Pigmentosa mutations. That's just not going to happen. You know, there's a couple companies trying to work on gene-agnostic ones that might cover multiple, but they're not there yet. Yeah. Okay. Let's do it. Yeah. Oh, I'm sure. We actually. EyePoint Pharmaceuticals, Jay Duker, the CEO. Thank you very much for joining us. My pleasure. Looking forward to seeing the presentation, and I'll let you take it away. Thank you very much. Thanks, everybody, for coming in late in the day. Yes, I'm Jay Duker, the CEO of EyePoint. The next slide, if it were to come up, would tell you that we are a publicly traded company, and we have a long list of disclosures, which I flipped right over, so feel free to go to our website if you are interested in those. EyePoint is the leader in sustained-release drug delivery for retinal diseases. Our lead asset is called DURAVYU. It is the small molecule tyrosine kinase inhibitor called vorolanib, which is best in class and patent protected. It is in our Durasert E delivery platform, which gives us the sustained-release technology. The Durasert sustained-release technology has been in four FDA-approved products. It's been in tens of thousands of patients, and there's a very good safety profile across all those indications. We've done four studies with DURAVYU, including a large 160-person wet AMD phase II. That DAVIO II data has been enabling us to do very rapid enrollment in our global phase III pivotal trials, which we're in the midst of right now and which I will update you on today. We also recently reported highly positive phase II data for DURAVYU in diabetic macular edema. We have a strong balance sheet with $371 million in cash and cash equivalents as of the end of last year, and that takes us into 2027, well past data for wet AMD in 2026. Our two programs for DURAVYU, wet AMD and diabetic macular edema, represent significant market opportunities, given that these two indications are 80% of the global VEGF-mediated disease market. This is our pipeline: DURAVYU, again, in wet AMD, well into phase III. DURAVYU for DME, which has positive phase II data, which I will review. We also have EYP-2301, which is the small molecule razuprotafib, which we've been able to put into Durasert E and make it last six months. This is a TIE2 agonist. By agonizing TIE2, you upregulate Angiopoietin-1, you downregulate Angiopoietin-2, and that stabilizes retinal vasculature. Once again, DURAVYU, formerly called EYP-1901, is vorolanib and Durasert E. The E stands for erodible, or not all that imaginative. Again, vorolanib, small molecule tyrosine kinase inhibitor, acts at the receptor level. This is a new mechanism of action for VEGF-mediated diseases. Vorolanib blocks all of the VEGF receptors, which means it blocks all isoforms of VEGF, including VEGF C and D. In addition, it blocks PDGF, which theoretically should give an antifibrotic effect. In the long term, the three causes of visual loss in wet AMD are under treatment, geographic atrophy, and fibrosis, and we hope to take care of two of those. At the doses we're using in humans, we do not block TIE2. I mentioned TIE2 already. You want to agonize it. You don't want to antagonize it. If you block it, you will upregulate Angiopoietin-2, which destabilizes the retinal vasculature. Durasert features no delay in onset. We have certainly evidence in animals that we get immediate bioavailability within hours, and now we have some pretty compelling DME data showing that the benefit comes as early as four weeks. We feature zero-order kinetics, which means after a short initial burst of drug from the surface of the insert, it within weeks goes to a steady state and stays at that steady state release every day, every week, every month until the inserts are nearly depleted of drug. That allows what's been referred to as microdosing, which means relatively small amounts of drug in these inserts can give excellent efficacy results over long periods of time. Our inserts are designed so that the drug elutes before the matrix completely goes away. That's deliberate. You don't want free-floating drug in the eye, and you want to be able to control drug release till the end using your matrix. The version of DURAVYU that we used in the DME trials that we're using in the phase III wet AMD trials, and we will go to market, is 94% drug, only 6% matrix. That matrix should go away within months after the drug is completely eluted. This is interesting, and we think actually for retina specialists may be very helpful, but you don't need to cold storage our drug. It's shipped and stored at ambient temperature. Retina specialists have refrigerators, obviously, in their offices where they keep all these biologics, and now that there are so many to choose from, the refrigerator is getting pretty crowded. They won't have to make room for us. They can put it on a shelf. These are the four studies that we've completed: DAVIO, which was a phase I wet AMD trial; DAVIO II, the phase II wet AMD trial; PAVIA, an NPDR trial; and VERONA, the diabetic macular edema trial. We've treated over 190 patients with at least year follow-up in all of them, and we've had no ocular or systemic SAEs reported due to our drug or due to the inserts. The safety profile looks very good. Besides this safety profile, you may be aware that vorolanib, when it was formerly called X82, was studied in wet AMD as an oral drug. It went through phase II with really pretty good efficacy, but it didn't get past phase II because of systemic toxicity. There was no ocular toxicity reported. We have a database of another approximately 150 patients in wet AMD from oral vorolanib with no safety issues. You can see the efficacy outcomes on the right, and in all the studies, we did show efficacy. Let's go into the phase III pivotal trials that are ongoing. They are called LUGANO and LUCIA. They are two identical global trials with the primary endpoints the same: non-inferior change in visual acuity from day one to combined 52-56 weeks compared to an Eylea control. In order to inform the structure of the phase III, we used the phase II trial. Again, how we came up with the phase II, we originally were contemplating going directly to phase III after the phase I. In 2022, we had a type C meeting with the FDA and agreed on a phase III protocol. We then elected not to go directly to phase III for good reason, because we learned a lot from the phase II, but we used that outline of the protocol to design the phase II and hence the current phase III program. This summarizes the phase II data. We had two doses of our drug, 2 mg and 3 mg, against an Eylea on-label control. These were all previously treated wet AMD patients. They all received a load of Eylea. That's a monthly injection on day one, week four, and week eight. Our drug was dosed once, and you can see the primary endpoint at eight months, six months after our drug went in, was there was essentially no difference in visual acuity in both doses of our drug against the Eylea control. The p-value for difference was 0.0009, so essentially identical. Again, I mentioned safety already. I'll probably mention it two more times because it's so important in the retina community. There were no safety issues that developed in this trial. Secondary endpoints: significant reduction in treatment burden, 80% or more depending on how you measure it. Supplement-free, two-thirds of the eyes went up to six months with no supplement, and we had very good anatomic control. OCT, again, about 300 microns is the normal thickness on OCT of the macula, and the standard deviation is 10 microns of the test. You can see we were below standard deviation difference. This is the outline of the two pivotal trials. Once again, very similar to what we ran in the phase II, with a couple differences. First of all, we are repeating our drug every six months. We are going for an every six-month label. The primary endpoint is a blended visual acuity change at week 52, week 56. That blended endpoint is what's desired by the FDA, and we think it's a good thing also. We are going against Eylea 2 mg on label. After the load, every other month, Eylea. We are able to submit the NDA after that 52-56 week endpoint, but the study will be carried into the second year for safety. There is no non-inferiority margin for the second year. We certainly will measure efficacy, but the primary efficacy endpoint is at approximately one year. We're enrolling about approximately 75% of the eyes will be treatment naive when they would go into the study. About 25% in each study will be treatment experienced. We expect full enrollment for both of these trials in the second half of this year, which means the readout for the data top line will be a 2026 event. We have been able to execute really, really well, and this gives you a timeline for how we've been able to advance DURAVYU and wet AMD so rapidly. We announced in February, just about two weeks ago, that the first trial, LUGANO, was 50% enrolled, and I can tell you with a little asterisk down at the bottom there, as of last night, we were 60% enrolled. You can do the math. It took about two and a half weeks to go from 50% to 60%. We are still guiding that full enrollment will be in the second half, but obviously, we may well do better than that. Top line data is 13-14 months after last patient in. That's the way you can do the calculation. We're really proud of the manufacturing facility that we built. It was very obvious to us when we started this program four years ago that our Watertown, Massachusetts office didn't have the capability to make these inserts at scale, and therefore we needed an alternative. We actually searched across the United States, multiple states, over 70 sites were considered, and we ended up about 45 minutes west of Watertown in a very small part of central Massachusetts called Northbridge. We built this ground up to our specifications, eight large clean rooms. It is in the process of doing early registration batches, and we fully expect it to be fully FDA and EMA compliant. All of the current batches for the phase III wet AMD trial have been made in Watertown. Everything after that will be made now at the Northbridge facility, and we are preparing for commercial success in the sense that this facility should be able to supply both United States and global with DURAVYU. We'll be able to make over 1 million inserts a year here. On to diabetic macular edema. DME, again, a very large potential market for us, very large unmet need. Diabetics tend to be younger than wet AMD patients. They tend to need more intense treatment, especially in the first year or two. Because they're often working age and have multiple doctors, they tend to not come in for visits. Missed visits and lost follow-up are really important here. Looking at the numbers, in another five years, it's estimated we're going to have over 50 million diabetics in the United States. A quarter of them develop DME. It'll be a $4 billion global market by then, and missed visits matter. About half of the patients have delayed or missed visits, and there's data that suggests even one missed visit can result in permanent loss of vision. Here's what we're trying to accomplish with DURAVYU. The top four lines are four of the current FDA-approved products that are being used. You've got Eylea and high-dose Eylea, and you can see the frequency on label of each of those drugs. You've got Lucentis monthly, and then you've got VABYSMO, and then you can see under maintenance what we hope to accomplish every six months. If we can show similar, or if you look at the DME results, we may even be slightly superior to Eylea with an every six-month dosing. We think we will capture a lot of the market. The VERONA trial was designed as an open label Eylea control for active patients with DME. Active means they had decreased vision and they had fluid. This is the first trial that we ran where everybody was active. When we did the wet AMD trials, patients could be active or they could be dry. We did not make a distinction. They had to be active here. All the patients were previously treated. They all had fluid, and they were randomized to three different groups. Our high dose of 2.7 mg, which represents two inserts of these higher payloads that we're using in the wet AMD phase IIIs, 2.7 high dose, 1.3 mg or one insert low dose or an Eylea control. This is what I would refer to as a PRN study. What that means is after the initial treatment on day one, which consisted of Eylea in everybody, and then 30 minutes later their dose of DURAVYU or a sham, there was no further treatment for the eyes in this trial that was mandated unless they met supplemental criteria. The primary endpoint for this study, again, was not visual acuity. It was time to first rescue. We were attempting to show longevity in this trial, and we certainly accomplished that, but the secondary endpoint was change in visual acuity. Rescue criteria. All of these trials, as you may know, the sustained release trials all have what's called rescue or supplement criteria, and I'd like to say from the outset, if you talk to my colleagues, they'll say, "Oh, I don't use those in the real world," and it's true. We don't use supplement criteria when we have a patient in front of us. There's a lot of factors that go in why we would retreat a patient. In these trials, you need to have it, and I think we'll also make the obvious statement that the FDA doesn't seem to mandate one set of supplement criteria over another. Each company does it a little bit differently. We use the same supplement criteria in this phase II DME study as we did in the phase II wet AMD study, and those are the first four criteria you can see up there. We also added a fifth criteria for just this study. Now, remember, all these eyes were active, and we did not think that it would be right to watch a patient with active disease for six months without therapy if they were not getting better. We put this fifth criteria in, which is by month three, if they had not improved 10% on their anatomy, then they were going to get supplemented. This is not a supplement criteria that anyone else had ever used. It was also not a supplement criteria we are going to use in the phase III, but it actually accounted for 80% of the supplements in this trial. Without this criteria, there probably would have been fewer supplements. Nevertheless, we hit the primary endpoint. Not only did we have more maintenance than Eylea, but we had improvement in the vision and improvement in the anatomy. The improvement was about seven letters at the end of the study, and the anatomy on central subfield thickness was about 76 microns. Also listing these safety issues that did not happen, I think these are the concerns that some people have. We did not have any impaired vision due to our inserts, no endophthalmitis. I always like to add, "Look, we're doing an injection. Someday we're going to get a case." So far, we have not had any. Retinal vasculitis, do not expect to see any of that because we are not a biologic, and no insert migration. This is a graph of the primary endpoint, and you can see at week 24, we were superior to the control. Our high dose is the blue line, our low dose is the magenta line, and the Eylea control is the green. One other note is eyes could have been supplemented as early as week four, but nobody was. The first supplements in all three groups were given at week 12. If you look at the week 12 results, that's purely our drug versus purely one dose of Eylea, if you want to look at head-to-head. The other thing I like to point out here is the supplement up to week 24. Why is that important? This is the way most of these studies are reported, up to the time that you would have in a larger trial or a pivotal trial repeated your dose. Remember, we're a six-month trial, a six-month interval, so that in the pivotal trial, we'll be repeating our dose at week 24, and therefore you can't be supplemented if you've got a mandated injection. If you're trying to go head-to-head against, if you say, "How well would you do against VABYSMO?" that's the number you want to look at with the week 20 number, not the week 24 number, the up to, and obviously 73% made it supplement-free up to week 24. How about visual acuity? Here's the graphs. Again, blue is the high dose, magenta the low dose, green is the control. That's purely our drug against the single injection of Eylea up to week 12, and you can see there's a considerable improvement in the blue line, and it comes early at week four. There's substantial improvement in the vision within four weeks, showing again that we have immediate bioavailability, and we were numerically and anatomically superior to Eylea at week four. That's again an important endpoint, and as you get to the end of the study, it's true that at the end of the study, all three arms ended the same, about seven-letter improvement, which we think is great because most likely we will do a non-inferiority trial against Eylea, and it doesn't mean we have to be better than Eylea. We just have to tie them, and actually we don't even have to tie them. We can be slightly worse because I like to remind people that the high dose Eylea was 1.4 letters worse than 2 mg Eylea, but it was not inferior. Also, just to put this in perspective, if you look at VIVID and VISTA, which were the two trials that got Eylea approved, there was about an eight-letter improvement. If we improve seven and they improve eight, we're going to be non-inferior. Very comfortable with this, but buried in this data is one outlier. Notice the blue line at week 20 takes a big dip between 20 and 24. That is a single patient caused that, and that patient came in late. The week 24 visit should have been at the week 20 visit, but they were outside the window, so it counted as week 24. Had they come in at week 20, that would have been frame shifted to the left, but I want to show you what is that? It would have been 10. 10 letters. It would have been. There it is. Exactly right. This is without that single patient. The rest of the 10 eyes improved 10 letters. Now, is that fair to do that? No, I might tell you it's fair to do it, but this is the facts in that in a larger trial, if you have outliers, they're going to be randomized to both arms. This again is the OCT data, immediate drying effect in both doses visible at week four, and unlike the visual acuity, which ended up the same, the drying effect in both our drugs' doses was much better than Eylea. If you talk to the retina specialists, this is what they really look at. Visual acuity can be slow to improve in this disease. Not only that, sometimes you can't improve the vision because there's damage to the retina, but the anatomy doesn't lie. It's quantitative, and you can see our drug dried the retina better at the end. Did a subgroup analysis where we just looked at the eyes that didn't get a supplement. The reason this is important is you could criticize a supplement trial like this and say, "Well, if you set your supplement criteria too high, too lax, you'll have eyes that in the real world would have been retreated because they were getting worse, but in your study, they didn't get retreated because they didn't meet the criteria." This shows you that the eyes that didn't get supplemented didn't need to get supplemented. They improved to 10 letters by week eight, and they stayed at 10 letters for the rest of the study. When this drug works, it worked really well in these eyes. These eyes were really stable. OCT, same story. You do see a dose response here, but the OCTs improved 117 microns. These eyes started at about 420 microns, 420 minus 117, you're around 300 microns, which is almost normal thickness, and this next slide reflects that. If you ask the question in the unsupplemented eyes, how many finished the study with no DME? About half of the DURAVYU eyes had no DME at the end of the trial. None of the control group had no DME, which also tells you that the control group was probably undertreated in this study. I would agree, but even had they been treated more in this trial, I don't think they would have done better than 10 letters. Couple of cases. I don't know if you can see this at the top here, but this eye had two Eylea and a VABYSMO going into the trial. The VABYSMO was about six months before the screening, which is up top left. For those of you who've never seen an OCT before, this top right there, that's a normal OCT. There's a dip in the middle. That's the center of the macula supposed to be there. Anyway, you can see the fluid, you can see the vision, and then in the week or two between screening and day one, you can see the VABYSMO is really wearing off because there's even more fluid and worse vision. Look what happens. Eylea and our drug given at day one, at week four, dry, and look at the visual improvement, almost 20 letters, and it's sustained. You might say, "Well, Jay, look at month six. There's a little bit of fluid there on the temporal side." Yeah, it's coming back. Didn't meet criteria. I think most of my colleagues wouldn't retreat that, but that's six months after our drug. Look at six months after VABYSMO. We did much better than VABYSMO in this patient. Here's another example. This patient was getting monthly VABYSMO. They were getting monthly because they still had fluid. Two months after the last VABYSMO, 72 letters. That's okay vision, moderate visual drop. They've got fluid, and once again, look at what happens between screening and day one. The VABYSMO effect is going away. They got even more fluid and worse vision. Day one, they get the two drugs. Month one, it's better, but not dry. Month four, even better, not dry. By month six, completely dry. What does that also tell you? First of all, look at our drug six months later compared to three months after the VABYSMO. We did much better in this eye than VABYSMO did. The second thing it tells you is this effect, that's all our drug. The Eylea is out of the eye in weeks. You could argue that the month one result is assisted by Eylea, and I would not argue with that, but not the month six. It does not last that long. Again, safety, no DURAVYU-related ocular systemic SAEs. We are doing really well from a safety perspective, and we talked a little bit about this, so I will not go into more detail, just to then clinical trial summary. Met the primary endpoint, immediate clinically meaningful decrease in fluid and increase in vision, significant reduction in treatment burden, and the results were really driven by our drug. We have been a real execution story. I do like to brag that we dosed the first patient with DURAVYU in wet AMD in January of 2021, and we are here now in a little after January 2025, halfway through a pivotal trial in this drug. We expect to continue with the execution that we have done. We're well-funded to do that, and we are now fully concentrated on wet AMD. We made this announcement last week, and just to reiterate here, we have no intention of tapping the equity markets this year. DME pivotals will be a 2026 event for us. We're going to fully prepare for them, but not execute until 2026 because we want to make sure that we have the cash runway after the wet AMD readout. Thank you very much, and happy to answer any questions anyone might have. Let's talk about what are the key debates? What are the key questions you get that seems to be? Why is your stock so low? I mean, that's it. Really, I got to say, I don't think anybody would deny that we have a potential multi-billion dollar asset here and that if we're approved, that doctors will use us. Last week at the Cowen meeting, there were two KOLs who both said that they would use TKIs in 80% of their patients. Our data suggests 25-45% penetration. Can they talk about how they'll use it, like in the real world? Yeah, run it in the background on everybody, just about everybody, because if that way, if you get a patient out six months and you want to, you can. Remember, one of the things is that we are a different MOA, and it's not an either/or. You can't model us as we're going to take away market share from them. We will probably to a degree, but people can still use the ligand blockers together with us. Go back to the DME data. The DME data is explainable in two ways. Either our drug works faster and better than Eylea because our drug may be a better DME drug, or it worked in combination with Eylea faster and better. Doesn't matter to me. Either way, we win. The idea that doctors may choose to use our drug every six months and sometimes see patients sooner and use a ligand blocker in between, they may. Two MOAs, it makes sense that they might do that. Do you think this is used in year one, like right out of the gate? Do you think it's used after six months? Like people get their loading dose and then a few doses of Eylea and then let's switch over? I think it'll be a couple different ways. I think you'll have the early adopters take their patients who can't get longer than, let's say, eight weeks intervals and switch them over and see how they do. They can do it either as a PRN, meaning they'll watch them carefully to see six months, or you can do a treat and extend, meaning you treat with both drugs and then you see them back at a longer interval, treat with a ligand blocker, see them back at a longer interval, and keep going until you see how long you can go. I think the third way is something that I talked about already is that people may put on a schedule. Just say, "I don't want to do the treat and extend. I don't want to worry about it. I'm going to put everybody on an every three or four month schedule alternating drugs, and that's going to actually probably control well over 90% of the wet AMD population doing that. A priori without thought, just put them on a schedule. Just every four months they get your drug. Yeah, every three or four months and alternate. As you look at our phase II data, that suggests over 90% of wet AMD patients will be under good control that way. You'll get the advantage to MOAs. You'll get anti-fibrosis. You'll also get what I like to call the insurance policy, which is you've got a sustained release insert in there that if that patient gets sick or misses a visit, you don't have to worry as much that they're going to really head south because of undertreatment. Yeah. Interesting. Anybody got any questions? Good. Thank you. Thank you for joining us. Appreciate your attention. That's great.