Thank you, everyone, for joining. I think we'll go ahead and get started. Okay, that's a good one. If I should just say first thing first, I mean. Let's get going. It's fun. Yeah, yeah, yeah. All right. It is my pleasure to introduce the participants for the panel titled In Vivo Gene Therapy: Breaking into Competitive Ophthalmic Indications. From far end from me, we have Chris Simms from 4D Molecular Therapeutics, Shankar Musunuri from Occugen, Rafiq Hassan from Complement Therapeutics, and Stéphane Boissel from SparingVision. Welcome, everyone. I appreciate you joining us for this panel. Thank you, everyone, for joining. To kick things off, maybe if you could take a minute or so to introduce yourself and introduce your companies and maybe the lead program that you're working on. Stéphane, we'll start with you. Sure. Stéphane Boissel, I'm the CEO of SparingVision. We are an ocular gene therapy company, obviously, working on AAV. We have three programs in development, two in the clinic. The lead is in phase two, completing phase two as we speak in retinitis pigmentosa. Those three products are gene-agnostic, mutation-agnostic, and also disease-independent. You have to look at them as platforming products. We start by first in man in retinitis pigmentosa to prove the concept, and then we'll expand into indications such as geographic atrophy. We only target prevalent indications with no standard of care. Oh, I got my mic. Rafiq Hassan, CEO of Complement Therapeutics. As our name suggests, we're developing medicines that basically address complement dysregulation. Our lead asset is an AAV-based complement modulator gene therapy about to enter the clinic for geographic atrophy secondary to AMD. It's a complement modulator, and we recently achieved IND clearance. We're just gearing up to go into the clinic in the U.S. and then potentially to the U.K. and beyond that as well. Shankar Musunuri, Chairman, CEO, Co-founder, Occugen. We're a leading ophthalmology gene therapy company with two in the late stage, one potentially entering next year into late stage, targeting retinitis pigmentosa, which covers about 300,000 patients in the U.S. and the EU. Stargardt disease, about 100,000 in the U.S. and the EU. The last one is late stage dry age-related macular degeneration, GA, which covers 2- 3 million patients. What we work on are modifier genes. These are master regulators. Genes don't work in isolation; they work as a network. We regulate key functioning genes in the network with a master regulator. Because of that, we're able to target the entire disease, not one gene at a time or one mutation at a time, unlike traditional gene therapies or gene editing. We are planning to file three BLAs and three market authorization applications in the next three years, starting with RP 2026, Stargardt 2027, and 2028 is geographic atrophy. Thank you. Good morning. Chris Simms, the Chief Commercial Officer with 4D Molecular Therapeutics. 4D is obviously a genetic medicines company. We have invented and are developing novel therapeutics and novel vectors for both rare and large market disease opportunities. Our lead program is 4D-150. 4D-150 is currently in phase three in two phase three trials. The first Forefront 1 we started in March of this year. Forefront 2 was initiated in June. In wet AMD, we are developing 4D-150 to be a global program. We are pretty excited with the progress we made so far. In addition to wet AMD, we have a regulatory path forward for both the FDA and the EMA for a single DME study currently on funding, but both large market opportunities that we are pretty excited about. We also have a program in cystic fibrosis, 4D-710, that we just announced a partnership with the CF Foundation to advance that through to phase two. Excellent. Thank you, everyone. The way I'd like to lead this conversation is to focus on three topics. I'll talk about market landscape first for large ophthalmic indications, then I'll talk about clinical development and regulatory challenges, and then I'll touch base on commercial and access points. As you mentioned in the introduction, all of you have programs for large indications spanning geographic atrophy or dry AMD, wet AMD, and diabetic macular edema. For those indications, we do have some approved options that are available. For wet AMD in particular, we have a number of options that are available and are on the market. With that, what differentiators do you think will define the success of new entrants such as yourself to this more or less established market in those indications? Chris, maybe I'll start with you. Yeah, happy to. You know, I've been in the retina space on the commercial side for 12, 13 years now. Genentech, Novartis, and last IZERVAY for GA at Iveric Bio. When it comes to diseases, certainly like wet AMD and DME, the unmet need has continued to be about better durability. We know that to be true because if you see new agents such as Eylea and HD come to market, they offer an incremental benefit of durability of a week or two. Despite what's largely an incremental benefit, they become very, I think, robust commercial successes. If you talk to the retina physician community, and they do this through something they call the ASRS PAT survey, which they administer every year, what physicians continue to look for is advances in durability. I think real differentiation comes from an approach that provides not just incremental benefit from a durability standpoint, as another week or two or a month or two, but what we're aspiring to do is actually create a differentiation that's measured in years for many patients. That's what we think the promise of a genetic medicine approach can provide. It's really changing or setting a new paradigm where you have backbone therapy like a 4D-150 in place, and then all of these other bolus therapeutics, which are highly efficacious, can be used in supplementation. That's how we see a possible future and how we would differentiate. Got it. Thank you. Shankar? Yeah, our approach at targeting late stage dry age-related macular degeneration, GA, there is a significant unmet medical need. Even though we have a couple of therapies in the U.S., EMA rejected both of those programs because they could not show functional benefit. In order to treat a disease, you need to go to fundamentals, how the disease starts, how disease progresses. There are four key pathways: oxidative stress, lipid metabolism, inflammation, and complement system. The first two pathways are the core. Disease pathogenesis actually initiates and also continues to progress. You really have to go to the core, fundamentally control it. The way Aurora, another modifier gene that modulates all these four pathways, and also resets homeostasis and creates a healthy environment for retinal cells to survive. That's very important because retinal cells are non-dividing cells. What you have is what you have. That's why, as we all age, we have retinitious. If I can do something to reset and create a healthy environment for them to survive, potentially they should survive the rest of their life. We do have very strong publications in Nature in all our gene therapies. Now, what we are seeing is in phase one, two, clinical trials, consistent data, not only looking structurally at a lesion growth, controlling the lesion growth compared to untreated, as we have seen in the approved therapies, we're also seeing functional benefit with visual acuity. That's really important. What we are seeing across the board, this is very important. Why? Remember, these patients, if you talk to physicians on the front lines, retinal surgeons who are treating them, if they have to take monthly or every other month, even every three months, it's a big burden on the family. If you're 74, somebody has to drive you to the doctor's office for an appointment. How many times are you going to go in a year? They're dependent. This is a real issue. People really talk to a lot of retinal surgeons. They'll tell you 90% of them say major issues here. If there is a gene therapy out there which can not only have potential to control disease progression, it has potential to stop or stabilize or even improve with a one-time therapy. I cannot call it cure because FDA doesn't give a label like cure. These are potential curative therapies, one-time treatments. That'll be a paradigm shift. That's what we're working on. We are planning to finish our phase two the first quarter next year. We are getting consistent data, good data in our phase two clinical trial, as we have seen in phase one. Also, the therapies seem to be safe so far. In all our gene therapies, we don't have any SAEs related to our gene therapy. It's safe, promising results so far. I think if you can show structural as well as functional benefits and with a one-time therapy for life, I think that'll be a paradigm shift. That's our approach. Excellent. Thank you, Shankar. Rafiq? Yeah, I mean, I think just building on some of the points already made, for sure, there's an unmet need in terms of efficacy. I think we've seen with the IVT complement inhibitors, slowing of disease progression by probably around 15% in year one. As Shankar said, that hasn't necessarily translated into a functional improvement. One of the challenges there is that patients coming back, they came back in the early days with IVT anti-VEGF because they saw better. That was a big motivator for them to come back to the clinic. In geographic atrophy, when they're not seeing that improvement, to come back every month is a major burden. I think from an efficacy perspective, there's certainly room for improvement. I think durability, the same concept, and clearly we've seen the anti-VEGF market evolve, starting with monthly treatment now out to Q4 months and potentially beyond that with new entrants on the horizon. I think in geographic atrophy, that is even more so an important paradigm because, as I said, if people are not seeing a functional benefit, what's the motivator for them to come back for treatment? Thirdly, even safety. Similarly, with the IVT complement inhibitors, we've seen around 10% of patients developing new onset CNV, where potentially then they need to be treated for that with an anti-VEGF. I think on all three dimensions, there's an opportunity to improve. I think certainly with our approach, we see the potential for multimodal complement inhibition addressing different complement pathways, but then broad ocular biodistribution addressing the disease in different compartments of the eye. I think when you package that in a potential one-time administration, there is definitely the scope to differentiate versus other assets. Got it. Thank you. And Stéphane? Most has been said, so I'm not going to repeat what was said by my colleagues, but I'm just going to make two comments. First, on the AMD space, we really differentiate wet AMD and dry AMD, on GA in particular. Wet AMD, there is indeed a standard of care, which is functioning well, which is safe, which has some issues, but which is there. In GA, we don't believe that with the two drugs approved only in the U.S., there is a standard of care, and we don't believe there will be a standard of care before a few years. You are talking about two different spaces in which gene therapy are being developed. When there is a standard of care, like in wet AMD, yes, there will be a room for gene therapy, but it will be challenging to displace an existing standard of care, like we've seen for other gene therapy, like in hemophilia, for example. For GA, I think it will be, again, probably easier, at least in terms of commercial penetration, as long as you prove that you have some efficacy and, of course, a good safety profile. My second comment, in your introduction, you speak about challenges of developing and introducing gene therapy in prevalent disease. RP and IRD in general, when you take a gene-agnostic approach, are prevalent disease. When you speak about gene therapy in the eye, please don't forget about RP and inherited retinal disease. If you go one mutation after the other, you are talking about a very tiny market and probably spaces in which it will be very difficult to find return on investment. If you look or if you think in terms of a gene-agnostic way, then it's a space which, to us, commercially, is very comparable to what you can expect in GA or wet AMD for gene therapy. Got it. Okay, excellent. Thank you. In contrast to the panel that we just had, where companies are developing programs for indications for which there aren't really any competitors, this space is clearly quite different. We have three programs here targeting GA, and that's just gene therapy. There are others as well. For indications for which there are several competing programs that are in the clinic now, advancing through the clinic, how important do you believe is being first to market, or do you believe that the market is large enough to accommodate multiple entrants and variations of those new therapies coming in? Maybe, Stéphane, I'll start with you. I'm probably not the best person to speak to that. I think it's more a question for Chris to start with. I'll take that one. I mean, I think unlike wet AMD, where it's been fairly homogenous, anti-VEGF is the key pathway. We see attempts with other pathways, ANG2, IL-6, but really, you see some durability benefit, but not really beating them on efficacy. I think GA is quite different, very heterogeneous, and you get a sense from the different approaches of different companies targeting different pathways. Ultimately, I don't think a single pathway is going to win. I think there are going to be segments of patients who will respond better to one or the other. Therefore, being first, I don't think is such a huge advantage. I think ultimately, the first entrants, and we've seen that with the companies in the U.S., have to also then invest in market development. You see DTC, you see new referral pathways developing. I think actually coming later, you can benefit from some of that that others have done as well. Ultimately, my own perspective is that this will be quite a segmented market. Just given the numbers of patients, the dynamics in terms of demographic changes around the world, there's a lot of commercial opportunity for multiple companies in this space. Got it. Makes sense. I'll wear my commercial hat. I was working in big pharma half my life. We had autoimmune disease as a product. Enbrel came out, and then Humira came out with less frequent injections. What happened? The market expanded. I think GA, the current programs may not be that great from an efficacy perspective, but at least there is something for the patients in the U.S. The rest of the globe, there's nothing, right? I would consider this as a significant unmet medical need globally. As Rafiq mentioned, the safety is an issue. It's not less than 1% or 0.1%. You just see it on the product insert. This is like 10%- 12% getting a neoasp for treating. That in the long run is an issue. What these therapies are doing, if you watch DTCs, direct-to-consumer ads on TV, they're educating people. This is exactly what happened when you had pioneering companies coming up with new therapies for diseases that didn't exist. Take autoimmune, right? A lot of them. It is actually educating consumers and patients. They're also then the retinal surgeons in the field. Everybody has to learn about them, which is good. They're really setting up the field. When the therapies come, they differentiate themselves, and they'll find their path. Ideally, if it's one-and-done therapy is available, and it's safe, and that becomes a choice for patients. How the pricing works out, we can have that discussion. I'm not sure if I have a lot more to add. I would just say, listen, clearly, if we were going into small rare diseases, the benefit of first mover advantage is much greater. That's not certainly the AMD, DME, or even the GA space. Coming in second, third, or whatever the order of entry is, I think it's more of a function as to, well, what are you bringing that's different and it's meaningful? If you have real differentiation in your second or third in terms of entry, as we've seen consistently in this therapeutic area, you can have some great success. I mean, the classic example is Eylea versus Lucentis, right? Benefit of a couple of weeks, I was on Lucentis at the time. I'm not sure if the benefit in the real world was as much of a Q4 versus a Q8. Despite that, and coming in second, you all know the results of how Eylea has performed commercially. I think it places the onus back upon us and says, you're coming in second or third, you need to come with something that is truly meaningful for the patient, the physician, and the payer. I think that's good for the space. Got it. Chris, for you specifically in wet AMD space and diabetic macular edema, who would you consider the greatest gene therapy competitors for those indications? Would you say it's more established anti-VEGF agents with higher dose, longer treatment intervals? Would you consider emerging DKIs or anything else? Yeah, that's a great question. I try to answer that in an unbiased way as much as possible. I'll tell you about how we, the 4D vision for what we think is the future of this therapeutic class. That is, we think 4D-150 can be a backbone therapy. When we say that, we think it means that the majority of patients should be considered for having 4D-150 on board to provide continuous expression of aflibercept, continuous disease control. You have a wide number of highly efficacious and really safe bolus therapeutics to use in supplementation. It's not so much like who's the primary competitor. I think it's more around how the treatment paradigm can shift in a way where it's really good for patients and for physicians. That's how we view our future positioning, a backbone therapy, and all of these other agents from the existing anti-VEGF agents on the market to TKIs in development can be a fantastic bolus supplement for patients that may need supplementation occasionally. It's more of a view from a different way of how the market, I think, operates in the future with a therapy like ours. Got it. Okay. For geographic atrophy, except being each other's competitors or supplements, would you consider, would you say there are other programs that are in development that are competing with? Maybe Stéphane, we'll start with you. At SparingVision, we are coming to this space with a very different approach to everything that is currently being developed. We are targeting the cones, either to preserve the cones or to reactivate function in dormant cones. The way we are looking at the space, and again, I don't see a good standard of care emerging in that space for the next five years, is that there will be a lot of room to complement, no pun intended, across different approaches, across different biologies. I can definitely see all kinds of biology, which is, again, specifically aiming at the cone compartment, to work synergistically with complement inhibitors that could help other compartments or departments of the retina to function in that kind of disease. Currently, no standard of care, many things being developed, and I think there will be room because of the size of the market and because of the complexity and the heterogeneity of the disease for different approaches. Got it. Perfect. I mean, I fully agree. I think just coming back to that heterogeneity, so many pathways are being evaluated and not just with gene therapies, with other sort of IVT approaches, even oral therapies, we know RBP4 inhibition, for example. I think ultimately, let's see what happens over the next four or five years. Will we see a standard of care emerge? Probably not. I think nothing is that sort of, you'd say, is going to be established. Ultimately, it allows other companies to enter. Like I say, I think we're going to see less of this sort of one-size-fits-all as we've seen with wet AMD, DME, and much more targeted tailored therapy. How we get there, will patients undergo some sort of more diagnostic evaluation, I think, is yet to be seen. We don't anticipate sort of genetic profiling as yet. I think it'll be interesting to see how that emerges and how that evolves as other therapies come into the market. Got it. Shankar, are you? I think, yeah, definitely. I mean, the complement system, everybody, it's like when you work in large pharma, you understand everybody goes in the herd mentality. They all go in, everybody had a program in complement, and now they're seeing the results. Definitely, people will look into other options going forward. There are definitely, the system is not set up for large gene therapy subretinal delivery, right? We are paving the way, and some of the companies in the space, it's not that simple. It's not an infusion gene therapy for systemic diseases. You can go to any hospital and do the infusion. It has to be set up. You need specialized centers. Definitely, even though we have one-time therapies, it takes time for us. If there are other therapies out there which can show good efficacy with good safety and what regulators are asking for, both functional and structural benefits, they'll definitely have a room because it's such a global footprint, it's so big. If you take AMD by itself, it's more than 200 million patients. At some part of their life, they're going to get it. It's just a matter of time. Once these therapies are out there for people where their atrophy is identified in central vision blurriness and you can actually evidence, and they can go backwards like biomarkers. We're not there yet. Is there a way to prevent it? This market is wide open. Got it. Okay. Makes sense. All right. As we're going to shift gears and talk about clinical development and some of the regulatory challenges for those gene therapies, as the field is generally moving to late-stage clinical trials, we have some programs advancing to late-stage clinical trials. What would you describe as the biggest advances in gene therapy for ocular diseases? What would you say are the remaining biggest challenges that still remain? Chris, we'll start with you here. Yeah. I'll speak specifically to the program that we have and that the others talk to, things in geographic atrophy and otherwise. Certainly, in wet age-related macular degeneration, to the point I made earlier, the continued unmet need is around increasing durability and therefore the reduction of treatment burden. That's why our program is designed the way it is. I think the key thing that underpins all of that is a statement of the obvious, I suppose. In an environment where you actually have, at least for wet age-related macular degeneration and diabetic macular edema, highly efficacious and very safe therapeutics available today, the table stakes of entry is you have to have a medicine that's safe, right? As someone who launched Beovu at Novartis several years ago, and for those that are familiar with that asset, highly efficacious, but safety concerns in the real world, that is a must-have. We believe a core differentiation to 4D-150 is our safety profile. We think that starts with our science and how our vector has been developed and how it targets the right tissue and delivers the right dose. I think that comes up in terms of our clinical development program. It certainly is a concern that the regulators have. When we have conversations with the FDA or other regulators, how we design our program, how we plan to manage for safety is critical. At least in the wet age-related macular degeneration space for the U.S., you have to show a functional benefit. You have to show a gain in vision. The requirement to show a vision benefit in your phase 3 program also then has an effect on what type of patients you select. That's why you see phase 3 programs for wet age-related macular degeneration largely target a treatment-naive patient population so that you can show that vision gain. Many patients on existing therapy have already reached that max in terms of vision potential. Showing an incremental vision gain is challenging with an existing or with a patient population that's been on existing therapy. Okay. Shankar? Yeah. No, I mean, since we talked a lot on GA, let me go back to the rare diseases, which are big, like, RP, retinitis pigmentosa and Stargardt. We have registration trials going on both of them. I think if you take RP, from 2017, I got the first product approved for RP65, covered probably less than 2% of the entire 300,000 patients you're talking in the U.S. and the EU. There's nothing. About 20 companies attempted to work on gene therapies targeting specific genotype, genetic defects. There are regulatory hurdles, and a lot of companies got out, even though they had okay data early stage because there's no commercial viability. If you work on a disease which has 50 patients, I mean, you have seen Luxturna. That's not a good example of commercial success. Focusing on, unfortunately, ultra rare or in a population, even like a couple of thousand patients, eventually you're going to run out. You need to have good pricing models which are missing. Number one, focus on technical success. If you focus on a little bigger population, you have commercial success, and then you can keep moving. Number two, agencies, both FDA and EMA, including VMDA, are very supportive of gene therapies. At least in our case, we're getting very good support. For both retinitis pigmentosa and Stargardt, EMA so far is super supportive. Whatever design we had with FDA, single trial, they said they agreed we can submit market authorization with our U.S. trial, which is a big win. We're still working with VMDA. We're getting at least some positive support. That's a big win for at least rare diseases. I mean, these are big diseases. Number two, agencies are very receptive with our endpoints and how we can be successful. They want us to be successful. They're collaborating with us. That's all I can say from a VA perspective. They're very open. If some companies are trying to get into the clinical trials, especially on the gene therapy side, try to get the RMAT designation with FDA, Regenerative Medicine Advanced Therapy. That has all the bells and whistles of all other things, accelerated approval to, number one, jumping on the calls with you in a collaborative way and discuss during your phase two or phase three. Recent success we had with the Stargardt disease, we had limited data in phase one, just like anybody else in gene therapy. You do the dose escalation with nine patients. By the time you discuss with FDA, you only have even a fraction of those patients, a valuable subject. The data looks very promising, and it is very good safety. We sat with FDA and said, we don't want to go to phase two and phase three. There's a significant unmet medical need. Can we convert that into a registration trial with endpoints that are very collaborative? They said, we don't want to do three, four, five-year trials, because you have such a desperation from a patient's perspective. FDA understands it. We want to do a one-year trial. FDA said, if you're doing a one-year trial, continue to use your lesion as a primary measure and use usual activity as a secondary. Usual activity, sometimes you may get good results. It may take longer to show differentiation between treated and untreated. These are all the elements. I'm sharing our successes with the agencies, and they're very receptive to orphan diseases. Take advantage of it and continue to move. I think there will be some successes coming forward. Also focus on commercial viability. For investors, that's very important. They have seen more than 20+ gene therapies getting approved. Every time there is some safety issue or something goes wrong, I see articles in Barron's, is gene therapy dead? Gene therapy is not dead. This is the greatest discovery of the 21st century. Pioneering companies go for technical success. It's very normal for any new technology. People will figure it out. What makes it work? Balancing shareholders and patients. Got it. Okay. Thank you. Rafiq? Yeah, no, I think certainly for geographic atrophy, the whole debate around endpoints is quite topical. I think we've seen, as we've discussed, with the intravitreal complement inhibitors, they got approved in the U.S. and have struggled outside the U.S. Clearly, some of the agencies are demanding functional data. I think that alignment on endpoints is something that I think we would all benefit from. Certainly, I think our approach is looking at some of the more novel endpoints. Shankar said, running three, four, five-year trials is really quite impractical. Investors want to see an early signal. They want to see that you've got something that potentially has that ability to deliver both a sort of structural benefit, whether that's slowing of lesion growth. How does that translate into a functional benefit? Unfortunately, in a way, we've been spoiled by the anti-VEGF agents because we saw such great vision gains that a lot of the agencies have got very focused on best-corrected visual acuity. We want to see the same in GA. That will take you three, four, five years to see. You may not see that in all patients anyway. There, I think a more novel approach looking at more novel sort of structural endpoints where you have good correlation to function. Things like what we're doing is ellipsoid zone attenuation, which again is a hot topic of discussion. Also, newer technology, I think you mentioned things like AI in the previous discussion, using AI to really focus in terms of doing other types of functional assessments. Something that we're looking at is focal microperimetry and using AI to really identify the areas of the retina which are most sensitive and potentially where you may see the benefit of treatment. I think these sorts of approaches are something that we hope that over the next three, four, five years, we'll get greater alignment so that actually we can run studies that are then relevant to multiple countries. I think one question I just wanted to expand is I think that Rafiq made a very good point. I think when agencies are looking at the wet AMD, I mean, you've got a leakage. Anti-VEGF agents work pretty good. In weeks, you'll see dryness and your visual acuity will go up. Scientifically, it's possible. Degenerative retinal diseases, unless you have inactive area of photoreceptors, they're gone. Unless you reactivate and through somehow, otherwise you end up long clinical trials. Please discuss with agencies who have been discussing and trying to, you need to continue to educate them. You cannot apply endpoints from this disease to another disease. They're very different. I think agencies understand it. What they're looking for is show the clinical meaningfulness through some orthogonal methods. If you can come up with that argument, they're willing to listen at least. Don't go by theory. You need like three lines. Yeah, you'll get three lines, treated versus untreated if you go for three to five years. Yeah, okay. That's one thing I think very important. Thank you. And Stéphane? Yeah, we aim at starting phase three in 2027. We have two years to address three key challenges. I see those challenges as being very similar across the two main indications we are targeting, RP and GA, which is first the heterogeneity of the patient population. You have to be very careful as to the way you select your patient population because the outcome could really differ based on that patient population. The second one is the endpoint. I think that we need to be dependent on the biology. You won't have in RP in particular one set of endpoint. The endpoint will be specific to your biology. Last but not least, the big challenge we will have will be the control group. What kind of control group do you take? For GA, will you take the complement inhibitors control group? For RP, naturally, studies will be good enough as control group since the FDA is not going to accept the contralateral eye, for example, as a control. These are, to your question, the three main categories of challenges we are looking at before we start our phase three. Got it. Thank you. Maybe in 30 seconds or so, I wanted to touch on commercial and access for gene therapies for large indications. One of the questions is, will the ophthalmologist or retinal specialists agree to one-time therapies versus the monthly or bi-monthly injections that they are so accustomed to? How aligned do you think the one-time therapies are with the current reimbursement models? What are the challenges to adoption? Stefan, maybe I'll start with you. Just one provocative comment. I think you have to look at this question from a different angle, whether you are based in Europe or in the U.S. In the U.S., it's a business. In Europe, it's not a business. The one-time therapy, of course, if it works and if it's safe, I think will be a no-brainer in Europe. In the U.S., you are going to displace an existing business in which physicians are making a lot of money. I am coming back to the hemophilia example. It will be a different call to make. Got it. Rafiq? I mean, it's interesting. I think, as Stéphane said, there's this clear difference between the U.S. and their capacity constraints to treat patients. They're crying out for more durable therapies, the one-time approach. In the U.S., clearly there's a commercial model that really generates revenue for practices. Ultimately, I think coming back to the demographics, there are a lot of patients out there. GA is an untapped market today. From what I hear, probably only about 15% of patients are being treated. When you say, okay, what if we get to a point of 50%? I think some of those capacity challenges may also start to penetrate into the U.S. That segmentation, some patients will do well with a one-time therapy. Others will need other approaches. I think there's probably room for everybody, but that will take a bit of time to develop. Okay. Shankar? Yeah, very quick. I think I take from the economic perspective, the vision loss diseases, there's significant unmet medical needs. All the things we're working on, RP, Stargardt, AMD, they contribute to $134 billion economic impact today in the U.S. Over a period of 10 years, $1.34 trillion. If we have one-time therapies, if we can cure all these patients in the next five to 10 years, we'll have more than half a trillion impact on a 10-year segment. That's an impact. I think we need to focus on a bigger picture rather than worry about how it's all about patients. Patients have to get treated, and they're going to be phenomenal. The productivity they can add onto rather than getting treatments multiple times. What is in it for me, like providers and physicians thinking? Their ultimate choice should be how my patient gets better and does well in life. I think people really have to focus on patients. Got it. In 30 seconds, as the commercial guy on the panel. The practice economics question is an important one. Certainly, it's probably more relevant in the U.S. than many other ex-U.S. markets. I would just say on the surface, the first reaction is you're eliminating 80%- 90% of what otherwise would be bolus injections. That's going to turn the economic model of a retina practice upside down. That's how I think the first order of reaction is going to be. The reality, though, and I don't have time to go through it here right now, is actually, I think a genetic medicine like 4D-150 actually could provide better economics than the current standard approach for two reasons. One, capacity that others have alluded to. The other comes back to how the reimbursement model works today and the timing of reimbursement and the profitability that they make as a function of the price point. Once you actually look at it from that perspective and you add in the potential to significantly increase capacity and pull forward reimbursement, the economics for a retina practice is actually, I think, better than the current standard of care. Got it. Makes sense. All right. Thank you. With that, I'd like to thank our participants for participation in this panel. Thank you very much, and thank you for joining.