subretinal process fitting into it? Because these patients do not want to come back to you. Your data clearly shows that they do not want to come. What are the decisions you would make on those patients tomorrow if you had a choice that would give you this type of optionality?
I think maybe each one of you, wherever you want to start, I will start this time with Ramanath and then come back. We can close it with that.
Yeah. No, I think, for those patients that fall off, to start them with a cornerstone or foundational treatment will be huge for their prognosis next year, the year following, two, three, four years down the line, to have something that you could do once that could be on board for the rest of their lives. Because as we see it, there are several barriers, as Ram was saying, to get in, and sometimes it is their health, sometimes it is their transportation, sometimes it can be a lot of different things. I think this could be a real foundational therapy for the rest of their disease.
Yeah, I agree with Ram. I think what we saw during COVID was patients who did well were the ones that were in either gene therapy clinical trials or had the Port Delivery System where they had the sustained delivery of anti-VEGF. My hope would be that patients drop out because of the treatment burden. I have very few patients dropping out if they are coming every six months or every four months to my clinic. A lot of patients drop out if they are coming in every month or every other month. My hope with gene therapy is that we will reduce that burden for those patients. Then life happens to many of these patients. They break a hip, and now they are in rehab, and then they show up one year later with a massive bleed and blindness.
Having gene therapy, sustained gene delivery of anti-VEGF, gives me a reassurance that these patients actually will maintain their long-term vision. I think optimization of visual acuity, long-term disease control, and I hope that this will help our patients maintain their independence. My hope is that we will lower the rate of that dropout, Ram, with seeing them much less often than we currently do even with the second-generation anti-VEGF agents.
And just to add to that, I think all our patients will definitely say yes to foundational therapy that would involve one-time procedure versus recurrent. We talk about need and recurrence, but if you really ask our patients, they do not want to have recurrent injections 100% of the time. They all want to enjoy life outside of our clinic. Just yesterday in clinic, I saw a 96-year-old, actually with a significant other. His wife was there. They just came back from South Africa trip where they celebrated 50th anniversary. Our patients want to enjoy life outside, and they are living longer and all. So I think the foundational therapy would give them opportunity to, yes, have something as a baseline, but also enjoy life outside of our clinic with good visual acuity results.
Yeah. I would just echo what the other physicians have said on the panel. I think loss to follow-up, loss of adherence is a huge issue that most retina specialists have no idea. We are so busy in our clinics. If patients don't even show up, we have no idea. If they don't show up for three months, it is not even on our radar. But when we look at the data from a macro level, we see these high rates of loss to follow-up, high rates of loss to adherence. It is not just a lost economic opportunity.
I think it is a lost opportunity to preserve vision for these patients. One thing we have learned as we have looked into this, the ones who do the worst are the ones who have poor visual outcomes. We know the ones who have good visual outcomes are the ones who get the most injections. So it becomes a feed-forward kind of down cycle. They don't get treated as often because we know in the real world we don't give as many treatments. Their outcomes are not as good. As a result, they are less likely to follow up. So it just gets worse and worse and worse.
The reality is, if we can tackle it from the get-go and give them the best outcome from the beginning, maintain their vision, it would probably improve adherence because they are seeing the benefits of it and could help prevent a lot of the downward spiral that happens.
Ram, all of the above is what I would say to what my colleagues have stated. The only, again, issue is that our patients should have choices, that they're wanting us to do things in a different way. We have to keep an open mind and be cognizant of new ways of dealing with diseases. I don't know how many people were at the Subspecialty Day meeting, but there was great excitement about every therapy that's injected under the retina, right? Both for AMD and for inherited retinal diseases. There was a clear, palpable excitement in our field. One thing I want to add that was on your slide in terms of those tier one, two, and three practices and clinicians you showed, I would almost have to bet those tier one, two, and three probably train 99% of the retina fellows who are now going into practice.
This all sort of fits with the workforce is there, the current trainees who are going to be doing these procedures is there, imaging is there, machines are there, and technology is there. I think we have to be open to new therapies and have access as organizations to make sure our members have them as the ASRS does.
Ram, can I- Can I follow up real quick on that?
Yes.
Gaurav, kudos to you, Diana, and the program committee. Great AAO Subspecialty Day program, and I share the excitement. I gave a talk on an investigator-initiated trial on DME with sura-vec, and I actually had a lot of people come to me afterwards and said, "Wow, this is exciting because we had a lot of enucleation in diabetic patients already because of complications, and if we can inject this and maintain their disease, not getting worsening and control DME, that would be great." One other thing I want to mention was when I was at Euretina, I gave an invited talk on gene therapy in the Euretina session, and there were about 12,000 attendees this year. I will tell you, the excitement about gene therapy is real.
This is not people are afraid of, this is not people are shying away from, because as you saw the data today, and you have seen data from other programs, that is actually real efficacy, real disease control, and we have optimized the procedures and prophylaxis to actually get to a level where the safety is looking very good. I just wanted to share that, Gaurav, that not just AAO, which was a phenomenal program set up by you and colleagues. That was your fourth job you did not mention.
Yeah, that is right.
Also serve as a chair of the AAO Subspecialty Day, which is the biggest retina show of the year. I think just want to say that this is not just U.S., it is global excitement. People come to me all the time. "How do I get to do gene therapy? How do I participate?" People from Brazil, people from Spain, people from all around the world, and that is why you saw that PAT Survey. I just wanted to piggyback on what Gaurav said, that this is not four or five of us talking. This is actually the community that is super excited because we want to help our patients have better outcomes.
I am going to add one more thought to that. Sorry, Ram, we are running for time.
No, no. Speak.
All of us went into retina, really. We did not say, "Boy, I want to do retina because I want to do all these injections." I did not know what an injection was in 1997. We are surgeons at heart, and I think that I have been waiting for a procedure like this to come. As somebody had mentioned, we really did not think this was going to be possible. So I really want to congratulate the entire team to hopefully bringing this to us.
Thank you. I think stay here with me for two more minutes because I look better when you guys are up here. I just want to wrap this up. I think some of the things you have heard a lot of information today from across our clinical program, the type of data that exists, and potentially what this could all mean. Hopefully, this will go from potential being a reality when you come into December and later going into next year. We have a global partner, which is a big part of the equation here. We have a global partner that has an existing infrastructure globally and is our partner to help launch this product in multiple countries as a first-in-class product coming in on the other side of the data.
I think that itself is another capability that other competitors lack for bringing this therapy on a global basis into the market. I think we think about wet AMD, and we've gotten so used to thinking about every patient being the same. I think what the last few years have taught us is these patients are all very different. I think because of the inclusion/exclusion criteria that are being used in different clinical trials, you're starting to actually notice that these patients have a different level of disease activity and a different burden of the disease in terms of treatment itself. Criteria we talked about, how you pick the patients into the clinical trials, is a very important concept because commercially, you go the other side. You pick the high disease activity patient first, and then you think about the low disease activity patient.
When you get into the marketplace, it's the initial experience that drives your behavior as a clinician and as a patient.
Given the fact that we've been so consistent with how we have established the safety and efficacy in our early trials, and potentially if this all plays out, really that experience spectrum that physicians go through in using the drug first in patients and expanding it is a big advantage for the TPP of the product. You heard from everybody, these are all patients live really in long distances. The people that are dropping off are those patients because they cannot come in. When you start thinking about gene therapies, you have to think about the totality of the net burden. Hopefully you guys heard that from them is, it's not a simple decision as intravitreal or subretinal. It's a decision for the patient of a therapy that you have to put into them establishing that foundation.
You have to think about all these aspects is what is the net burden of one choice versus other. As you heard, there is a surgical aspect to one. There is a whole net burden of extended prophylactic steroid regimen that goes on for months, and these patients are gone. There's a potential for them being non-compliant. There's a potential for their pressure going up. All these things fit into the type of phenotype you're picking as a patient that you have to distribute and think about: who do I use this in? I think Arshad brought up a good point. There are so many comorbidities in these patients. It's not a simple choice that you come in and you just go on a therapy. The point being, there are hundreds of thousands of patients that fit into these different phenotypes.
I think retina generally, with all the choices that exist and how we are evolving, is going to be like the oncology space. It's not going to be one answer for every patient. That spectrum and this paradigm of treatment is shifting. Hopefully, we've been able to help you understand how this is going to work in the clinic and what our TPP is potentially coming on the other side of the data. Thank you, and I will give you guys a chance to ask some questions at this point.
Thanks. We get to the audience participation point of the meeting. Ram and Steve and I do this a lot with you in one-on-one meetings, but we have five of the best lifelines you could ever imagine sitting behind us. We want to give you some time to ask your specific questions. I saw Annabel's hand go up first.
Thank you for this. That was very comprehensive across the board. The drug's not approved yet, so we're still in clinical trials, so I just want to ask you a clinical question first. In terms of the study design, Lejla, you mentioned the benefit of having enrolled a broad set of patients for human experience, low burden activity, high burden activity, and we understand the benefit of that. I'm just wondering if on the flip side, if there's any handicap to that. Does it present more variability? Could it potentially present a risk to the trial outcome as you see it? Maybe you can talk about that aspect of it, before all of this, the commercialization, the benefit, the economics, et cetera. Maybe you can speak to that or any of you can speak to that.
Yeah. Happy to take on a question first.
Yeah.
You highlight a really important question. First of all, exactly what you mentioned in terms of this was a very broad inclusion. What was also mentioned today, this is actually one of the first, really the biggest and the first gene therapy program that has been very much undertaking the wet AMD. A lot of learnings have resulted and benefited other programs down the road. What I do appreciate as a clinician is that the fact that we still very much included the very low and the high disease activity patients, because in the real world, it's going to help me understand how to use that. I very much, like Ram mentioned, will start this in patients who need it, need injections more frequently, those high disease patients first and see. You're right. At the end, what kind of results are we going to see?
I most certainly hope to see positive results in terms of to bring this to the market. Yes, this variability may introduce variability in those results as well. I think I definitely want to point that out to take that into context as we review the data from the trial as well.
Annabel, I can also add a little bit to Lejla's point of view on that. I think it shows the confidence in the team at REGENXBIO to actually go for both high and low disease patients. They have a very efficacious drug. We've all seen it, as investigators and people who've recruited patients. I take it as a sign of confidence.
Yeah, I just wanted to add that it's in clinical trials, obviously, high need patients can drive vision down over time. I get your question, but the good news here is that the supplemental criteria are very tight. They're not very loose. We're not allowing 75 microns of fluid and five letter laws or 100 microns of fluid. I think as we go into the data readout, I think you asked a really important point that we have to keep in mind. Do I expect monthly Vabysmo patients to be injection free with sura-vec? Yes, a subset, but other half, no. Am I reducing the burden significantly for those monthly patients to every four or six months injection, maybe one or two a year? I think that's a huge Achievement, I know from Wall Street perspective, is always about injection-free and not about treatment burden reduction.
I think you bring a really good point where when we look at the data, what I've learned, and after AAO, again, a great program, I walked away with a lot of questions than answers. Many times, I think when you look at the data, you look at the top line, but I think details are important to look at when the data is presented. I think this is something to pay attention to. Like, how are we doing with those patients that are monthly? Because you may not have those patients in other programs. I think the supplemental criteria will protect vision so that we can potentially meet non-inferiority.
Yeah. To add to that just a little bit is, that's why it's so important to contextualize the injection-free rate when we look at the top-line results that come out across the board.
Go ahead.
No, go ahead.
Just one real quick comment. How we define high and low need is also very different depending on the patient, right? Somebody might say, "Well, gee, four or five is low to me." Somebody else might say, "For this patient, four or five is high need." That's another variance in clinical acumen that we're going to use. in December we'll know in terms of after hopefully it gets approved.
Next.
She wants the mic.
That's
Oh, hi. This is Shelby. I'm here for Luca Issi from RBC. I know a few of you highlighted that there's no prophy steroid regimen required for the gene therapy itself, but we were just curious if you could clarify if steroids would still be required for the surgery, and again, just how impactful that is to patients compared to maybe other therapies. Thanks.
I can answer that question. Steroids are required for any surgery, whether it's cataract surgery or vitrectomy surgery or LASIK surgery or whatever you do. But that steroid regimen is typically very small, so about two to three weeks, maybe four weeks or so. You start to see issues with steroid use in terms of IOP not after that point, but it's typically sustained steroids. One is short-term, and one is sustained. That's the difference. Hopefully, that answers that.
Thanks. Graig Suvannavejh at Mizuho. Great panel and great program. Thank you. I would like to ask each of the KOLs if they could just quickly provide their thoughts on, let's assume that all of the experimental agents gene therapy are on the market. I am curious as to knowing that all patients are variable, but broadly speaking, what percent of your patients do you think, if you thought about your practice, do you think would be appropriate for gene therapy? Then maybe just trying to get a sense of the uptake of these products. Is this one obviously a different dynamic than when HD came to the market versus Eylea 2 mg, like pretty much new Eylea as a product, but is gene therapy going to take a little bit longer to get people comfortable?
Just trying to get a sense of adoption and uptake and how long that might take. Thanks.
I started last time, but do you want to start?
Oh, yeah. Sure.
I'll pass it to you.
Yeah, that's a great question. In the real-world practice, I think Lejla showed a slide where we saw the percentage of patients that actually get out to Q16 weeks in the real world, and I think that was somewhere in the teens, if I remember correctly. When we think about the optimal patient for which type of gene therapy, the patients who need less or have lower disease burden, those are the patients that are great for potentially IVT. We see that percentage based on how many patients can get out to Q16 weeks, right? Those are the patients that are going to do well on IVT gene therapy because you have to reduce the dose for safety. We've seen that across the IVT trials.
When we think about the other patients, the ones that are actually high need, and there was another slide there that showed the need and which patients are eight weeks and less. Those might not be ideal for IVT because they're higher need. They're not going to be meaningfully reducing the potential injection burden or reducing it to zero, as is the case with sura-vec.
Yeah, I think what I would say, nice to see you, Graig, as always. I would tell you that with my experience over the last decade in low need, moderate need, high need, and I'm talking about gene therapy as a class now. I've seen efficacy in all of those patient populations. As long as the gene therapy is safe, it's a one-time injection or one-time subretinal injection or intraocular injection. My question comes is, why would we not treat a patient that is needing three or four injections and can get sick and not show up to my clinic for two years and go blind? Why are we going to just limit it to a small subset of patients, right? As part of gene therapy trials, like many of my colleagues here, they were very easy to recruit.
Having that opportunity, as I said earlier, not having injections half of the time and reducing the injection burden is a huge achievement. As Rahul said, this is like a reality, and this is a big paradigm shift. For me, I think it is going to be patients. Now, obviously, we can talk a lot later if you want about IVT and subretinal. I think as Ram said, the market is big, and there are opportunities for both. But I think to me, it is going to be payer driven at the end of the day. Do payers want us to go through all the injectables in our toolbox? We did the TRUCKEE and Taylor study, again, faricimab added two weeks to aflibercept 2 mg, and I do not think aflibercept 8 mg is any stronger.
We are still sitting at this one or two-week incremental benefit over the last 20 years. Here, we are seeing months and months of benefit, if not long-term benefit in terms of vision, in terms of fibrosis. To me, I have been through all of those patient profiles, and I have seen it work. As Ram said, if you are low or medium need, likely injection-free, if you are a high need, significant reduction in treatment burden. Hopefully we can convince, as a community, and Gaurav, you will be super important and Rahul too, both of them work closely with AAO, that if we can show better long-term outcomes for patients, we will hopefully have this available sooner for our patients. That is where I stand. My question would be why not why I should. A little bit different way to think about it.
Well said, Arshad. To add to that point, similarly, all of us as we started these clinical trials, we very much were eager to enroll the high disease activity patients and felt comfortable doing so. Just like other drugs after approval, we will very much mimic that in the real world, starting with those high activity patients to see what the response is. I can tell you similar, like the rest of the investigators here, as we progress through the programs, I very much grew comfortable to now enroll my recently diagnosed or newly diagnosed patients in other programs. So the comfort will change with time. It is going to be based on efficacy and safety, most certainly.
But if I look at my larger patient population, I think the graph that I showed earlier is very much consistent with 40% of my patients right now fall into that high category, high disease activity category, and then the rest outside it. But eventually, all of us will feel comfortable treating all of those. At the end of the day, the payers will drive the decision-making, and to this date, I wish I could offer what I think is the best in class for all my patients, but it is going to be dependent on all of those factors and equations.
I'm going to give you just a little. I agree with what they've said before. I think we all have a very similar perspective because we were all involved in these trials. We enrolled these patients. Our first set of patients were the high-need patients, and then once we got rid of all them, then we started talking to our other patients, and we started feeling more comfortable with it, and we started using it. I think when you take someone in practice who's not been involved in the clinical trials, there's going to be resistance. There's going to be lots of reasons not to do it. It's something different. It's going in the operating room. There could be financial considerations. There can be all these issues that may blunt the uptake a little bit, to be frank.
I think as people start looking at it, they're going to use it first on their high-need patients who need it all the months, and they see good results there. Then they'll start branching out and going to other areas. I can give you my experience with even the "second-generation agents," everyone, they came out with a lot of hype, and I used them on my high-need patients, and I found they did very little. They didn't move the needle very much, and so I think that's, in practice, that's our clinical, our laboratory. Those are the patients we're going to see it on, and if this product can make a difference there, I think it's going to get a lot more uptake, and it'll build off that. But to also keep expectations real, people who are not involved in these trials, it will take some more time.
Now, that being said, for all of us who were involved in these trials, because it was so safe, we had such good outcomes, there was very good uptake. We had another surgical device for neovascular AMD that had excellent outcomes, but there were some severe complications that many of the investigators saw. So when it became available, there was not a huge uptake for it. I don't see that with this product just because of the great efficacy that we've seen so far.
Another little point to what has been made. The last part of your question is what's going to be the uptake, the ramp-up, and so on and so forth. I think as surgeons, we make these decisions every single day. When I see somebody with a retinal detachment, I say, "I can do this technique in the operating room, or I can do this in the OR for the right patient." I have to weigh the risk benefits. This technique has a 67%, and this is almost a 98%. So we make these decisions surgically all the time. So I think that's going to be patient-dependent. The issue is there going to be a ramp-up? There's always going to be some time to ramp up this procedure, but as I had mentioned, we already have over 500 people trained already to do it. We do this every single day.
We do it at facilities that do it every single day. We have facilities wanting to do this. We have patients demanding to do this. I think the market is going to go where patients want to go, and I hope most importantly from an organizational standpoint, from the ASRS Academy standpoint, we have to make sure we get the payers on board. Because from the global picture, it doesn't really matter what we want to do. It's what they allow us to do, quite honestly.
I think when we talk about payer support as well, this was one of the main elements of the AbbVie relationship. Why we signed up four years ago to partner with them was the commercial muscle that they bring to bear.
Yeah, and that's critical.
Absolutely critical.
Yeah.
All right. Brian Skorney from Baird. I would love to get input from really everyone on the panel, but just when we see the phase III data, it seems to have the nuance of having a primary endpoint, which may not really satisfy anything other than hitting the primary endpoint, but usage may be more determined by the secondary endpoint. So I guess from your perspective, if you could put bars around some of the secondaries for what sort of definitively practice-changing, a commercial street fight and irrelevant. Is it a 90% reduction in treatment? 90% of patients have no treatment. What are the bars that you see there? Second question I would also have, is there an ASP for sura-vec that could make this more profitable than anti-VEGF injections for your practice? And what would that ASP be?
I will take it. You take it.
Oh, we can start right here then.
Yeah.
I think for me, I think if we can have half of the patients injection-free, I think that is a huge achievement. Remember, the disease is heterogeneous and variable at times, but majority of the patients are still sitting on frequent treatments. If I can get half of the oral population injection-free, that is a huge promise and a paradigm shift in my mind. When you look at injection burden, right, even as Rahul said, second-generation agents are adding a few weeks, not months, few weeks. If somebody is getting, let us say, every six weeks or every two month injection, and you reduce six injections down to, let us say, two injections, that is a huge achievement. So I think the number I have been telling all of you for years, I hope it is true, at least we hit that, is 50% for me as a practicing physician.
I can just tell the patient, "50% of the time you won't need injection. We'll have enough drug to control, or we're going to have significant reduction, 50%-75%." So instead of getting an injection every six weeks, now you may get it every four months. Something like that I think would be ideal. From the ASP piece, I don't own the surgery center, so I don't see that. So I will not see the profit on the drug unless there's different ways to do it, because I don't own the surgery. It may be different for Ram because he owns the surgery center.
Yeah. I'll say that from my perspective, I agree with exactly how Arshad phrased it. In fact, that was basically what we talked to patients about when we recruited them for the trial was, "You're sitting in the chair and you're going to be on a chronic injection schedule for the rest of your life. And I have a treatment that can potentially 50% or 60%, based on the phase I, II data, can make you injection-free." And that was enough of a sale because the thought of getting an injection in your eye when you're sitting in the chair with the doctor with the needle in their hand makes you think really quick about potentially not getting that injection. So from that perspective, I think 50% would be a big win.
From the ASP perspective and net cost recovery, our typical injections are somewhere priced around $2,000 for the anti-VEGF intravitreal injections. If we looked at something in the $35,000 - $50,000 range, which is, we see the other kind of intraoperative procedures, and some of them are up to $250,000, $450,000. I think that would be a great number, at least from my perspective. And to be clear, I have no insight into what the commercial team's actually going to be doing on that.
Yeah, and another with, again, exactly, it's the denominator, right? That determines all of that as well. So of course, the answer is more, right? That's always the answer. But I do think we also don't want to lose fact of the facility fee, right? That the facility fee that your institution or surgery center has the ability to charge. Because there is no facility fee unless you do your injections in an ASC, where I guess that's how it's done in Europe. But we do our injections in the office, most of us, or I would say a vast majority of us. So there is a facility fee component that is not part of the intravitreal injection component.
That becomes a valuable asset if you own your ASC, but also if you are partnering with an ASC or a hospital system, because again, you become a valuable asset that brings another valuable asset, and that is how health systems think.
I would just say, I think it is really hard to come up with a number. The reason why, it was back to your question, is a lot of the clinical trials that have been designed the last five to six years are by really smart people who have really taken advantage of a lot of the way things look. AMD is a very variable disease. When you start selecting for certain patients, you can really cook up your outcomes in a certain way. You can also very cook up your outcomes with having low rescue rates if you have very high non-real rescue criteria. You have vision loss that we do not accept in clinical practice. Yeah, you can have 100% injection-free interval if you say, "Look, they have to lose so many letters," right?
Unfortunately, the devil is in the details on how these studies are designed, and I think one of the real challenges is that we know AMD is a very variable disease. We know from the original studies, nearly 50% of patients can go to 12 weeks with ranibizumab and aflibercept. So that is with our old, quote unquote, "treatments." So if you select for those patients, you can definitely have better results. I think the one part that is, I think, very reassuring with this program is that in their phase I study, they did not look at those. They looked at the really, really hard patients, the extreme ones there. Because there are such great signals there, I think that is what gives us a lot of confidence that this is something that is not just been clinically designed.
They have not just selected for the easier patients, but rather took the more challenging patients and saw a signal. Now we want to see, is this something that is mass producible, and we can see where it goes.
Yeah, and one more thing, and I like to get latest and put it on this. When you go to a health system and you're bringing something new such as gene therapy or Encelto, they're interested because your other colleagues in neurosurgery and orthopedics and all these people are like, "Oh, this is really something new and interesting," akin to when robotic surgery, the da Vinci, came about for prostate surgery. Every hospital system, every surgery area wanted the da Vinci. I think that is that effect of, quote unquote, "surgical gene therapy." That's what I've seen, because I got an answer from the neurosurgeon saying, "Hey, what is this something new that we saw in the proposal for gene therapy in the Sutter Health system?" There is a cachet to that as well.
Yeah. There's definitely all around excitement as we are hearing excitement from our retina community, excitement from our patients. When your question comes, what is that target in terms of injection for your treatment burden? I really would go back to, I think Ram said it earlier, foundational therapy. Having something that is really controlling it steadily, even if we need to top off, so to speak, an additional injection, will be, I think, really disease-modifying therapy for my patient. While yes, down the road, we'll learn what that truly means as we see the results from clinical trial and long-term. But I can't help to wonder why having something that's steadily produced in the eye is not changing permanently the disease activity and really leading to beneficial outcomes long term.
I definitely hope that's going to pan out and what we're going to see in pivotal trials and further down. But having something long term I think is really key. Then the other question is in terms of seeing what kind of reimbursement and whatnot. Having practicing in a hospital system, we most certainly can and do charge these facility rates and do charge hospital rates for therapies. I do think that would be beneficial for hospital system to adopt this technology and therapy.
Hello. Great. Thank you. I'm Max Skor with Morgan Stanley. Let's say one patient received the gene therapy in one eye, then the second eye converted. How long do you think you would follow the patient post-procedure to be comfortable treating the second eye? What are you specifically looking for to get comfortable around that? Thank you.
I'll take that question just because I actually participated in the fellow eye study. Being a part of the fellow eye study, we had treated patients initially all with sura-vec in their initial eye. We had a certain set of criteria that the folks at REGENXBIO put in place for the fellow eye study, and we could only offer that to a handful of the patients who had bilateral disease based on their inclusion/exclusion criteria for the fellow eye study. Every single one of the patients that I offered fellow eye treatment to, they all uniformly accepted and wanted to have the treatment done right away. It really comes down to the patients. But what I saw in my practice when we recruited patients was every single patient who got sura-vec in the first eye wanted it in the second.
I don't know if my colleagues have a different take on that.
Yeah, no, I agree. My experience also in sura-vec, but also with the other program Rahul mentioned, it's the Port Delivery System, is sustained delivery is actually very beneficial to patients. I tell people that PDS gets me more hugs than ever. Patients come in with no anxiety, no fear. I think one thing that didn't come in the conversation today is the patient-level anxiety and fear, and how their life gets disrupted with 24 hours of irritation from the injection. I think, to me, there's obviously, theoretically, if you have a bilateral disease, you do well in one eye with sura-vec, you automatically want it. Even if I don't want to do it, the patients will want it. But from a practical, real-world perspective, I personally would like to wait three to six months. I would like to let the eye heal.
I'll see how the disease activity is controlled, how things are looking. I think your question was probably about that real world. I would say probably in my practice at least, I was going to do three to six months before I treat the fellow eye. I don't know about Lejla.
Yeah. No, I agree with you. I would want to wait till I see how they responded to surgical therapy. In sense that I want to taper them off those surgical post-op steroids and just see them. Routinely for other therapies, I wait one month to three months. So I would say about that range, one month to three. I also want to piggyback on prior thing. Our patients that have been enrolled in trials, such as this one, are absolutely loving it. I can tell you the number one recruitment for me have been actually these patients that were in current clinical trials. So they very much talk while they are waiting in our waiting room. They talk in their community centers and whatnot, and they absolutely love the fact that this is maintaining the vision but really keeping them injection free.
So we cannot underestimate the patient component of that. I know more and more we will see patients coming to us saying, "Doc, I have heard about this. I found out from ChatGPT or whatnot." They will be asking to have that longer duration without injection therapy for sure.
I think one thing I just want to add, just more from a global issue, is if you look at complications of vitrectomy, there is early complications and late complications. I think that is what you are referring to. I think it is important for the community because you have been all used to just injection, injection. We have to change that mindset. So the early complications with vitrectomy are really infection, so on and so forth. Those typically it would be about a week, and all the other things I have mentioned, we typically wait about three months for all the other rare complications. So there is an early and a late, but typically I would say three months is probably appropriate, for just the surgical procedure, agnostic of whatever you are putting in the eye.
So if that answers that question, because it is a different mindset, it is a different therapy, but it is something we have been doing for umpteen number of years, and now the technology, again, it is like driving a Tesla versus what you drove before. Again, nothing. I do not have any stock in Tesla, so.
Hi. Lili Nsongo with Leerink Partners. Maybe two questions, one for everyone and then maybe one for the REGENXBIO team. Starting with the pivotal trials. Do you have any differences in expectations for ASCENT versus ATMOSPHERE? Are there any rationals to think that expectations or outcomes would be different for either of the studies? Then I guess the second question would be thinking about the two doses.
Do you expect to take both doses and make them commercially available? Would they serve different patient populations?
I can take the second one. Steve Pakola here. One important point is we do have our global partner, so we cannot really give any kind of specific aspects, and of course, it depends on the actual result. I do not think you would look at it any different than the way you do in general in drug development of weighing safety and efficacy. The panel has all rightly said safety first. So if there were a safety issue with a higher dose, but you still had good efficacy in both, that would be a hypothetical example of the lower and other scenarios. But I think the overarching aspect is we in AbbVie are very excited that we have got two shots on goal.
I think the design, Steve, you can cover that too, I think. I was part of both, and I do not expect The control arms are different. Otherwise, everything is the same, but you can address that.
I mean, obviously, one is more U.S.-based, and one is more global. That is a little bit of a difference. The control arms are a little different. One is monthly ranibizumab, while the other one is aflibercept, but those are both shown to be non-inferior, so there shouldn't be any difference on the outcomes, and there's substantial data that both control arms have similar efficacy, and those are the standard of care that we have there. I don't think there should be any surprises there. Obviously, whenever you have. I think our global partners now, I think the quality of our work internationally has gone up so considerably that I think in the past with some clinical trials, when we had a lot more sites internationally, there was some uneven data.
I think that has really changed, and I think we have really great global partners, great clinical trial sites. I don't see anything that would really jump out to me or a concern that would be there.
Yeah. Similarly, I didn't see any concerns and again, mimicking the real world in terms of therapies that we use currently in the real world. I would say, again, globally, yes, there may be some variation disease between different areas, but overall, really, I wouldn't expect differences.
Certainly, one of the benefits of such a large program is it minimizes the risk of random chance differences between the trials.
Thanks. Paul Choi with Goldman Sachs. Thanks to the company for hosting this great panel. I want to maybe just turn to a related topic and ask the physicians just how they think about sura-vec in adjacent indications such as DME and DR and just maybe some high-level thoughts there on its application. As a second question, if sura-vec were available commercially tomorrow, how do you think about potential maybe off-label use in your DME or DR populations as you think about its potential use as a therapy for those patients? Thank you.
Well, I think recently, I presented the data from ALTITUDE study, three-year data, very impressive findings in DR regression. It's a suprachoroidal injection, obviously, and that's now in the phase II-B/III NAVIGATE study. So more data to be seen in the future after enrollment. But we have seen this long-term benefit over three years now in patients with DR, with significant reduction in vision-threatening complications, as well as improvement in DRSS, which we have not seen with anything else to date. So I think DR is a very large market. A lot of my patients, we all know anti-VEGFs work, but the burden of treatment is so high in patients who see well. So having a one-time in-office treatment obviously would be very well accepted by the community. I think so DR program is very exciting. DME, I initiated the investigator sponsor trial, the ELEVATE study, which we presented.
Again, Gaurav was the co-chair of the program at AAO. Very well received, but early days, but we have actually seen efficacy in maintenance or improvement in visual acuity, in disease activity, as well as significant reduction in treatment burden. We are also using two doses. But a small study proof of concept that we are seeing the signals of benefit in DME. So I would hope that once we have longer-term data, then the team can actually evaluate because I think that DME is another large market where patients actually are even less compliant, and they have a lot more missed visits and loss to follow-up. But I think we are quite advanced in the diabetic retinopathy trial, and I think gene therapy for DR is needed, not just in the U.S., but around the globe, so we don't have young patients losing their vision.
Yeah. When we talk about unmet needs, that one's even greater in DR/DME patient population. Why? Because this really working-age patient population, and we all know how hard it is to put in all those appointments on your schedule and come back. When your second question was regarding potential off-label use, I think as the retina specialist interest retina community uses many drugs off label. I do think there will be a challenge with use of this particular therapy when approved off label because of the fact that the OR will have to be covered, the drug cost will have to be covered. I find that my patients often when they hear that they would need to have to pay something out of pocket, they often shy away from it. So if the insurance were to pay for it off-label use, yes.
If it does not, I find that patients are unlikely to say yes.
It's a no from me. Gene therapy, it's just going to be difficult. I don't plan to use it for DME unless it's approved.
Yeah. I think that I appreciate that question even before we have an on-label that we're talking about off-label. So that shows there's interest.
That's the mentality of a retina specialist. You know that.
We're very promiscuous when it comes to therapies. The issue comes in is I think Ram is going to get the teams and get us samples like we get for off-label stuff. Again, I don't see that happening. It's very easy for me to take an anti-VEGF, either samples or bevacizumab for off-label use. But I really think for this, the OR is not going to let you do an off-label of this issue. Again, now, if there's a way to target this therapy in some of, like Arshad has shown, maybe there's a way. But I just think we should concentrate on the approval first and then on-label and so on and so forth. But I really appreciate you thinking farther ahead. So that's great.
Hey, guys. Alec Stranahan from Bank of America. Thanks for hosting this really great discussion. Maybe a follow-up on the fellow eye and also the off-label, on-label. Do you think you'll need specific language on the approval on the label for fellow eye administration? Or if this is more just a physician education based on the 71 patient subset that you have. Then maybe one for the panel just around going in, obviously, fellow eye or retreatment with a gene therapy was not a given. Were there any, I guess, reservations that you had and how has the data, either on neutralizing antibodies or something else, how has the data made you feel more comfortable around administration?
Yeah, I'll take the first one, Alec. I think what's important here is we've discussed this with the FDA, and we've actually aligned on this. Given everything all the panelists have said that the ability to treat the fellow eye is a big deal. And you see the interest from the patients. Well, the FDA is aware of that, so they want to make sure that there's exposures that can help understand, can you safely and effectively administer to the fellow eye? So this has all been aligned with the FDA.
Yeah. What was your first question? Can you repeat it? I am sorry.
Second one was about-
How come that-
Fellow eye and neutralizing antibodies and other things. I think
Maybe Steve, you can answer that, too.
Yeah. Theoretically, and also even from preclinical data and any of the clinical data out there, we know that the immune privilege status of the subretinal space is really the best that there is. It's a relative immune privilege, but we know from all the different studies that have been done that you have less systemic spillover. When you think of fellow eye treatment, that's the key issue. Do you get a systemic response that then you prime the immune system for the fellow eye? You'd hypothesize that wouldn't be the case with subretinal. That's what we've actually seen. From the bilateral data that's been shown, we've seen no effect or difference in the type of safety and efficacy that we're seeing in the fellow eye.
Yeah.
Thanks.
One other comment on off-label use. I don't think it's something that we typically see anymore with the new branded products. The reality from a person who does a lot of buy and bill is we don't get reimbursed for off-label use. If we talk about from a practice economic standpoint, that will kill the economics of your practice if you do a lot of off-label use. I think with gene therapy, the other issue is liability that can be involved. We want to make sure we're always on the right side of the label, especially when using any new modality.
Yeah. It's easy with bevacizumab because there is no approval.
Right.
You can use it for anything. But yeah, for branded, for example, myopic CNV, we were just discussing about, we don't have approval for aflibercept or Eylea. We still use Lucentis for it. Yeah, for branded drugs, we have to follow the label. I think fellow eye studies are super important. I think whether it's subretinal, whether it's intravitreal, we need to know can we safely deliver a gene therapy treatment? Our neutralizing antibodies also can affect efficacy, right? If you have a lot of neutralizing antibodies, you may actually get. I think both efficacy and safety are important, and I think studies are actually needed for all gene therapy modalities to show that it's safe and efficacious to apply bilaterally.
I was part of the study, just like Rahul was and many of others, and looked at the data, and we didn't see anything in terms of safety or efficacy that was creating any signals. It's actually very good to see that. Hopefully, potentially, if it's approved, then fellow eye is definitely a concern because as Rahul showed the case, you can treat one eye, and the other eye needs monthly injections. The treated patient still has a visit burden as well as injection burden. Our goal is eventually all patients become bilateral, usually say 10% per year risk. I think it would be nice to have that option.
Yeah. Back to the question of bilateral eye treatment. We already are doing that for gene therapies in IRDs. My comfort level as a specialist who takes care of IRD patients and treat those with gene therapy, such as Luxturna, I can tell you in that protocol, we actually administer the other eye treatment two weeks after first eye treatment. So we already have in a real-world setting experience with that, most certainly. There are other inherited retinal disease trials that very much are following that enrolling and treating the second eye within two weeks of initial treatment. So we have strong, clearly data from other programs, not just wet AMD to tell us that, yes, in subretinal approach, definitely we have great outcomes in terms of safety.
All right. Thanks to the panel for the discussion. This is Sean McCutcheon from Raymond James. Arshad, you spoke to this a little bit earlier, but maybe open it up to the panel. Can you speak to your retreatment paradigm, that your threshold for fluid, how this aligns with the ATMOSPHERE and ASCENT rescue criteria. In this context, how you'll be looking at ATMOSPHERE and ASCENT at one year to assess whether sura-vec is driving a meaningful treatment benefit, and what a sufficient portion of the population will be to garner utilization in your clinic.
Yeah. I can answer that one. I'll tell you, in the phase I study, which took these really hard treatment criteria, they had the most open policy to treat. Any reason the physician wanted to treat, you could. It was small studies, a phase I. You're taking these hard to treat patients. Even that reduction burden of 60%, it was actually pretty impressive because the physician could use any reason. There wasn't a criteria. You didn't have to have a certain amount of fluid, vision loss. It was really up to the clinician. That really, I think, to me, was very reassuring. Now, when you move to a phase III study and you have 300 investigators, you can't let anyone just treat as they treat.
You have to have these strict criteria, and this is where it gets challenging because some of these criteria are maybe a little bit too conservative. Some are, they're usually too liberal and there's too much fluid being tolerated so they can have better outcomes. I can just tell you, I was involved in the ATMOSPHERE. When I looked at their criteria, their fluid, and their vision loss, it seemed very reasonable and nothing out of the blue that seemed egregious or anything of that nature that seemed too much, or we were tolerating too much fluid. A lot of patients that I was concerned about, I could always talk to the monitor, and if I wanted to get the treatment, it was there. I didn't have any resistance on that level.
For me, the retreatment criteria really, it wasn't pure real world because at the end of the day, it's not a clinical trial and that's the difference. But it wasn't also an unrealistic retreatment criteria, which is something we don't mirror in the real world.
One thing, just as a general point is, as much as we've learned in the clinical trial so far, I think the learning will be exponential as the product hopefully gets approved and we have it in our hands, both from a treatment, retreatment, patients, surgery, what do we do. All of these things are going to be a very steep learning and it's going to be very fast for all of us to, sort of, in our own patients that are not clinical trial patients, in our own hands for surgery that's not part of a clinical trial. I think that is going to be the things we've always learned in retina. When a new product or new way of doing things comes about, we're a pretty small community. We're not 40,000 oncologists. We're 3,786 members of the ASRS. That's the exact number.
Because I just looked at it last night of people who haven't paid their dues. There's a few, not on this panel, but they've all paid their dues. Again, I think that we are a small community that really, again, we all appreciate all the great studies that this team has done and all these members, but we all really trust each other's experience, and the experience is what's going to drive this. It probably drives all the analysts crazy because in retina we have great protocols in studies, and then when in a therapy or drug or anything gets approved, nobody really follows them. It's not like oncology. They have protocols, and they kind of follow it. We just sort of do our own thing. Sometimes I think that is hard to predict and hard to do, quite honestly.
There's just one last point I wanted to make, Sean, to your question is, meeting primary endpoint is super important because otherwise you don't have a product. The criteria that's been there is not tolerating too much disease activity. That gives, hopefully, potential shot on meeting non-inferiority. Then we look at the data in detail, and I have full trust in the team here to be transparent. We have had a lot of issues with transparency lately. What is real world fluid means? What are you using to define that criteria? What is the safety going to look like? I hope that as a field, we see the full data set. The full data set, again, let's say that injection 3 is 40 and not 50. I'm still fine because I want to look at how the high disease activity did, how the moderate and low.
I don't want people to fix it. Having a positive study in a pivotal gene therapy program for a common retinal disease will be a huge achievement for the field. I cannot specify how important that is for the field. Then everything else, as Gaurav said, is going to work out. We'll look at different subgroups, different baseline characteristics, and again, bringing value for many of our patients. But I would really want to highlight again, please hope and pray that this is positive because it's going to be a huge milestone for the field.
George, you're giving us the hook. I saw the finger go. I don't know if you were just cold or what the deal is.
Yeah. I think we're coming up to 4:00, and we'll have to stop the questions at this point. I do want to make sure we pause here to thank the panel. This has been incredible to have you here. I also want to thank the REGENXBIO crew that put this together. It's really been a great setup for our top-line data coming in Q4. We do have cocktails, I'm promised, next door at next couple of minutes. So those of you that are able to stay and mingle a bit and maybe ask a couple of questions over a cocktail, you're welcome to stay with us. But thank you for dedicating your afternoon to us. The support from you is also absolutely critical to this program and getting this therapy to patients. So I appreciate it.
Curran, can I just, on behalf of really the ASRS, I want to thank this entire team for being honest with our members and be upfront. I deal with a lot of companies, not as much as Arshad does, but I certainly deal with them on a different, kind of a global perspective. At every step of the way, you've been honest and upfront with our members, which is what we expect and what our patients deserve. I really want to thank their entire team for working with our organization to hopefully bring a new therapy to market that helps our patients, because that's what we're all about. Thank you