With EyePoint. As a reminder, if you have questions for those in the room, just raise your hand and we can take them. Welcome as well to those listening on the webcast. I'm Miguel Nahamab, a biotech analyst here at CITI. I have the pleasure to introduce senior management from EyePoint Pharmaceuticals, Dr. Jay S. Duker, CEO, and George O. Elston, CFO. Welcome, both of you. Thank you very much for making the time to chat. Obviously, a very busy time for the company and for the wet AMD space. To start out, Jay, if you could spend just a few minutes introducing the company, the therapy you're advancing, key trials, obviously in Phase 3 trials in wet AMD, and then we can get into a lot more detail from there. Thank you. Sure, thank you. And thanks everybody for coming. EyePoint does drug delivery to the back of the eye. We've had four FDA-approved products with our technology. The latest technology is a fully bioerodable insert that contains Vorolanib, which is a small molecule tyrosine kinase inhibitor that has activity against all the VEGF receptors. We're in Phase 3 in two trials for wet age-related macular degeneration, which is the largest market of all the retinal vascular diseases, about $10 billion a year in the United States alone. We recently announced that we are fully enrolled in both of those trials. They are identical trials, which the primary endpoint is non-inferiority change in visual acuity against on-label aflibercept control. We are very excited. Generally, where we are right now, as I said to many people, if we had mapped it out four years ago when I first joined the company full time, that this is where we would be at this point, I would have said very low probability of success. Here we are, and that's because we've really had a great, great group who are able to execute on all these milestones that we've achieved, including this enrollment for these two trials. Each of the trials enrolled in approximately seven months, which are the fastest enrolling wet AMD trials on record. One of the reasons, of course, is that we had really good Phase 2 data in wet AMD, which was helpful for the sites to convince patients that this is a trial that they might want to enroll in. It also, I think, speaks very well for our potential commercial success in that a sustained release insert that releases drug therapeutically for six months or longer with a single injection is something that's very attractive to both patients and practitioners. I was going to ask what you attribute to the speed of enrollment. You sort of got to that already. I did, sorry. I should have paused and let you ask your question. No problem. There are other reasons, though. Yeah, OK. Our Chief Medical Officer, Ramiro Ribeiro, who's here, I need to give him and his team full credit here. Ramiro's experience, he's run Phase 3 retina trials internationally before. His experience and his ability to lead a team, I think, has been very helpful in our success. The fact that we did run a Phase 2 trial and we learned a lot of lessons from the Phase 2, not just got great results, top line and safety, but we learned about how our drug works. We learned about the statistics of the trial. I have to say, at the beginning especially, we made a few mistakes. We learned from the mistakes. Towards the end of the enrollment in the Phase 2, we were enrolling very rapidly. We took those lessons and applied them to the Phase 3. Our Phase 3 program, again, we took a de-risked view of this, meaning we did a non-inferiority type trial design, which is how the last four approvals in wet AMD were structured. We were able to really connect with the retina community based on our data, based on our personnel, and based on what we call the patient-centric focus of the trials. Everybody in the trial gets treated. We have rescue criteria or supplemental injection criteria, which means if a patient was losing vision in either arm, either the treatment arm or the Eylea arm, they could get a supplement injection to help ensure that they don't lose vision in the long term. These are the type of things that doctors and patients are very appreciative of. Speaking of the rescue criteria, if you could go into a little bit more detail and how those rescue criteria sync up with how one would behave with a patient in a real-world setting and how closely that aligns. Let me start by saying that the idea of a rescue criteria, supplement criteria, is relatively new. The sustained release treatments, all of them, which started to be studied several years ago in the Phase 1, contained supplement or rescue criteria, meaning if a patient wasn't doing well by some measure, they could receive an extra injection. The problem, as you point out, Yigal, indirectly there, is if you say, how does that correspond to the real world? It doesn't. None of us, and I am still a practicing retina specialist, use strict criteria in deciding whether to either give a patient an extra injection or shorten the interval between injections. The reason is we individualize therapy. We have a patient sitting in front of us, depending on whether their vision is good or bad, whether they're otherwise involved, whether they perceive a problem or not, and there are social issues around intervals. Some patients just cannot get treated every month, even if they need it. That idea of a supplemental injection or rescue injection is not something we use in the real world. It is something that you need to ascribe in order to get these trials done and have them given the FDA sign-off. Interestingly, if you look at these trials, you'll realize that the supplement criteria is different with different trials and with different companies. That is because at this point, the FDA acknowledges that there's not a standard out there and allows sponsors to determine their rescue criteria. A little more detail around that. In Phase two, we had a lot of different rescue criteria. Ramiro and his team took a look at the Phase two data and asked the question, which of the rescues actually made a difference and improved the visual acuity? It came down to just one, five-letter loss from best on study associated with 75 µm of new fluid on OCT. That was the single important rescue criteria we came out with for the Phase 3. In addition, in the Phase two, we allowed doctors' discretion to do a rescue. About 20% of the rescues in the Phase 2 didn't meet any of the criteria. Doctors just decided they wanted to do another injection. We're not allowing that in the Phase 3. We also have a rescue criteria for new hemorrhage in an eye that is sight threatening due to wet AMD. That, however, we like the sites to adjudicate with a rescue monitor, meaning if they see a new hemorrhage, we like them to take a picture of it. We have rescue monitors on call to talk to them within minutes about whether or not it's an appropriate rescue. You say, why did you do it that way? Simple. When Ribeiro's team took a look at the rescues in the Phase 2 due to hemorrhage, there were nine of them in all three arms total. Six of them either didn't have a hemorrhage, or the hemorrhage wasn't sight threatening, or the hemorrhage wasn't due to wet AMD. We would like to minimize the number of rescues in the Phase 3 while not sacrificing vision, and hence the changes that I just spoke about. There are two Phase 3 trials, and they're kind of almost concurrent, essentially. The readouts, just remind us when the readouts are expected. The first trial is called LUGANO. We announced last patient in the end of May. We expect the top line data release to be sometime mid-summer 2026. The Lucia trial was several months later. We announced last patient in the end of July. We should have about approximately two months between the top line from the two trials, both in 2026, in approximately one year or less. As you pointed out, it's a non-inferiority study, both are. There's a margin, which you've talked about before. Obviously, you have to achieve that. What else, though, besides just hitting on the primary endpoint would kind of capture success for you for these studies? Yeah, in the end, I think it is rather simple. We need to be statistically non-inferior to the Eylea control arm. The non-inferiority margin that we were given is minus 4.5 letters. In the Phase 2, the lower limit of the non-inferiority margin for both study arms was around 2.6 letters. We were very far from the minus 4.5 letters. In addition, we need to show continued safety. That's one other big advantage that we've had. We've treated over 190 patients with our drug between one Phase 1 and three Phase 2 trials. We've had no ocular or systemic SAEs attributable to the drug or the insert. We've had no safety signals attributable to the drug or the insert. We're quite pleased with the safety. We did make an announcement just recently that our Data Safety Monitoring Committee had met in the Phase 3s and recommended no change in the protocol. At the same time, taking a look at the masked data from both trials, there doesn't appear to be any safety issue that would not be expected in a typical wet AMD trial. That's the second thing, continued safety, which we're optimistic. In addition, we need to show a reduction in treatment burden. In other words, compared to the Eylea control arm, how many injections did the study arms get? We need to show a reduction in that. In the Phase 2, the reduction in treatment burden was measured in several ways. It was about an 80% reduction. That's really good. If you ask KOLs what type of reduction they'd like to see from a sustained release insert that's bioerodable, they'll tell you around 50% is good. We certainly hope to do better than that. We think if we're non-inferior, safe, and we have at least a 50% reduction in treatment burden, then we will have a very successful commercial drug. That sort of gets into how this would be deployed in the real world. What are you thinking in terms of the expected interval, whether it's, as you point out, the reduction in the background use of one of the anti-VEGFs, or if it turns out that you could even go as long as six months between the DURAVYU administrations? Another way of asking you this, just how do you see this being integrated into the management of wet AMD? I mean, we've talked about this before. There are many ways it could be done. Different retina physicians are going to take maybe different philosophies. If you could kind of walk through that, that'd be really good. I think, again, to review the data, we had about 2/3 of eyes make it six months, up to six months after our insert went into Phase 2 without supplement. With just one injection, we didn't repeat the injection of DURAVYU in the Phase 2. 50% went a full year. We know in a tough-to-treat wet AMD population, probably 50% of the eyes, or maybe greater, could go a full year with our drug. We chose a six-month interval for several reasons. First of all, we're pretty confident that in humans, based on animal data, we'll have a therapeutic level of Vorolanib for at least six months in virtually everybody. We also believe by nine months, the drug should be pretty much fully eluted in just about everybody. That six-month interval gives doctors more flexibility. For example, if I have a patient who I'm treating with DURAVYU and I'm watching them, and at month seven, they get fluid, if we have a six-month label, obviously, they can retreat with DURAVYU. If we had a nine-month label or 12-month label, they couldn't. They wouldn't get paid to do it, be off label. The payers wouldn't pay for it. How it's going to get integrated into practice? I think at a high level, you can think about it the same way that doctors treat wet AMD now. There are basically three strategies. The most overwhelming strategy right now is what's called treat and extend, which means you get the patient as dry as you can get them, and you then try to extend out the interval between shots until you see fluid again, and then you back off. That's called the fluid-free interval, and you pretty much stick with it. Most patients, at least in the short term, can be adequately treated using that method. The problem is, in the long term, patients still lose vision. They miss visits. They're probably still undertreated despite our belief in this strategy. If you look at the long-term visual acuity results, the number one reason why patients lose vision when AMD is under treatment. That's one strategy. The other strategy, which is rarely used now, is called PRN or as needed, which means you see that patient every month, but you only treat them when you see fluid. The problem with that is you're essentially letting the eyes recur, and in wet AMD, recurrences are bad. We believe that if you continue to let fluid come back, patients lose vision. Unless the patient requests it, most doctors don't treat that way. The third way is put them on a schedule. I think the pharma companies realized at the beginning that retina specialists like to individualize therapy, and they don't read labels. It's very few who right now automatically use Lucentis every month or use Eylea every other month automatically. VABYSMO and high-dose Eylea have four-month labels. I don't think there's anybody that I know of who automatically goes to four months. The patient needs to prove that they can get out that long. If you look at the trials and look at the real world, 50% of patients on even VABYSMO or high-dose Eylea still need treatment more frequently than every eight weeks. It's probably a patient-specific thing, not a treatment-specific thing. Putting someone on a schedule in that sense may not make sense. I actually think that may be the way we do get used more than the other two methods. If you look at our data from the Phase 2 and you ask the question, what percentage of patients could be treated with just our drug or one or two Eyleas for a year? Now, again, we need to extrapolate because obviously we didn't reinject in the Phase 2. If that data holds, you could treat 90% of patients a priori by altering your treatment every three months with 2 milligram Eylea and DURAVYU. Make it really simple. Just put everybody on a schedule. You know exactly when they're going to come in. You might be overtreating some patients. I think that using the two MOAs in this fashion, because Vorolanib does have a different MOA, I think that would be advantageous. I think going back, it's a long answer to your question. You're going to see all three of those methods used till doctors get comfortable with how our drug works in the real world. Another important real-world question is a pharmaco-economic one, obviously, which is price. Anything you want to comment on that? Is it a bit too early to say much? Maybe a little too early to say much. I think the simple way if you're modeling the pharmaco-economics is to think about if the studies hold, one DURAVYU is approximately equivalent to three Eyleas. We would expect that that's a model that could be used as a baseline to model the costs. If we have additional benefit, and the additional benefit would be, we hope, better treatment outcomes in the long term, we may also see additional benefit. We've got some preclinical data that suggests that our drug is neuroprotective. It may also be antifibrotic because we block PDGF. It also may lead to less atrophy, which all of these three things we're going to be looking at in the pivotal trials. If we can show any of those things, I think that we would be able to price it even more of a premium. By the way, I should have clarified before, those two studies, Lugano and Lucia, they're essentially identical trials, correct? They are essentially identical. I think their only difference is PK sampling from the serum. That's it. OK. I think you've made the statement in the last several quarters that you now expect to be first to file amongst the other companies that are developing these long-acting inserts. Is that sort of still an accurate statement? I think it's quite accurate, and every day that passes increases my confidence in that statement. To go back in time, we dosed the first patient with DURAVYU a little over four and a half years ago in a Phase 1. We've subsequently done one Phase 1, three Phase 2s, and fully enrolled two Phase 3s in about four and a half years. We've executed really well. Going back four and a half years ago, we were in last place. There was a race of multiple companies trying to do sustained release in wet AMD. We're now a lap of the field, and we strongly believe we're in first place. Why? Because we're going to have last patient out next summer, and we should be able to file, we hope, by the end of next year. Even with a standard type of review, which we hope will be eligible for a quicker review, we're optimistic that we should be able to launch this drug if approved by the end of 2027. Our nearest competitor, they're all still enrolling their Phase 3. When you do the math on when they're likely to finish their second trials, we think we're at least six months, if not a year, ahead of the nearest competitor. Let's talk a little about another sort of commercial topic, which is super important. Your manufacturing facility is just down the street, figuratively speaking. Not in the high rent district here. No, we're not on Newbury Street. It's a little more than down the street. Yeah. It's in Massachusetts. Tell us about the CGMP facility and what the capacity is there and how much of the market you could supply. First of all, we don't believe we have any exposure to tariffs. We manufacture this here in the United States. As you all said, it is not right down the street, but you drive an hour west of here, you'll see a very nice bucolic town called Northbridge, Massachusetts. That's where our facility for manufacture is. Our API is also, by the way, made in the United States. Northbridge was conceived about four years ago when we realized that if we were going to be successful, we would need a commercial facility dedicated to making these inserts. It's 41,000 square feet CGMP for both Europe and the United States, eight large clean rooms. At capacity, we believe we should be able to make close to a million inserts a year in this facility. That should be able to supply even, well, maybe not our wildest expectations, but let's call above our base case expectations, should easily be able to supply the entire world with these inserts. We are in the midst of preparing for a potential launch by upgrading the facility, getting it ready to go five or even seven days a week with two shifts. We are in the midst of doing registration batches there now and preparing, of course, for the FDA inspection for pre-approval. All of this, again, is all mapped out and so far on target. We're quite optimistic that not only will the facility be acceptable to the FDA, but it will be able to supply us and the world with enough of these inserts to be quite successful. Can you describe to everyone listening and here in the room just how does this actually work with these inserts? Obviously, with the traditional anti-VEGF, you draw it up from the vial. Here you have a physical drug delivery device. What is the structure of that injection, and how does the physician do it? Sure. I mentioned that we had four FDA-approved products prior to DURAVYU. Essentially, what we can do is take the API and put it into a matrix that holds the API together. All the prior approvals, the API was very soluble. If you just injected it as is into the eye, it would go away really fast. We needed to wrap it in a non-erodable shell made of polyamide. The shell had pores, and that allowed the drug to diffuse out. DURAVYU does not have polyamide. There's no shell to it. It's all drug and matrix. In fact, we've been able to make process improvements so that the inserts now are 94% drug, only 6% matrix. At nine months, the drug load should be completely spent. That matrix, we designed it so that the matrix would hold the drug together till the drug load is gone because you need to control release till the end. You don't want free-floating drug particles in the eye. That matrix is fully bioerodable and should go away in several more months. They're cylindrical-shaped inserts that are preloaded into a sterile syringe injector. It's actually quite simple for the doctors. It's shipped and stored at room temperature. It doesn't have to be frozen or refrigerated like our competitors. It does not contain any PEG. If you had followed some of the issues around the potential of PEG causing inflammation in eyes, we don't have PEG. We also don't have PLGA. The studies that we've done preclinically, and obviously, I talked about the clinical studies, have really shown no safety issues at all. It's quite simple. Shipped and stored at room temperature. Open up the package. Take off a cap. Take out a wire. Remove another cap. You're ready to go. One of the interesting things we've learned as we've really prepared the market for potential approval is that even the large retina groups, who one would think is really concerned mostly about cost and the potential for fewer injections, that's not their number one concern. Their number one concern is don't slow down our doctors. Don't have a product that requires mixing, defrosting, or obviously get a J-code as quickly as possible, which we know all about, in order to be commercially successful. That idea of not interfering with the flow of these busy retinal clinics, we think we fit that bill really, really well. Speaking of this practice dynamic of not slowing down the physicians, in terms of the overall use of the anti-VEGFs, we've gotten this question, and I've probably asked you this question before, but some investors have asked, would it impact the overall use of the anti-VEGFs? You mentioned the three different approaches. It sounds like a lot of that would be a lot of averaging out, so to speak, in terms of use of Eylea or Lucentis, and it wouldn't really change that in a sense. Is that fair? I think it'd be fair to say that there would be some patients whose, if we're successful, whose usage of the other branded drugs would be less. How many doctors and patients choose to go every six months on our drug alone remains to be seen, even though it looks like, again, if the Phase 2 data holds, about 2/3 of the wet AMD population probably could be managed with our drug alone. The idea of using a second MOA together, that's really been part of medicine and chronic disease treatment all over the body for years. In ophthalmology, you look at glaucoma therapy. They mix drops with different MOAs all the time. Ophthalmologists are used to this idea of two MOAs. Doctors have no lack of patients needing injections right now. They want more flexibility in their ability to control the rate of injections, especially with the rise in the anticomplement drugs. There are just so many injections that need to be done out there. There's also pressure in the retina community to continue to be the deliverers of injections in the United States. If the volume can't be handled by retinal specialists, there's a worry that non-retina specialists would become the main deliverers of the injections. That's something that I think the retina community is cognizant of and truly believe that it should be in the retina specialist's hands because they're the best ones to be able to judge the efficacy of the injection as well as deal with any potential complications. Again, a long-winded answer to say it doesn't seem to be an issue around retina specialists feeling like this is going to be taking away injections from them. They're not worried. You mentioned the capacity globally. The two Phase 3s, could they support, or what is the plan to support the filing in Europe or even other territories? We did announce that the EMA did approve our protocol. We did have European sites in the second study. Approximately 20% of the second study was enrolled OUS, enrolled very rapidly, again showing how excited the doctors outside the U.S. were about the possibility of fewer injections. That also, because EMA approval of a protocol obviously doesn't guarantee that you get approved as a product, even if you have positive data, it is a closer step for that. The EMA, my understanding is that they not just look at, is the protocol safe, is it likely to show good data, but is this a potentially approvable product in Europe. We believe with good data, we will be approvable there, as well as the rest of the world. Would the filing for Europe be staggered? Strategically, you know we're in an interesting time right now in that we know that our value is primarily in the United States. We are confident that we can launch this drug ourselves successfully in the United States. What our European strategy will be, I think, will also depend on some of the external things that are happening in the world. We will be prepared from a regulatory situation to have a launch in Europe. Whether we do launch all across Europe or get a partner to do that, or only selectively launch in certain countries, those are all options that we're weighing at this point. We will be prepared for us or potentially a partner to launch OUS. OK. Let's shift gears a little bit because you have also done work in diabetic macular edema, DME. Can you just summarize the data that we've seen there? I know that there's the potential to start a pivotal, but you're not quite pulling the trigger on that yet. Explain the reasons for that and when you might be willing to go in that direction. Sure. The DME trials of Phase 2, the Verona trial, we tested, this is the first trial that we did the higher payload insert in. We tested two doses, 2.7 mg and 1.3 mg, against Eylea control. This is the first trial that we did where all the patients had active disease. In fact, they couldn't be enrolled unless they had fluid and they had decreased vision. They couldn't have received an injection within two months of enrollment or screening. Based on the excellent results we got, we're very confident in our drug's ability to treat DME because this was all an active population. The primary endpoint was time to first rescue, which both arms of DURAVYU did better than the Eylea control. Also, from a visual acuity perspective, one of the really fascinating things is both arms of DURAVYU showed significantly better vision and significantly better drying effect at four weeks than Eylea did. If this holds, if we can be non-inferior to Eylea, but we can get the same result Eylea gets, but it takes them five or six months to get the patients dry and better vision, and we can do it in four weeks, we are going to have a huge competitive advantage. If you look at the subgroup analysis from the Verona trial, just look at the patients in the high dose, 2.7 mg, who didn't receive a supplement. It was over 70% did not. They gained well over 10 letters. Eylea usually gains, naive, about eight letters. They had 120 μm less fluid. There was really a significant drying effect in this population that corresponded with the improved visual acuity, giving us, again, confidence that this drug works really well in an active DME population. With respect to the pivotal trials, we are really focused on wet AMD right now as a company. We want to make sure that given how well things are going with the wet AMD trials and how well things went with Phase 2, that we make sure that we do not put any of the wet AMD aspect of the company at risk, which means, as you said publicly, we do expect to run a pivotal program in DME. We expect the first patient to be dosed sometime in 2026. We've had a successful end-of-Phase 2 FDA meeting, and we're quite pleased with the way things came out. We will, later on this fall, update about the type of protocol that we're going to run in DME. First patient will be a 2026 event. Anything more specific you want to convey on the end-of-Phase 2 FDA meeting in terms of what they suggested regarding the details of the study? Again, I think more specifically, we have said this. The end of the trial can be significantly less than wet AMD. The agreement around control group, once again, the FDA reiterated, if you want to do a non-inferiority trial, you must do it against on-label Eylea, which means randomization on day one before the first Eylea dose is given. That's what our expectations were, but they did reiterate that. OK. In order to do that, would you need to raise additional capital? What's the, George, maybe you can chime in on that part? Yeah, our current cash guidance is into 2027. OK. It does exclude the actual trial costs for DME. I think between now and sometime into Q1, we'll have sorted out, and it'll be part of our design and plan and how we talk about the Phase 3 pivotal design. OK. There are some other retinal diseases that you have looked at as well beyond the two we've discussed. Could you comment on those? NPDR, for example. There are others. Yeah, so we did a trial in NPDR, nonproliferative diabetic retinopathy, which is a disease that does not typically carry a decrease in vision. There's no edema. There's no vitreous hemorrhaging with NPDR. There are two approved products. Lucentis and 2 mg Eylea are both approved for NPDR, but almost nobody uses them. The market penetration is about 2%. The reason is frequent injections and the fact that doctors are optimistic that should a patient show a sight-threatening complication, like the development of DME, they can just treat with anti-VEGFs at that point. Our trial did show a reduction in the number of patients who got worse DME. We didn't hit the primary endpoint. The primary endpoint was improvement in NPDR based on a fundus photograph. Given that result, it's not that we probably couldn't get a label for NPDR using another endpoint. Given the market size, the size of the study that we needed to run, we made the conclusion that from a financial perspective, it didn't make any sense to continue with an NPDR program. As far as catalysts and other things, of course, everyone loves catalysts. You've already talked about the big one, which is the Phase 3 data sets coming next summer. Ahead of that, what other sort of intermediate updates might we get? What's your presence going to be at some of the eye meetings? Just to fill in the gap between now and the big reveal. Sure. I think we're going to have great presence at eye meetings, including Retina Society in two weeks, where we're going to have a little bit more of the DME data to show. The EU Retina meeting is occurring starting tomorrow, and later in the week, I'll be off there. We have some presentations at the EU Retina meeting as well. Other catalysts include, we will or we plan on updating the safety. After the DSMB meets again, we'll give some update in safety. Probably at the beginning of next year, at some meetings, we will start to show some of the full demographic data of the Phase 3 trials. At some point this fall, we do expect to talk more about the DME program and give a little more color around the actual study design and when we expect to dose the first patient. That reminds me of something else. You mentioned pooled. When you show the data for Lucia and Lugano, or Lugano and Lucia, I guess is the order, is it going to be all at once? Are you going to have each one separately? Is that TBD? We're planning on doing them separately. Separately. no reason in our mind to hold the Lugano data once we know it. Given how soon the two studies are together, we think that there's an advantage to really show them one at a time. Once you have one, is it going to be like a rolling BLA? You just wait to do both? How does that work? Technically, when you say rolling NDA, we may or may not have permission from the FDA to do what they call a rolling submission. We're rolling the preparation now. We have some of the modules written already because they're preclinical and the data is not going to change. We know what they are. From an internal perspective, we're rolling the preparation. This gives us another advantage because assuming Lugano is positive, I think it's highly likely Lucia will be as well, given that they're identical trials. We can start to write the clinical modules from the Lugano data and then just dump the Lucia data in, which I believe will give us another kickstart to getting the NDA in quickly. Awesome. All right. Thank you again. Great progress. Appreciate the time, both of you. Thanks very much. I look forward to the meetings and then the data, of course. Thanks, everybody, for listening. Thanks very much.