I'll point that out if I have, just so you should know. It's kind of, yeah. Yeah. Irrelevant. Okay, I think we're live. Good morning, everyone. Welcome to Guggenheim's Second Annual Healthcare Innovation Conference. My name is Yatin Suneja. I'm one of the biotech analysts here at Guggenheim. It is my pleasure to welcome our next presenting company, EyePoint. From the company, we have the Chief Executive Officer, Jay Duker. We also have the Chief Medical Officer, Ramiro Ribeiro. Gentlemen, thank you so much for your time. Jay, I'm going to hand it over to you. I think investors sort of know the story very well, and you are entering this pivotal time where you're going to have a lot of readout coming up in the next, let's say, 6-12 months, pivotal readout. Why don't you maybe orient our investors just very briefly? What is EyePoint all about, and what are the next few things that you are watching out for? We'll go into the Q&A. Sure. Thanks very much for having us here this morning. EyePoint, our mission is to improve patients' lives through improving their treatment of retinal disease. At heart, we are a drug delivery company. We are in pivotal trials, as you said, in wet age-related macular degeneration. We have two identical trials, the LUGANO Trial and LUGIA Trial. They are both fully enrolled. Each of them enrolled over 400 patients in record time, approximately seven months. We will have the readout of the LUGANO Trial top line mid next year, and the LUGIA Trial will be shortly thereafter. We're obviously really excited about the potential to improve patients' lives by, in the long term, improving their wet AMD care using a sustained-release option with a new mechanism of action. We also recently announced that we are in diabetic macular edema phase III. We will be dosing and randomizing the first patients in two identical phase III trials, COMO and CAPRI are their names, and that will be in the first quarter of next year. Given how rapidly Ramiro's team was able to enroll the wet AMD trials, the pressure's on him to enroll these DME trials just as rapidly. If we can do that, that puts us into last patient in 3Q of next year and top line 4Q 2027 from both phase III DME trials. Got it. Recently, we announced publicly that we have strong preclinical evidence that our drug, vorolanib, not only has an anti-VEGF effect, but has an anti-inflammatory effect by blocking the JAK1 receptor and therefore blocking the downstream result of elevated IL-6. For those of you who are following retina and posterior segment, IL-6 has been on the radar of retina specialists for over 10 years as initially the reason that we get macular edema and uveitis. More recently, there's strong evidence that it plays a role in diabetic macular edema and wet AMD also. Therefore, this multi-MOA approach that vorolanib can provide along with sustained-release, I think really puts us at the forefront of the future of wet AMD and DME therapy. Got it. Very good. I'll come back to the IL-6 and the DME later. Maybe first, let's discuss the LUGANO and LUGIA study, right? Both enrolled very rapidly. What were the key drivers behind this rapid enrollment in those studies and how careful you are in terms of the type of patient that you wanted in? I'm going to let Ramiro go into the details, but I think the top line take-home message from this type of rapid enrollment is patients and physicians are really excited about the difference that the review can make. I think the first point that we heard from investigators is the strength of our phase II data. As you know, we have run the largest phase II study in TKI and wet AMD with 161 patients, and we show great results there as well as safety, which is very important for patients. That gave confidence for investigators to offer our phase III study to patients. Also, as Jay pointed out, the fact that we're trying to show a treatment of six-month interval, very easy to sell that to patients. The way that we designed the study, we made it in a way that it's very patient-centric. Every patient gets treatment either with aflibercept on label or with the reviewed investigational drug. We try to make this study very easy for the clinical side, for investigators and for patients by making the logistics also quite easy. As Jay mentioned, I think we're trying to replicate all the learnings that we had from the wet AMD and now to the DME study. Got it. Are there any, maybe could you highlight the key differences between the W2 and LUGANO and LUGIA? What are their key differences? I know the patient population is a little bit different. Can you just summarize for us what are some of the key differences? Yeah. In terms of the clinical design, they're both noninferiority drugs, right? Our W2, LUGANO and LUGIA. For our phase III study, W2, we only enrolled previously treated patients, but also they were very hard to treat patients, meaning that they have been receiving anti-VEGF for a long time, and they were also receiving anti-VEGF very frequently. The average number of anti-VEGF in the past 12 months for that patient population was 10 injections in the phase II study. Even in that patient population, we did really well. We did noninferiority and also with a good reduction in treatment burden. For the phase III study, we have previously treated patients in our study. That's 25% of the patient population. Also, we now have naive patients. We believe we're going to do even better with naive patients because we know that a good portion of those patients, they do not require that amount of anti-VEGF treatment. Even with that changing patient population, we're still confident with the results. Got it. Maybe just on the naive patient population, I think I understand that you would do better, but I think the expectation would be that the control arm should also do better. On a net basis, how should we think about it? When you say the control arm will do better, we really know pretty precisely what the control arm should do. That's the beauty of using on-label Eylea. Other than the port delivery, which used Lucentis monthly as the control arm, every other approval in wet AMD ever since Eylea has used Eylea 2 mg on label. That's important for two reasons. The first is regulatory. The FDA insists that if you're doing a non-inferior trial, you have to go against on-label Eylea randomizing on day one or on-label Lucentis randomizing on day one. If you do not do that, you run the risk of not counting as a non-inferiority trial. The second important thing, though, is the physician's interpretation of the results. Because all these other trials use 2 mg Eylea on label, the physician community knows exactly what the results are going to mean to their patients and in their practice. I think that makes it much easier to integrate once approved, integrate our drug into practice. Got it. Got it. As we head into the readout for LUGANO and LUGIA, obviously, I think we and investors would like to sort of understand what exactly you would like to produce or what we should be expecting. If you can touch on a couple of things, including safety. Sure. Yeah, all of that stuff. I think the expectation, again, is we will be statistically non-inferior to the Eylea arm. What we hope is to be statistically superior. That is a stretch, but not impossible. Even if we are numerically superior, even a half letter or a letter, I think that puts us in a great commercial position because what doctor is not going to look at a patient and say, "I can get a second MOA, I can get anti-fibrosis, I can block IL-6, I can do it on a six-month basis, and I might get a little more vision?" That sounds great. The end is we need to be statistically non-inferior. Again, replicating the change that we got in W2 would be terrific, but we do not have to be statistically non-inferior. I like to remind everybody that high-dose Eylea was 1.4 letters worse than 2 mg Eylea. Yet it's obviously got a market share, and everybody really doesn't make a big deal out of that. The second thing is safety. This is hugely important in all aspects of medicine, but especially in retina. We have to have similar safety results to the approved drugs. I'm delighted to say that, and we've said this publicly already, that on a mass basis, we've looked at the safety so far, and our DMC has looked at the safety, and it is consistent with the prior trials that we've run. Got it. Just on the safety, I'll come back to the BCVA. Just on the safety, can you just talk about what have you observed or modeled regarding the fate of the insert after the drug release? What exactly happens? Are there any risk of buildup? Sure. I think now you have three dose patients. What are you seeing? Again, we've probably redosed now maybe 40% of the eyes in the pivotal trial. From a safety perspective, no issues. We have never had a patient lose vision due to the insert. We haven't had a patient report the insert blocking the vision. We haven't had insert migration to the front of the eye, and we haven't had any patients request that the inserts be removed. Nobody's dropped out of the trials due to the insert. Once again, to remind everybody, the latest version of these inserts, the higher payload version, are now 94% drug. It's only 6% matrix. Each insert is only one five-thousandth of the vitreous cavity. The inserts contain no PEG, and they contain no PLGA. That's important from a safety perspective. Based on animal data and some of the human PK data that we had from earlier studies, we're confident that the inserts should be essentially devoid of drug by month nine. We're also confident that in virtually everybody, they should have therapeutic levels through month six. Hence, the every six-month dosing. Based on animal studies, we believe the residual 6% matrix will take several more months to go away. The issue really is when you think about it, one five-thousandth of the vitreous cavity is not very big. These inserts are heavier than water. After they're injected into the eye, they drop to the bottom of the vitreous cavity, and they're really hard to see, and they're really hard to photograph. Without serial photographs watching them go away, once the drug is gone, they're quite small, and they're hard to see, and they're hard to photograph. It is difficult in patients to know exactly when it goes away. Suffice it to say, the safety so far has been really, really good. The potential for buildup of inserts with this type of matrix is really not an issue for us. Got it. Very good. Helpful. Going back on the BCVAs, obviously you want to be non-inferior in line to the control arm. What about OCT, rescue free rate, and injection frequency? How should we think about those three things? OCT is interesting because from a regulatory perspective, OCT is not an endpoint for wet AMD or DME. It's visual acuity. While I think if your visual acuities were not consistent with the OCT findings, the agency would have to be a little bit head-scratching as to why. On the other hand, if you have a different MOA, not just anti-VEGF, you may actually be able to show visual acuity improvement that doesn't completely align with OCT because you're treating another aspect of the disease. However, OCT obviously is a biomarker that we retina specialists use all the time in practice. Therefore, the OCT is important to retina specialists. Again, going back to our phase II data, we had very consistent OCTs compared to the sawtooth pattern that you see in every other month Eylea, especially in the higher 3 mg dose. The OCTs were really stable after month four. They are only minimally different than Eylea. In fact, when you looked every other month, the OCTs of the 3 mg arm was essentially exactly the same as Eylea. Remember, a normal foveal thickness is up to 325 microns, and we were about 10 microns difference. You are talking about very small amounts of thickening, so much so that the average clinician would not be able to see that clinically. Got it. Got it. What about treatment burden? That's a secondary endpoint, reduction in treatment burden. I think, again, if you extrapolate back to our phase II in a very tough-to-treat population over one year with no reinjection, so essentially after month nine or ten, these inserts were probably devoid of drug, we had on a whole basis about one supplement in our arms approximately. If we can match that, we're going to be in really good shape. Got it. Okay. And then where are you on the B or the NDA front? What will be needed for you to file the NDA and when it could be filed? Ramiro, I'll let you answer that one. Yeah. For wet AMD, what is required for the submission is the two phase III studies. We're in good shape for that. We had our end of phase II meeting with the FDA this year. We discussed our plans, that we are all aligned with what we need for the submission, as well as the safety database. We also have the CMC package. I think the beauty of our clinical program is that we're going to have first the readout of LUGANO. The results are, the studies are identical. With that result of the first study, we're going to be able to start writing all the modules, all the reports. Once we have the results from LUGIA a few months after LUGANO, it's going to be in a way very easy for us to just put the data there and therefore do the submission. Okay. I will add also, I think everybody knows most CRLs come from CMC. We're well aware of that. I think you're all aware that we have our own manufacturing facility about an hour west of here. We have no tariff exposure. Our parole item is made in the United States. We make our inserts here in Massachusetts. There are really two things going on in our manufacturing facility right now. Number one is preparing for the pre-approval inspection by the FDA. We have been making inserts for decades. We know exactly what they want. Therefore, as I've been telling regulatory quality ops manufacturing, it's an open book test. We know exactly what we need to do. The second thing that's obviously really important is we need to gear up for commercial success. We need to be able to make hundreds of thousands of inserts two years from now. We are in the process of doing that. We have made the registration batches successfully. Things are going great out there. Anybody who wants to take a tour, we're happy to take you out. Got it. Got it. Can you also now touch on the competitive landscape? What are you seeing on the competition front, either from VABYSMO or the monoclonal antibodies? You have a TKI that is a competitor also has a program. Sure. Obviously you look at a drug like VABYSMO, which appears to have a better drying effect in about a third of patients, with some better longevity than 2 mg Eylea. I think it depends on what report you read. It's anywhere from eight days to about two weeks. That's a $4 billion drug and growing. Patients and physicians want more extension. I think for a six-month drug, that speaks very well about the potential commercial success. High-dose Eylea, for reasons I think we all know, had a little bit of a slower start. We don't believe we're going to be direct competitors to either of those drugs because we have a different mechanism of action, number one. We're six months or longer. We also have an anti-inflammatory component, which they do not have. This is, again, a sea change in the way physicians are thinking about how to treat a chronic disease like wet AMD. It's unusual that there's only one MOA for a chronic disease. I guess you could argue VABYSMO really has a second one. Also, we've been treating it with an acute treatment, a short-acting biologic. We're not telling the doctors to get rid of your short-acting biologic. Remember, in the wet AMD trial, we're inducing with three injections of Eylea. There will be supplements. The idea of using two MOAs to treat a chronic disease is attractive. Got it. What about something like an ocular product? How does that compete? First of all, based on the current status, we will be first to file. If approved, we will be first to market. The data is certainly out there to support that. Last patient out for us will be approximately nine months, let's say, prior to theirs. We should be able to file faster for the reasons that Ramiro already stated. We believe that if approved, we will have a six-month label, which we believe will be advantageous. I also like to point out, back to safety, we've had no safety signals at this point. In the Australian ocular phase I trial, they did have a safety signal with a 17% loss of vision due to their insert. We have, again, less regulatory risk. I can go into the details of that. Back to us, this first-to-market advantage is going to be important. The label is going to be important. I think, again, our competitors are going to be the well-established anti-VEGFs. Got it. Got it. Now, in terms of the—thank you for that. In terms of the KOL feedback, the type of patient, what are you hearing? I mean, obviously you yourself are a retinal specialist. But what type of patient do you think the adoption will be initially and where eventually it goes? Yeah. Obviously that depends on the results. The KOLs are now getting more and more attuned to the potential of sustained release via a second MOA. I think they're very excited about the potential for IL-6 blockage with vorolanib. We did a QualQuant study prior to our phase II results. With a TPP that was worse than what we got in phase II, we had about a 25% market penetration at that point. We're redoing it, and we fully expect this should be much higher. In fact, when you hear some of the KOLs on the podium now, they're talking about using TKIs in 80% of their wet AMD patients. The idea of having two MOAs on board, having a TKI running in the background, and periodically, if you need to supplement, it's no big deal. Got it. Got it. Okay. Very helpful. Moving on to the DME side, obviously VERONA study, you show very rapid and sustained improvement. Could you just talk about, put those data in context, talk about the phase III program that you are running? What are some of the differences and what exactly will be the expectation from those two studies? Sure. Just to remind everybody, in the Verona trial, the first time we used our higher payload insert, obviously successfully and safely, we enrolled only patients who had active disease. They had to have fluid. They had to have decreased vision. On day one, everybody got an Eylea, and then our patients got their dose of our drug or a sham. At week four, the eyes that got our drug were significantly better than the Eylea-only eyes. Three to four letters better vision, and OCTs consistent with that, 30-40 microns drier. That is, again, where we really needed to go back to the R&D folks and say, "Why did we get such a great result? It cannot be anti-VEGF alone in that short period of time." That is, again, where the data around IL-6 came out that we have an anti-inflammatory effect as well. At the end of that trial, we were equivalent to Eylea, seven letters better. Of course, we had an outlier. If you look at, for example, the 70% of patients who were supplement-free, those supplement-free eyes improved 10 letters. Now, in a previously treated DME population, we just saw that as a control group in a recent approval. They improved seven letters at a year, five letters at six months. We were 10 letters at six months in a similar population. We are really excited about the potential there. Again, I'm going to kick it over to Ramiro to talk about the design of the trials and what we expect and hope to show. Yeah. We're going to be starting Q1 of next year, Coleman-Capray, two identical phase III studies, noninferiority. The control arm is going to be only aflibercept. That's going to be five loading doses followed by every eight weeks. On the DURAVUE arm, we're going to be dosing DURAVUE at day one. That's slightly different than what we did for the wet AMD, which we're dosing at week eight. The reason why we want to do that is because we want to block the IL-6 pathway, as we show in the Verona data, and hopefully be able to show that rapid improvement in BCVA and CST. The primary endpoint, again, very similar to our wet AMD program, BCVA average week 52 and 56. We have safety as one of the secondary endpoints. We're going to be using a lot of the sites from our wet AMD. We expect to be having a quick startup on that study and have full enrollment also in a quick fashion. The other important aspect of the DME program is that we were able to have a discussion with the FDA that for that submission is going to be as an sNDA. We're going to be able to leverage the safety database from the wet AMD program. Therefore, the size of our DME study is relatively small with 240 patients in total. Okay. And then with regard to this IL-6 mediated mechanism, is that mechanism more relevant in one disease versus the other, basically more relevant in DME versus DMD? I think the evidence is it's more relevant in DME. We have known DME is an inflammatory disease for decades. Why? Because corticosteroids work. In fact, they work arguably as well as anti-VEGFs do. In saying that, there's some pretty good data showing that in DME patients, the IL-6 levels are really, really elevated in the vitreous. When you look at studies in wet AMD, it looks as if the quartile of patients who do the worst have the highest IL-6 levels. It may be that virtually everybody in DME has an IL-6 pathway issue, but only the segment of worst patients in wet AMD have that. That, again, gives us confidence in the noninferiority result that we're seeking. In both trials, if we hit noninferiority, we're able to test for superiority without penalty. I do want to make one other comment about the DME, though, which is if in fact we're three letters or four letters better at week four than Eylea alone, but in the end, we're noninferior, we're going to control most of the market. Who wouldn't want to get better faster? Who wouldn't want to do it with fewer injections? If we're numerically superior, which based on the Verona trial, we could be. Again, I think that we will become the treatment of choice in DME. Got it. DME is what? It's about 35%-40% of the market? Approximately. It's about a $3 billion market right now in the U.S. Okay. One final question. Any update on the ex-US strategy? How are you thinking about, number one, any regulatory update there and then? No regulatory update per se. I think you're aware, and we announced this last year that the EMA had approved our protocol, which again, the EMA can be stricter than the FDA in pivotal protocols. We felt that that was a very positive sign and given the feedback they gave us, a very positive sign that this drug, if successful, is approvable in Europe. Right now, we are doing the background things that we need to do to prepare for potential launch ex-US. Most favored nation status. We are well aware of that. We're not going to shoot ourselves in the foot. Nor at this point is it likely, other than perhaps Japan, would we do small ex-US deals. Doesn't make sense for us. It really doesn't. It is likely we will seek a global partner at the right time. Our intent is to launch this drug ourselves in the United States. Got it. The DME study, did you have a buy-in from the EMA on the program? Not. The DME phase III? We haven't submitted in Europe yet. I see. Okay. I see. Okay. We are planning to include European sites also in that study. Okay. Awesome. I think that's all I had for you. Thank you so much. Thank you. Thank you for your attention. Thank you.