Greetings, and welcome to the Clearside Biomedical KOL Webinar. As a reminder, this event is being recorded. I would now like to introduce your host, Jenny Coben, Clearside Investor Relations. Please go ahead. Good morning, everyone, and thank you for joining us today. Before we begin, I would like to remind you that today, during today's events, we will be making certain forward-looking statements that represent our views as of today. Various remarks that we make about the company, its future expectations, plans, and prospects constitute forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our SEC filings available on our website. Today's agenda is provided on slide 3. Dr. George Lasezkay, Clearside's President and CEO, will highlight the versatility of suprachoroidal delivery. Dr. Glenn Yiu, Professor of Ophthalmology at the University of California, Davis, will cover the real-world use of suprachoroidal delivery. Dr. Victor Chong, Clearside's Chief Medical Officer, will discuss pipeline opportunities. Dr. David Brown, Director of Research with Retina Consultants of Houston, will provide the large practice view of suprachoroidal delivery. After the formal presentations, we will conduct a question-and-answer session that will also include Clearside CFO, Charlie Deignan. With that, I am now pleased to turn the program over to George. Thanks, Jenny. Next slide. At Clearside, our singular focus is delivering on the potential of suprachoroidal drug administration. We are the proven leader in the suprachoroidal space. Our proprietary SCS Microinjector has been used in thousands of clinical injections to date. Our injection platform has been validated in several ways. We've developed the first and only product to receive FDA approval for suprachoroidal administration. We've established multiple strategic collaborations with companies that have tech, technologies or expertise that we don't possess internally. And thirdly, we've created a comprehensive intellectual property portfolio around the design, manufacture, and use of the suprachoroidal Microinjector platform, with many different drug categories in various retinal disease states. Finally, internally, we've developed a suprachoroidal-delivered tyrosine kinase inhibitor, axitinib, for wet AMD, that's just completing phase II-B trial in the United States. The data from this trial is expected late third quarter of this year. Next slide. At Clearside, we not only have an SCS Microinjector platform, but we have extensive formulation experience with small molecules for suprachoroidal delivery. We have an ISO-certified commercial-scale manufacturing capability for our microinjector. We have extensive experience in drug device combination regulatory pathway, as evidenced by our track record of obtaining the first and only SCS-administered product, Xipere, the approval from the FDA. Finally, we received a permanent CPT code for SCS injections to aid physician reimbursement for the use of suprachoroidal products. Next slide. This pipeline chart demonstrates the diversity and versatility of our internal, our injection platform, as well as our internal corporate strategy that has two prongs: one, developing internal products on our own, and two, partnering strategically our suprachoroidal microinjector with third parties. As you note at the top in light blue, CLS-AX, which is our phase II-B wet AMD product, is internally developed and is just finishing phase II-B. More will be discussed by Dr. Chong about CLS-AX later in this presentation. Xipere, which was the first product approved for suprachoroidal administration, is currently being commercialized in the US by Bausch + Lomb, and they're currently seeking Canadian approval for the product. That same product, known as Arcatus in the Asia-Pacific region, is being developed by our Asia-Pacific partner, Arctic Vision. It recently completed its confirmatory phase III trial in China, and Arctic Vision is seeking approval in the People's Republic of China, as well as Australia at the present time. Our SCS Microinjector collaborations, there's three important ones. First one was Aura, using their viral-like drug conjugate for the treatment of choroidal melanoma. They're exclusively using our SCS microinjector in an ongoing global phase III trial for the treatment of choroidal melanoma. REGENXBIO and AbbVie have recently completed two phase II studies in diabetic retinopathy, as well as wet AMD, using our microinjector, administering their gene-based therapy, RGX-314, for both those indications. And finally, our most recent collaboration is with BioCryst for the formulation of their small molecule, a plasma kallikrein inhibitor, which they would like to administer suprachoroidally. Formulation work cooperatively is going on at the present time, and BioCryst hopes to be in the clinic by late next year with that product. At this point in time, I'd like to turn over the presentation to Dr. Yiu for him to share his thoughts on the uses of suprachoroidal delivery. Dr. Yiu? Thank you, George. Thank you for that introduction. We can move on to the next slide. So I want to talk today a little bit about the real-world use of suprachoroidal delivery. I've been interested in suprachoroidal delivery and studying it, actually, since I was a fellow more than a decade ago. And even back then, Clearside has always been one of the main innovators in this space. Accessing the suprachoroidal space, so the suprachoroidal space is a potential space that's between the wall of the eye, the sclera, and the choroidal vasculature, which is underneath that, which separates it from the retina tissue that we're trying to treat. Unlike traditional intravitreal or subretinal injections, intravitreal injections work fine, it's easy to perform, but the drugs don't easily necessarily get to the space that you want. It actually also affects the anterior segment of the eye, like the iris, et cetera. Subretinal injections, which is often used for things like gene therapy, requires complex vitreo-retinal surgery. But the suprachoroidal space can be accessed either with microneedles, such as the product from Clearside, or with microcatheterization, which is also a surgical procedure, where you extend a cannula through the wall of the eye. Next slide. Now, several years ago, we've already demonstrated that actually, when you do a suprachoroidal injection, you can visualize that drug entering that space. First, with work from Charlie Wykoff, showing from anterior segment OCT. So this is imaging that shows a cross-section of the front of the eye. You can see that little gap on the right side, where the drug went in. But more interestingly, when we looked at the OCT images from the TANZANITE study, and I don't think that the plot is shown here, but essentially, we show that you can detect a measurable expansion of that suprachoroidal space in the back of the eye after these suprachoroidal injections. Next slide. Now, suprachoroidal triamcinolone acetonide has been tested across a variety of retinal conditions, but it's really the phase III PEACHTREE study, which randomized 160 patients to uveitic with uveitic CME to either suprachoroidal triamcinolone versus the sham control, which really demonstrated functional efficacy, where you can see patients who received the treatment gained vision compared to sham, and also with low rates of rescue out to past 6 months in the clinical trial. Next slide. So one of the questions that we've always been interested in is that that's only in the clinical trial setting, in the pivotal trial. How does Xipere, which is a suprachoroidal triamcinolone that we're talking about, how does it perform in real-world settings? So for this study, actually, the team at Bausch and Lomb conducted a study using the IRIS Registry. This is a national registry of many, many clinical practices, aggregating real-world data. And they essentially included all patients who were over the age of 18 with a history of diagnosed with uveitic macular edema, who had received the suprachoroidal triamcinolone acetonide. And they looked at patients from January 2022 to 2023, and that's roughly around those first year or so after the product was approved and had a J-code. The index date was the first time they got the injection, and essentially, they measured the second time any steroid, including more Xipere, or other steroids were given, out to at least six months. Next slide. The study demographics on the left was generally what we expect from patients who have uveitic macular edema, but two things of interest. First of all, on the upper right, you can see that, 41% of the patients have some glaucoma or ocular hypertension to begin with, and that's a good sign that physicians, in general, in the real world, are comfortable with the concept that this drug can be given in patients with a history of glaucoma. We know that in general, we try to avoid intravitreal steroids in patients with a history of glaucoma, with the concept that intravitreal steroids can you know, lead to a steroid IOP response. Whereas here, it seems like at least close to half the patients already have existing glaucoma. We also know that roughly a third to a half of patients have had previous corticosteroid use prior to them receiving this. So many of these patients are not treatment naive, that they are possibly resistant to treatment before they were given Xipere. Next slide. So this is what's interesting. This is a Kaplan-Meier curve showing the real world plotted against the PEACHTREE trial, so the real world data from the IRIS Registry and the PEACHTREE trial being the pivotal trial. What we found was that actually 86.5% of the patients in PEACHTREE did not require rescue out to six months. But even in the real-world data, which is the blue line above, you can see that actually very few patients actually needed a rescue in that real-world setting. Please note in mind that in PEACHTREE, actually, everybody had to receive a second injection at week 12, so they actually got two different Xipere injections at weeks 12 and 24. Next slide. When we look at the patient, the type of rescue steroids that were received by patients, we can see that roughly half of them were another Xipere, another quarter or so were intravitreal, and some were receiving intravitreal dexamethasone implants, et cetera. Next slide. Now, if you included any steroids, that includes topicals. The last slide was about injectable. When you include the topicals, that number does go down a little bit, but it's still significantly, it's still quite good that largely three quarters of the eyes did not require any steroids by week 24. Next slide. So what are considerations when giving a suprachoroidal injection in the real-world setting? First of all, patient selection is important. We try to be more mindful of patients who have high myopia or may have evidence of scleral thinning. We will try to maybe err on the side of using the shorter needle. Things like a history of glaucoma, ocular history, sorry, ocular surgery, particularly if they've had a shunt or a tube in the area where you're injecting, you might want to be mindful of that. I think, setting expectations are the most important, at least in my experience. I think patients who've had a history of an intravitreal injection can't assume this will be a, you know, bang, two-second thing and run out the door, like an intravitreal injection. I usually will explain to them, it's gonna take a longer period of time. We have to set you up, and we might have to even consider switching needles, and there will be a lot of pressure, when the injection is given. So I usually tell them that they'll have this sensation of, like, a pressure wave. It's not really like a sharp pain, but it's a, it's kind of like a, some people call it, like, maybe like an ice cream headache sometimes. The procedure takes longer, as I mentioned. Then when I do it, I usually have the patient lie back, make sure they have good head support so they're not kind of free floating. We usually give the typical topical anesthetic or subconjunctival in some cases, although we can talk more about that, but I generally prefer topical for suprachoroidal injections. We use the same antiseptic, and we generally recommend using a lid speculum because of the longer duration of the procedure. Next slide. The product comes in two needle lengths. It's a 900-micron and 1100-micron. We generally prefer the superotemporal or the inferotemporal because it's easier from ergonomic standpoint, coming from the patient side, and this is rough, pretty much the same as what we would do for an intravitreal injection. In both the clinical trials and in most previous studies, majority of injections can be successful with just a short needle from the superotemporal location, where the sclera is a little bit thinner, majority of the time. Next slide. Both us and a group of colleagues, including Dr. Brown on the call, have published on what we consider to be like a consensus expert guidance on what are the best practices for doing these injections. Critically, because this is a very short needle, so the more perpendicular you are, the more likely you will access the space more readily, and use the full length of the needle. So holding the injector perpendicular to the surface is important. Dimpling and maintaining firm contact during the injection to maintain that access to the space and slowly injecting it. That's one of the key criteria, I think, to minimize discomfort because usually any reports of pain or discomfort is because the provider is injecting it a little too quickly, and it's that first burst of the fluid entering the space. So I think applying it slowly and steadily, many of my patients have been very comfortable with that. Next slide. So I always think of suprachoroidal delivery as a platform technology. It's not just for delivering steroids. It can be used to delivering many different kinds of stuff, and I think that that's the information that... or the message that we're trying to convey to providers. There's been, you know, the question about uptake. You know, right now, uveitic macular edema is a relatively limited indication, and once it becomes—if there are more indications for that product, then it's important for providers to be able to use these different, to be able to know how to perform these injections. And one of the most exciting upcoming development is gene therapy for geographic atrophy. So currently, all the intravitreal biologics have failed with the treatment geographic atrophy. The only ones that are currently approved are small molecule or aptamers or RNA aptamers for blocking complements. But theoretically, GA is one of those diseases where I think patients are not really interested in repeated treatments. Oftentimes, whereas for wet AMD, you're doing an injection, you do an OCT, you look at the product, the treatment response, and you can make a decision to inject or not inject based on them. Whereas for dry AMD and geographic atrophy, you're pretty much just injecting on a regular basis with the hope that it would give you some treatment, some treatment effect in the long run, and you don't really get that individual personal feedback for every patient. Whereas for GA, because of that, for GA, it almost makes more sense for a gene therapy where it's a one-time treatment, you kind of set it and forget it. Many of these patients are older than your typical wet AMD patient, so they don't want to come in for frequent injections. So theoretically, a biofactory approach that generates a product that can be helpful for GA would be very important. However, intravitreal injections, as we know, generally causes more ocular inflammation, and that has been a major limitation for the development of intravitreal gene therapies currently. Subretinal injections, even for wet AMD, has been difficult for patients to accept. It's, it's still a surgery. It requires a vitrectomy. If you're aphakic, you can't get it, at least without knowing that you will worsen your cataracts. So perhaps suprachoroidal delivery may be the preferred way to go, and I think Victor will talk a little bit more about that later. Next slide. So the key takeaway is that the suprachoroidal microinjector enables targeted in-office delivery to the suprachoroidal space. It's the only FDA-approved product, the Xipere, which is used for treatment of uveitic macular edema. The durability of this suprachoroidally injected triamcinolone in the real world, from the IRIS Registry seems comparable to phase III trial results, with only about 12% of people who need a subsequent steroid injection over the six months. And so suprachoroidal delivery represents a new and innovative technique, with many potential applications, potentially including angiogenesis inhibitors and gene therapies. So with that, I'd like to turn this over to Victor, who I think will tell you more about those opportunities. Thank you, Glenn. Well, as Dr. Yiu have shared with you, our early suprachoroidal journey in the real world with our first FDA-approved product. And I think that I gave you a glimpse of our, and also give you a glimpse of our promising future in gene therapy. But let me share with you our plans for the next few years. Next slide. Oh, sorry. Yeah. Now, as a reminder, suprachoroidal injection are potentially safer than intravitreal injection, and we believe it has close to no risk of endophthalmitis, an uncommon but serious infection of the eye after intravitreal injection. To retinal specialists like me, endophthalmitis is one of the most feared complication, as patient can lose their vision completely and might even lose their eye. Suprachoroidal space is protected by the immune system, so any bugs and contamination get into the space will be killed by the immune cell in the choroid. Now that we have over 10,000 injections of suprachoroidal and have no case of endophthalmitis have ever been reported. The drug is injected into the coat of the eye, and hence flow behind the retina without any risk of floaters, nor the drug would be able to get into the anterior, anterior chamber, causing problem, which we do see sometimes in patient that, who have intravitreal implant. Importantly, that we can re-dose as easy and simple, just like a standard anti-VEGF biologics. The injection procedure is similar to intravitreal, but take about 10 second longer, like what Glenn had mentioned earlier. Now, this is actually reflected in the reimbursement rate of the CPT code, and reimbursement of suprachoroidal injection is about 10% more than intravitreal. So in money term, that's about $10 more. I think that is a pretty good deal for the surgeon, $1 per second for the surgeon's time. Next slide, please. So when we talk about intravitreal injection, we normally think about using a 30-gauge needle. For Clearside suprachoroidal injection, we're also using a 30-gauge needle, although it's a little bit shorter. However, to inject the intravitreal implant, 25-gauge and 22-gauge are needed, which are twice or four times as big, respectively. A bigger wound increase the risk of infection and also other potential complication, such as retinal tears. Next slide, please. Let me focus the next couple of minutes on our CLS-AX wet AMD program before talking about future pipeline. Next slide. Axitinib is the TKI that we use, and it is one of the most potent TKIs. The IC50 for blocking VEGF-A, all three VEGF receptors are often over 100 times lower than many other TKI. Well, what is that means? In other words, the concentration of axitinib can be 100 times lower to achieving the same blockage effect, allowing longer duration for the drug with the same PK profile. Our proprietary suspension formulation is FDA-approved as part of Xipere. Now, Dr. Yiu has already showed you that in real-world setting, more than 85% of patients did not require rescue therapy over six months, showing the possibility of longer duration. Similarly, CLS-AX is using the identical Clearside SCS Microinjector, and we believe our experience in navigating through the more complex combination product approval with identical microinjector and similar suspension formulation with, obviously, with a different API, we can potentially save time and allow us to overtake other TKI competitors to the time of approval. Next slide, please. So when we think about our TPP, it is really based on our understanding of patient with wet AMD and also the current wet AMD market. Next slide, and next section. In the next few years, we think that, when CLS-AX is approved in a few years' time, Vabysmo and Eylea HD are likely to be the market leader, at least in terms of revenue. And we do believe wet AMD patients have individual needs, and after the initial loading dose, CLS-AX can potentially be used as a maintenance therapy two to three times a year in almost all the patients, as comparing to three-four times a year in patients with Vabysmo or Eylea HD. And on terms of the number, it might not sounds very much, but we were encouraged by the uptake of Vabysmo, showing only a small duration benefit over Eylea can be very rewarding. Next. As I mentioned already, we can mention it one more time to reinforce the message... the injector used in our TKI competitor are differ from the approved product, and our SCS Microinjector device is identical to the one in our FDA-approved product. We are also gaining additional experience with our partner program in oncology and gene therapy using identical devices, as George mentioned earlier. Next. Well, due to the limitation of the redosing frequency of our TKI competitor, as they cannot really re-dose until the first implant is dissolved, they need to use anti-VEGF biologic to rescue the patient between the treatment. Now, in the clinical trial that you see the patient every four weeks, so you can identify who and when to rescue. But in the real world, if we need to see patient every four weeks, it would actually increase the treatment burden rather than reducing it. And as a treating physician, I know that my patient do not like visits as even more than they don't like injections. Next. So as I mentioned that CLS-AX has flexibility similar to biologic, so we are now planning to develop a phase III study, which will allow retinal specialists to use CLS-AX as a replacement of Vabysmo or Eylea HD in the real-world setting. And just like Vabysmo is replacing Eylea over the past year, bringing Roche over $4 billion of revenue. Adding to the potential advantage of low risk or very low risk of endophthalmitis, as well as CLS-AX is a small molecule, and you have a much lower risk of immunogenicity. And furthermore, it does not even need to be put in the fridge. David Brown and I talk about it in Stockholm, just think about a hurricane and power cut that might actually occur with our changing world. Next slide. So our phase II-B design is called ODYSSEY. 60 patients were randomized in a 2-to-1 ratio for comparing CLS-AX monotherapy to on-label aflibercept, as shown in this diagram. Both groups were started with three monthly aflibercept. CLS-AX was added with the second aflibercept, and CLS-AX can be used again earlier from week 12 if needed, based on some activity assessment. However, that if there were no disease activities assessed that was detected by week 24, every patient in the CLS-AX group will be re-dosed at week 24, and our primary endpoint is at week 36, and we believe that is very important. Next slide, please. As compared to our other TKI competitor, every patient in the CLS-AX group will be retreated at least once. As wet AMD is a chronic condition, we feel it is critical to understand the effect of redosing, and it is risky to move to phase III without any redosing data in phase II. And we will be the only company using TKI for wet AMD to have that data at phase II, and that data will... That, and we will have those data later on this year. And second, our primary endpoint is 36 weeks, which is similar to what FDA recommended for phase III wet AMD study. And if our phase II is positive, this will further de-risking our phase III study. As mentioned, we can potentially use our CLS-AX just like biologic, allowing much straightforward implementation in the clinical practice once CLS-AX is approved. I think Dr. Brown will discuss that a little bit later this morning. Next slide. So let me give you an update to ODYSSEY so far, and it is completely on track. As some of you know, there's some of you remember that we finished recruitment back in December last year. Every patient now has completed six months of treatment, so patient in the CLS-AX group, all of them have received at least two doses of CLS-AX. In early this month, Safety Review Committee meeting, the SRC recommended the trial to be continued without any changes. There were no drug-related SAE, in particular, no endophthalmitis and no retinal vasculitis. So we are on track to release our, our top-line data in late September, the end of the Q3 this year. Next slide. So what would success look like? Well, we would expect no drug-related SAE for safety. For efficacy, the majority of patients in the CLS-AX group should be able to reach week 24 without retreatment. We believe that BCVA and CST should be similar in most visits to the aflibercept control arm, in particular at week 24 and week 36. Next slide, please. Now, may I take the next few minutes to share with you our plans beyond CLS-AX? As most of you know, that I have a lot of experience in phase III clinical development, but I have even more experience in translational medicine, moving preclinical molecule to the clinic. And this is really just logical for Clearside to expand our pipeline into geographic atrophy. Next slide. Well, geographic atrophy is actually more common than wet AMD, so we believe the market size can be larger than wet AMD. It is exciting to have two FDA-approved product, but their efficacy can be improved. And even if we cannot improve the efficacy, extending the duration will be helpful... and furthermore, attacking another pathway beyond complement might also bring synergy and enhancing efficacy. Well, there is a misconception, at least in my book, that geographic atrophy is a primary RPE disease, retinal pigment epithelium, as RPE loss is used as approval endpoint. And indeed, most scientists, including myself, think that RPE loss is secondary to a choroidal disease that compromising the photoreceptor and RPE cell, leading to the demises. Next slide, please. Now, we believe that geographic atrophy is a primary choroidal disease, and our colleagues in Iowa have demonstrated very nicely that endothelial cell in the choroid are damaged even before any significant RPE changes. The vascular density is significantly lower in geographic donor eye, supporting geographic atrophy is a choroidal disease. Furthermore, VEGF level increases with lower vascular density, supporting the choroidal hypoxia theory as a key AMD pathophysiology in general. So treating the choroid is important, potentially for GA as well as wet AMD. Next slide, please. We know that complement activation are present in both RPE and choroid. Despite that we think that the choroid is the primary area of disease, the RPE suffer and complement get activated. As we know that intravitreal drug could be able to penetrate the retina to the RPE, but large molecules, such as biologic or even the current approved pegylated peptide, might not be able to get to the choroid. In particular, the Bruch's membrane separating the RPE and the choroid is even thicker with aging and also in AMD patient. So it would be even more difficult for large molecule to penetrate. But for a small molecule, it can penetrate and hence can treat complement activation in both the RPE and the choroid. Next slide, please. So Glenn has already mentioned a little bit about the potential benefit of suprachoroidal in gene therapy. However, I would argue that suprachoroidal would be the preferred route of delivery, as small molecule suspension can treat both sides in- to improve the efficacy and give a longer duration. Next slide, please. So from top to bottom, we think that there's a lot of advantage of suprachoroidal delivery in geographic atrophy, and we believe suprachoroidal delivery can reach the choroid first, providing the highest drug level, and as geographic atrophy is a primary choroidal disease, and that might improve efficacy. And furthermore, small molecule can treat RPE- in RPE and retina, because small molecule can readily diffuse through the Bruch's membrane. Suprachoroidal steroid suspension have already demonstrated duration of six months, and we have seen low risk of inflammation, and some of our efficacy have already seen in our partner in gene therapy delivering anti-VEGF. And furthermore, we have seen the level of inflammation with suprachoroidal gene therapy are also substantially lower than intravitreal. And Glenn has already mentioned that suprachoroidal is a simple procedure as compared with subretinal surgery. We believe with an optimized capsid, the way that we... the virus that is delivering and transfecting cells, we might be able to improve the efficacy even further. The procedure can be easily learned and performed in the office, and I think Dr. Brown will talk a little bit, more about it, as Glenn has already talked about it already. Furthermore, we believe that the complementation of suprachoroidal injection gives a high drug level in the retina, RPE, and the choroid, in particular the choroid, but a very low level in the front of the eye, so reducing the risk of adverse event, and as mentioned, that there is possibly no risk of endophthalmitis. Next slide, please. Let me finish by giving an overview of the potential target pathway of geographic atrophy. Over 10 years ago, Frank Holz, a good friend of mine and an expert in geographic atrophy, suggested some of the pathway that can be targeted, and some of these already failed over the last 10 years. Complement has two recent successes, but after multiple previous failures. HTRA1 is a very strong genetic risk, is a controversial topic after the recent Roche failure of an anti-HTRA1. I think we need better understanding of the pathophysiology of the role of this genetic target. Neuroprotection and lipid pathway are also challenging in drug development, and we have seen that in other ophthalmic area, such as in neurology. Clearside are looking into the changes in the choroid, in particular, several groups have identified specific immune cells present around geographic atrophy lesions, mast cells, microglial cells, and macrophages. So targeting them makes sense, and to me, a low-hanging fruit. Furthermore, improving the choroidal perfusion should be able to improve retinal function and might slow degeneration, and small molecules can be used to target these two pathways. Combining with Clearside device and suspension expertise, it would allow us to bring next-generation geographic atrophy drugs to the market. Well, let me stop here and pass to Dr. Brown to discuss how CLS-AX can be implemented into high volume busy retinal practices, and what type of potential phase III data that would help him and other retinal specialists to achieve our goal to treat wet AMD patient, will reduce patient burden, and maintain clinical trial efficacy in the real world. Dave? Thanks, Victor. Thanks for having me. I literally have two slides here, because this is mainly gonna be a question and answer with Victor and with the advisors. So next slide. You know, we do a lot of intravitreal injections every day. I mean, my record's over 100. And they don't take very long, and but they take way less time than when we started. In other words, if a retina surgeon is doing a procedure, whether it's entering in the operating theater or whether it's in the clinic, you learn how to make it quicker and quicker. The suprachoroidal injection, the first time you do it, you do have some nuances. I did several hundred, and it really doesn't take me much longer than an intravitreal injection. But from a patient experience, it's a very, very small part of the whole process. Like, this is way more efficient than my clinic. This doesn't, you know, this doesn't include the fact that my clinic doesn't work as efficiently as a Toyota production line. There's a lot of waiting. Our average visits, we're happy if we can get them below an hour and a half. You know, this implies that my visits are, like, 40 minutes, and even then, injection as a percentage of the whole time is a very small fraction of that. It's even smaller in real life. So if we have a procedure that allows patients to actually be treated three months, four months, five months, six months longer, it'll take over the world. We don't have any drug out there, despite ones I'm on the primary author of, where the majority of patients can go three or four months between injections. Next slide. One thing I like about the design that Victor has briefly announced, and the details aren't there, but the problem with our previous drug trials, again, ones that I'm primary authors on, is that the agency allowed more and more flexibility to try to get to... The sponsors pushed to make it look like their drugs worked longer. The reason people have retreatment criteria of 25 microns, 50 microns, 100 microns, make you lose vision, make you cough up blood and become disabled and lose your driver's license before you're rescued, is they're just trying to make their drug look good. If you really think your drug works, make it a real-world treatment criteria, where in the clinic, if you have two microns of new fluid, and I can definitively prove that on image track title board tracking, I shorten your interval. I don't allow you to get more and more disease. It'd be like your oncologist saying, "You know, we found a little recurrence of cancer, but we're not going to worry about it until it's, you know, big enough that it meets some criteria." It's ridiculous. Nobody in the real world treats that way. You know, a treatment criteria that's more real-world is absolutely what you need to know if your drug works. In a trial, we're totally comfortable seeing patients more frequently and having tighter criteria because it's better care for the treatment. Again, we've got good drugs out there. Faricimab is a great drug, and aflibercept. 8 milligram is a good drug, but you have no idea really how many patients can go 12 weeks or even 8 weeks if you rely on patients having to have preset criteria that are nowhere near what we do in the clinic. Victor, I know we talked about a bunch of stuff in Stockholm. Happy to have you go over whatever you think the analysts and Clearside wanna have a candid answer on. Yeah. Well, thank you, Dave. I think that, you know, like, you know, like, what you and I have discussed about that physicians do like the idea of flexibility, and we are going to try to aim for, potentially a label of Q12, in other words, every 12 weeks to Q24, every 24 weeks. And although that we think that might be very few patients would need, redosing at week 12, but then, you know, going to that, some investors have concern that as if that we don't believe our drug actually work. But I think that, you know, would like to hear your opinion, and, and on why that a, a kind of like almost far more flexible label can help you. Yeah, certainly we've learned a lot from intravitreal injections. You know, if you look at Eylea, the average patient can go by with 8-week dosing. However, in my clinic, 40%-50% need 4- or 5-week dosing. Why is that? And I think I've made a pretty good case at Retina Society, and then in a poster I showed at ASRS, that the main reason with our current agents is drug clearance. In other words, if you look at the faricimab filing data, 10% of the patients have a half-life less than five days, and 10% of the patients have a half-life over 11 days. In the filing data, they do the work for you. It correlates with increased—if you clear the drug faster, that correlates with needing more frequent dosing, 0.0001. So there's this big bell curve of variability, and if you have easy patients with a long half-life, sure, they can go eight, 10 weeks with 2 milligram of aflibercept. However, if you're a 5, 5-day half-life, you are barely going 28 days with either faricimab or aflibercept. 8 milligram would give you, by definition, 2 extra half-lives. For that patient with a 5-day half-life, that's only 10 extra days. To be honest, we don't know the clearance from suprachoroidal. It could be not the same. It could be that there's not this wide variability. It could be that there is, and those patients that need more frequent dosing are really hurt by labels that are limiting, like the 8-week Eylea 8 milligram label. It's a challenge, and I know Regeneron's working on reducing that. For a treatment-naïve population, it's a small part of the population. However, in my clinic, the easy ones go away. Like, if I'm only seeing you every three months, that's four times a year. If I'm seeing you every month, you're there four times more often. So I have four times as many tough ones as easy ones, and so in a real-world clinic, a lot more of the patients need more frequent dosing with intravitreal than our clinical trial suggests. And I'm not sure that the analyst and the commercial world kind of gets that. They kind of get what we show with treatment-naïve patients, which is that bell curve, and the first time you get a shot, you're in that bell curve. However, by the time we figure out that you need a bunch of dosing, you're with a bunch of other patients that need a bunch of shots. And so I applaud Clearside in pushing for a more frequent label. We will know more when we, you know, do this trial and run the horse race. If, you know, Clearside's correct, and we do have everybody going to 12 weeks, that'll be a game changer. We have nothing like that in the market today. Thank you. So the second question is about that. I appreciate about what you already said about extension in faricimab and Eylea high dose, and our competitor, on TKI, they are also trying to using rescue criteria. I mean, to be fair, even on our ODYSSEY, the criteria are not the same as you, as you mentioned. But, you know, if we believe the future world that all these TKI get approved and including gene therapy to get approved, and how do you think that in your practice that you're using those, in terms of the how do you identify when to rescue the patient, no matter what rescue criteria that you choose to use when they become approved? Because at the moment, as I mentioned, that they are seeing the patient every four weeks, and obviously, then you can find out who to rescue. Yeah, in the real world, you know, if you, if you come to me or you send your family member to me, I'm gonna treat you the best that I know how. And we don't have any data to show that it's acceptable to tolerate some level of disease activity. You know, there are some that if you have intraretinal fluid or subretinal fluid, and you give a great anti-VEGF, and it does nothing, sure, you don't need to keep treating it, right? It's non-VEGF responsive. However, if you have great response to therapy, all the fluid goes away on your OCT, you do your treat and extend, and they start getting fluid, you know your drug's worn off. And when your drug's worn off, whether it's an anti-hypertension or whether it's a cancer agent or whether it's an intravitreal agent for AMD, you need more frequent treating. And, the dirty secret of retina clinics is our visual acuities aren't very good. We don't refract. A lot of times, Grandma brings, you know, the wrong glasses, her neighbor from the nursing homes. She loses two lines of vision because she doesn't have her right glasses, but there's no fluid on OCT. I don't re-treat. We basically live and die on the OCT. If a patient comes, though, and says, "I'm having more trouble driving," and they notice a visual acuity change, we really look hard to figure that out. Sometimes that's an intraretinal hemorrhage that we can't see on the OCT. Visual acuity is not near as important in the clinic for determining treatment criteria as OCT because the OCT is very accurate, it's reproducible, and in the real world, if this thing keeps people dry for whatever period of time, that's where we'll figure out the interval to treat. So do you think... So, I mean, can you imagine a way that how, that you can incorporating the other TKI that need to be giving every six months, and then try to find rescue in between? I mean, how, how... I mean, would you think that would be easy to implement? ... you know, I don't, in the real world, people really don't use treatment criteria from any clinical trial. And so I know that the some of the other TKI programs, which I, to be honest, helped design some of those programs. You did what the agency would let you, right? As the agency was in transition, you know, there's still a debate whether the agency wants sham injections, which I don't think any of us are comfortable with. Not sham injections, but a true placebo injection. I don't think that most institutional review boards, especially at academic institutions, are gonna allow a placebo injection of saline with the risk of endophthalmitis. You know, if you have to go superiority, you often are pressed into something where you have to... And you have to have exactly the same dosing. That's why they have some rescue criteria that are really way higher than a lot of doctors will even accept for a clinical trial. We'll see how that pans out. I don't think anybody in the real world is gonna use their rescue criteria for retreatment, or they're gonna lose a lot of vision. Long term, you're gonna lose vision if you allow patients to have large excursions on OCT or documented loss of visual acuity. Right. But finally, for me, that you already hinted on, do you... I mean, like some of the investor concern about suprachoroidal injection is very difficult to learn because no one are doing it, and I think you already hinted on it. Kind of, you know, how do you think that, you know, when CLS-AX is approved, do you think adaptation will be a issue, from your perspective? Yeah, from my perspective, you know, if you can get these patients that are requiring every four weeks or five weeks for aflibercept, and you can really get them to 12 weeks, they'll put up with whatever it takes. I mean, the procedure is easy. I would say 19 times out of 20, it's not much different than intravitreal procedure. You have some squirrely patients that, you know, it takes. You know, they don't wanna look the way you want them to look, and or they have very tight lids, or they have very thick sclera, and you have to change the needle. You know, where it does take a little more, but I think if we're doing this 10, 15 times a day, it will become as routine as an intravitreal injection. Great. So I think that I'll stop there, and then open up to, other investor, or other, people on the line, and to ask them questions as well, seeing we've got an opportunity there. We are kind of right on time at the moment. To ask a question, please select the Raise Hand feature, which can be found at the bottom of the Zoom interface, to be placed in the virtual queue. Once it's your turn to ask a question, we'll call your name and ask you to unmute yourself. Our first question will be from Annabel Samimy. Hi, everyone. Thanks for taking the question. I had a couple here. So maybe this is for Dr. Brown. In your opinion, what is the correct rescue criteria for these patients? If you're not looking at BCVA, you're looking at OCT, there's a little bit of variability in OCT from, you know... What is exactly the right criteria for retreatment? Sure. If, again- Um, um- ... for BCVA, when you see, some trials have, rescue at loss of five letters versus rescue at loss of 10 letters, what is the right place to- Sure ... you know, to really rescue them? Yeah. You know, let me preface this. In terms of the visual acuity, visual acuity, I'm okay with visual acuity rescue criteria in a clinical trial. You know, the, just in the clinic, we don't do a 30-minute refraction. And in the clinic, our visions are often very spurious 'cause the patients, you know, don't bring their correct glasses, or haven't been refracted, or get the wrong glasses, or what have you. In a clinical trial, the ETDRS is a very regimented way of doing a visual acuity change. That being said, especially in macular degeneration, there's a five-letter fluctuation routinely in patients. If a patient has a rough night and doesn't sleep well, if they have the best night of their life and eat their favorite bowl of porridge, and do great on the OCT, do great on their vision, that's okay, but we don't have any agent that I know of that really addresses just pure vision. In other words, the reason our anti-VEGF work is they get rid of disease activity. They get rid of fluid, intraretinal fluid, subretinal fluid. So I think the best criteria is pure OCT, and if you have disease activity, subretinal fluid, or intraretinal fluid that increases from your lowest, that means you would do better with more anti-VEGF. Subretinal fluid and intraretinal fluid has been defined in studies with very weak OCTs years ago, right after approval of Lucentis. Carl Regillo and I wrote an invited perspective in AJO that defined those. Those exact pictures were used as the CATT criteria for retreatment. The CATT had great rescue criteria. If you had new intraretinal fluid or subretinal fluid, you got retreated. That's what we do in the clinic. That's the tightest. Pharmaceutical companies don't wanna do that 'cause they wanna make it look like their drug lasts twice as long as it really lasts... and if it's a mass trial, and you're going head-to-head, and your drug works better, no matter what your retreatment criteria, if you have tighter retreatment criteria, you will show that your drug is better. A lot of times you may not show it if you have a retreatment criteria that relies on vision, because there's so much variability. You know, 10 letters is a lot of letters, but it's gonna happen in diabetes or vein occlusion. With new fluid, you lose vision pretty quick because that's how you function. In AMD, it's variable. There's a delay as you gain vision when you lose fluid, and there's a delay before you. It's a lagging indicator. In other words, you dry up the retina with a retinal detachment repair, you can improve vision for up to a year. You improve somebody's edema from macular degeneration with an anti-VEGF agent, they can improve for several months, and so there's not a direct correlation with fluid and vision. I would encourage any sponsor to do as tight a criteria as they can, if they really believe their drug works. Okay, and then maybe, is there a way? Can you be a little bit more specific on the amount of fluid? Any fluid. You think- Any fluid. Any fluid? I, yes. Any fluid, not 25- It's like, it's like communism. Not- It's like cancer. It's like fire ants. Fluid in the nervous system is never good for you. Post-traumatic stress disorder, I mean, the reason boxers and football players become demented is they get edema in their brain over and over. The same thing happens in the retina. You lose neurons, you lose function. Like, why would you allow a little bit of renal carcinoma to come back before you retreat it, right? It's the same. Fluid's never good for you. Okay, and then one question for Victor. Are you going to be partnering with anyone for the gene therapy program? Do you have a... You know, and, and, and further from that, is there a good understanding of how the gene therapy the endpoint should be measured for a gene therapy program? It's not necessarily like anti-VEGF, where you see response, and there's retreatment. You're just kind of monitoring progression. So do they have a good idea of gene therapy endpoints at this point? Yeah, the first question is, we're already partnering gene therapy with Regenxbio right now. And again, obviously that, you know, that actually showed some promises with the current progression. So but yes, I think that we would be considering gene therapy partnership. Like George mentioned earlier, that, you know, at the moment, as a small company, go for low-hanging fruit first, and then gene therapy is certainly not immediate, but it's much more longer term. But again, there is a lot of company out there who have a lot of gene therapy expertise, but they might not have the right device, and so might be a match made in heaven for that kind of things in the future. Now, in terms of endpoint, FDA is very clear, and in fact, I was one of the earlier people to suggesting that we really want to use lesion growth as the endpoint, and because that is much more easier to do, to get a measurement and progression. So that have been accepted, as the first two drug approved, and I think that was still, to me, is still a good endpoint. However, that, you know, we already see those drug have problem, with Europe. So again, you know, if we can demonstrate functional benefit, that would be helpful. And you probably don't have to demonstrate both, and it depending on what would be the preferred, important. But at least for the FDA, that they always talk about this 15-letter, and actually it's quite hard to see the 15-letter change in geographic atrophy. Mm-hmm. So it might be a compromise that we have discussed it previously, is we can using a lesion size for FDA approval, a slightly different vision function endpoint for the rest of the world. So those is actually what we're looking at, and this is not just, you know, I don't think Clearside being a small company, we're not necessarily leading it, but as you know, in my previous role, that, you know, a lot of big pharma are working hard on that. Thank you. Next question will be from Andreas Argyrides of Oppenheimer. Thanks for taking our questions, and great, great presentation here. For Dr. Brown, and you've gotten this, I mean, we've kind of talked about this several times in this conversation. And you've got this question numerous times before as well, but what, what is really the ideal timeframe to go without an injection? Is it now every 12 weeks? And if that's the case, then what are you looking for from the upcoming results from CLS-AX that would differentiate it? Yeah, I think it's, I think it's two—there's two points there. One, you know, the... You'll see from some papers I'm writing and from the stuff we've been presenting, that variability in bell curve is the big problem. In other words, why did Eylea become an $8 billion drug or whatever it is? It became an $8 billion drug because for most patients, it was a week or two longer than ranibizumab Lucentis, right? And if—that doesn't sound that much. I mean, you take somebody to go from four weeks to six weeks, though, it's 13 doses a year to nine doses, right? It's considerable reduction in having to have their daughter take off work from school to drive them to my clinic. So all you really have to be is incrementally better than the best drug out there, and, and you can argue whether you think the best drug out there is faricimab or aflibercept 8 milligram, but there are still patients that need 5- or 6-week dosing with that drug. If you got every patient to 8 weeks, you'd run, you'd run the world, right? And so the- that being said, you, you have patients that can go 9, 10 weeks with ranibizumab half milligram. That patient, you would hope that with this drug, you could go considerably longer. And so, you know, if they really can get every patient to 12 weeks, that's- they'll take over all the drug market that we have now, right? Or any of these TKIs, right? You, you have, you have several different programs being on, you know, shots on goal right now. Two programs, you know, recruiting patients or at least getting close. And it just has to be better than what we have in the clinic. Okay, great, and that actually is a segue to my next question here then. So what are your thoughts on the safety advantages of suprachoroidal compared to, let's say, intravitreal injections, and then the use of the biodegradable inserts, as you alluded to? Yeah. So TKIs, I've been doing work with TKIs. I mean, I run the biggest clinical trial center for macular degeneration in the world, and we have had TKIs literally attempts at shots on goal for 12 years now, and they showed a biologic effect. I mean, we had one, TargeGen, that was an eye drop that showed an effect, but it stained the cornea red. The problem's always been just, pharmacologic delivery of these things. You know, the inside the eye, they've migrated implants. You've had snow globes with TKI. You know, the advantage of the suprachoroidal space is you don't have to have it, you don't have to have it, you don't have to have a clear molecule. In other words, when you test some of these TKIs in monkeys, you know, they're like swatting flies, and it's the same thing. Patients don't see any floaters with our current agents. They notice biodegradable implants. Some of them spin around like a baton. Like, your advantage is you're not having to be in that optically clear space. Your other advantage is that there's less inflammatory processes that we know of in the suprachoroidal space that exist within the eye to try to clear out anything. So yet to be proven if this TKI in the suprachoroidal space is gonna do what Clearside hopes it is, but if it really works, it has a lot of advantages of being outside the visual pathway. Yeah, I can also, also chime in a little bit in terms of the safety. One of the major advantages of the suprachoroidal space is that it's outside the blood-retinal barrier, and that's actually quite critical because, as Victor mentioned, first of all, when you're outside the blood-retinal barrier, first of all, you don't get endophthalmitis. If there is a theoretical risk of infection, you would actually more likely get things like a little scleritis or something like that. But because you're outside the blood-retinal barrier, there is actually inflammatory cells that are immune surveillance that will actually try to actually treat your infection. So that's why the risk of endophthalmitis is nearly zero if the injection is done correctly, and it actually enters the suprachoroidal space. So I think that that's why I think the safety is significantly better than intravitreal and certainly much better than subretinal. All right, and then just one quick last one from me, and I'll hop back in the queue, but we got updates at ASRS, and there were some updates on the intravitreal gene therapies in wet AMD. So I mean, I kind of probably know this answer, Dr. Brown, but your thoughts on the intravitreal gene therapy, and then, I mean, for it to really make sense, do you need to see durability out to, like, several years? Yeah, I've had a lot of—I've done a lot of work on gene therapy, and I had a lot of hope that we would've, you know, perfected things by now. You know, I'm not gonna comment on any particular program, but everybody's had more late surprises than we expected. You know, the inflammation or pigmentary changes or what have you that comes nine months to 12 months after you start a program is not related to the capsid, and that's the main thing we always kind of blamed. It almost has to be related to your gene product. And so for some reason, most of these programs are showing a reaction to gene product late in the development in the experiment. One possible explanation for this is that whenever I make drug in a CHO hamster ovary line or an E. coli line, it's a perfect cell line. But you still don't get perfect drug. You have to purify the drug because the gene constructs, you get some truncated proteins, you get some misfolded proteins. You purify that before you put it in a vial or syringe and ship it to my clinic. When I create a gene factory in grandma, I can't clean up her production line, and so it's possible that some of these, you know, truncated proteins, misfolded proteins, over time create you know, an immune response to, that, that is being reacted against. I hope that's not the case, because I don't have an answer for it. It would be pretty easy to figure that out. They could do AC taps and do gel electrophoresis, and see, you know, what size of proteins you're making, and how much% that, you know, is, is exactly what you wanna make, and how much% isn't. And maybe that doesn't exist, but I think we're gonna have to look harder to try to figure out why those late reactions are happening. I still think we'll figure it out, and I still have hope that gene therapy is gonna be one and done, but it's sure been harder than I think a lot of us expected when we started this journey 10 years ago. Thank you. The next question will be from Serge Belanger, Needham & Company. Hi, good morning, and thanks for the Clearside team for hosting this event. I have a couple questions for both Dr. Brown and Dr. Yiu. We've seen some high-profile approvals in this space over the last couple of years with Vabysmo and Eylea HD, and the refillable implant is also back as of earlier this month. Just curious how you've incorporated these products in your practice, how it's changed your practice, and what you've been able to achieve in terms of retreatment rates. Maybe how many patients get to that 12-week retreatment? And then Dr. Brown, you talked about the ideal phase III design for longer duration products. How would you incorporate these new products as an active control arm in these trials? Thanks. Glenn, you want to start, or I can? Either way is fine. Why don't you start? All right. So let's see, the first thing is how to incorporate it into the practice. You know, both drugs fortunately have not had the brolucizumab blow-up eyeball experience, so that's good. You know, there's a lot of patients that we are starting primarily on these drugs or switching. The majority of patients can go longer, but very few have dramatic changes. In other words, the 4-weekers can go five or maybe six weeks. The eight-weekers can go 9, 10, 11, and... But it, it's about what you expect just for having more anti-VEGF. I-- To be honest, I think that's the main benefit we're seeing with faricimab, is it's 2.4 times the anti-VEGF of 2 milligram of aflibercept, and by definition, 8 milligrams, 4 times the anti-VEGF of 2 milligrams, so you're just getting extra half-lives and less clearance. That's you know, we use it exactly the way we use our other drugs. We treat and extend. I typically don't reload. If you're on 8-week of Aflibercept, then I move you to 2 milligram from 8 milligram, I do one interval at 8, and then I go to 10, and then I try 12, and when you fail, I go back to 10. What percentage I get out to 12 is I don't know if it's that relevant because you know, the ones that get out to 12 or longer were ones that you know, were probably seven or eight on Ranibizumab, right? 0.5 milligram, and it's not you know, they're it is better, they're happier, and it is an incrementally better drug. We have a lot of insurance plans. Most of our insurance plans make us step through Avastin. Many of us have them step through aflibercept ranibizumab. And so by the time you step through two things, you have a tougher population, and not many of those can go 12 weeks, right, to be honest. After I've failed Avastin and failed ranibizumab, which is a pretty good drug. Once we get into aflibercept biosim, if we ever do, I think then you're gonna have to fail 2 milligram aflibercept, which is a high bar. It's a great drug. So that was how we're incorporating. In terms of what was the last question again? I'm sorry. The clinical trials? Yeah, how you would incorporate these new products as- It's tough part of an active control arm and yeah. It's tough because in the clinical trials, they all had a dose regimen and criteria, right? And so if you don't. It's. Before, the agency didn't make you go head-to-head. So the reason people played these games is, you would go against 2 milligrams of aflibercept, which you gave every 8 weeks, and then you would have some criteria that allowed you to go longer and longer with your drug to make it look good, 'cause you're comparing against a drug that didn't have the same criteria. If you use the same dosing, in other words, if you go PRN, which I don't really like in the clinic, but I'm okay with a tight PRN in a trial, or if you have a rescue that's exactly the same in both arms, you could easily do a faricimab or aflibercept and, and have a pretty long dosing interval, make it 16 or whatever the highest is in their label. But at every four weeks, have the same dosing criteria for both rescues, any fluid, subretinal fluid and intraretinal fluid. And if the Clearside molecule is really lasts the whole four months, and we know that very few patients are gonna last the whole four months with tight criteria with either faricimab or 8 mg, you'll win. So I think you could do it. The agency's gonna make you give... It's a little challenging if you have to give it two, six months, which is what, you know, Clearside thinks they can get, because then you'd have to do both at six months. You could do both at four months. That's probably the easiest, because both have a 16-week label. You might be treating the Clearside interval more frequently than you need to, but to be honest, I kinda like that. It you know, whenever you dose more than what you'll do in the clinic, you really test the safety aspect, right? In other words, if I give the drug too much, and I still am safe, that's gotta give the agency and clinicians comfort, as opposed to not knowing that safety curve. I guess, in terms of me, I actually completely agree with Dr. Brown, how exactly I would use, incorporate these, newer drugs in the real-world setting. I guess coming from a more academic perspective, we typically I also only observe really incremental improvement with the newer faricimab or, high-dose Eylea. I think we did actually an internal study of real-world outcomes, and most of our patients can extend maybe a week, maybe 2 weeks on. Like, it's, like, a little bit more than 1-point-something week on average if you just continuously extend from their prior interval to and switch them to a new drug. And I think that that's pretty much what, most people in our community have experienced. From an academic standpoint, we generally try to. At least my practice is a lot of Medicare, and generally, there's not as many restrictions in terms of step therapy, so we actually typically have switched a majority of our patients to one of the newer agents. For me, it's primarily been Vabysmo, mainly because of the more limited treatment interval options for Eylea HD. So we've been using primarily a lot of faricimab and switching over to that. In terms of incorporating into a clinical trial setting, I again agree with Dr. Brown. I think that, you know, in my sense, I feel like the ideal interval would be close to four, maybe even six months. I actually don't think that there's need to go even longer, mainly because I think most of us retina specialists feel uncomfortable with sending a patient and said, "We'll see you in two years," in terms of their next visit anyway, so we're probably gonna be seeing them at, you know, at least every six months. So I always feel that six-month is kind of the ideal dosing interval and visit follow-up interval, if I can get to that point. So I think that the challenge, as Dr. Brown mentioned also, it's this whole FDA requirements of whether it be, you know, similar in terms of the retreatment criterion interval. So I think that every four months, essentially every 16 weeks or every six months would be reasonable design. Our next question will be from Yi Chen of H.C. Wainwright. Yeah, thank you for taking my question. My question for Dr. Brown and Dr. Yiu is: have you observed any difference between Eylea HD and Vabysmo, in terms of treatment efficacy or safety, besides the treatment duration in your patients? I guess I can start this one. At least personally, I have not used the high-dose Eylea very often, so I don't think I have a good comparison of the two products. But, you know, there are some challenges to using the high dose of aflibercept, mainly because it's a slightly larger volume. And also, you wouldn't be... I, I generally don't give it to people who are, like, on monthly or every six-week previous treatment on Eylea, mainly because of the label that only allows us to give it every eight weeks. So at least for me, I haven't seen a significant difference between the two products, but I'd love to hear what Dr. Brown thinks. Yeah, they're both great drugs. I mean, we, it, aflibercept 8 milligrams is an easier sell because most of the patients are on aflibercept 2 milligram, and you go, "We're going to, you know, from Tylenol to extra strength Tylenol," and they kinda shake their head. And so I think there's just an innate comfort level of using a drug where there's been 80 million doses of a molecule given, right? Especially with our disastrous ranibizumab and DARPins and, you know, some... There's been some, you know-- That being said, Vabysmo has a great safety record, and I haven't had any problems with it. I think they're both, I think they're both good, high-end drugs. I think in the real world, what's gonna happen, though, is that once we get a Aflibercept biosim, the insurers are really gonna push us to use to have a Aflibercept 2-milligram failures before we go from a- It's probably gonna be a, you know- it's probably gonna be a less than $1,000 drug pretty quickly. You know, to go straight to a $2,300 drug for a healthcare system, I think, I think you're gonna have a pretty strong step to get there. And then you've got basically your, your Vabysmo and your 8 milligram is gonna be your cleanup, your, your Mariano Rivera, you know, ace in the hole if you have trouble from your... You know, if you can't win the game otherwise. And so we'll have to see how big that market actually is. You know, you hope that innovation doesn't get stifled. If those drugs are, you know, go to $2 billion-$3 billion drugs instead of the $8 billion Eylea is now, there'll be less people trying to make a better mousetrap, and that's a shame for patients, but you never know. They're both great drugs. ... Yeah, a quick follow-up. So do insurers always request you to use regular Eylea before using either Eylea HD or, Vabysmo? They don't, they don't at all because it's a $1,800 drug, right? You're kind of going from 1,800- the big difference will be when we have a biosimilar. Like, we're gonna have a biosimilar. The biosimilar ranibizumab ASP is gonna be less than $1,000 next year, right? And, and that's, that's a big difference. If it's less than 1,000 versus $2,300, it doesn't take a finance major to figure out that the more you can push to the $1,000, the more you'll save healthcare, right? Got it. Thank you. We'll now take a question from the virtual audience. Jenny Coben, please go ahead. Thank you. This question is for George. Will the patent protection for the SCS Microinjector be long enough to get a potential small molecule through the clinic? The current patent protection we have on the microinjector lasts until at least 2034. I mean, it's way too early for us to put together a development timeline for a GA product. We're in very early stages of formulation and product selection. But the microinjector itself is covered at least until 2034. We have pending applications currently that might extend that into 2040, and as we continue to develop a GA product, I would anticipate the possibility of filing additional applications that would take protection into 2040 and beyond. So we currently feel very good about our IP protection for the injector and the injector platform. I think that's our last question, so let me thank you all for joining us this morning. We appreciate your interest in suprachoroidal drug administration and in Clearside Biomedical. We're excited about our future opportunities, and we look forward to providing you updates on our progress. Operator, you may now disconnect. Thank you, all. Thank you all.