EyePoint, Inc. (EYPT) Earnings Call Transcript & Summary

Morning, everybody. Welcome to EyePoint's R&D Day 2024. We're really glad you could join us. We're very excited to discuss not only our Phase III plans for DURAVYU in wet AMD. But our terrific 12-month data from the Phase II DAVIO 2 trial. I'm Jay Duker, President and CEO of EyePoint. We're going to be making some forward-looking statements today. And if you want more details about that, you can go to our website. I'm going to start with some introductions and then go over our agenda. I already introduced myself. But for background purposes, I'm CEO. I've been CEO for about 1 year now. I was Chief Operating Officer prior to that. And in my former life, I was the Chair of Ophthalmology at Tufts for 21 years. I'm trained as a Retina Specialist and actually still practice half a day a week. Joining me from the executive team is George Elston, our Executive Vice President and Chief Financial Officer. I think most of you know, George. George has been in biotech for over 25 years, extensive experience, especially in oncology and ophthalmology, and George has been with EyePoint for about 5 years. Our newest member of the executive team is Ramiro Ribeiro, MD PhD. Ramiro joined us from Apellis about 3 months ago, Ramiro, it feels like 3 years to you, I'm sure, but it's only been 3 months. But Ramiro has just been a terrific addition to the team. He is also trained as a Retina Specialist, which is terrific for me because he and I get to spar together over various theories as to why things are occurring. Most of the time, he's actually winning the discussions at this point. Ramiro has also extensive experience in biotech for the last 15 years exclusively in ophthalmology and he has run pivotal trials in retinal indications, both in the U.S. and globally. Also joining us this morning are really 2 terrific key opinion leaders. Carl Regillo is again a guy probably, if you follow ophthalmology needs no introduction. Carl is the head of the Retina Service at Wills Eye Hospital. He's also a member of one of the largest and most prestigious retina groups in the country, Mid-Atlantic Retina. Carl has worked with literally dozens and dozens of companies down through the last 3 decades helping products get approved. Carl's really is -- when people talk about a key opinion leader, his opinions are really, really held in high esteem. Also joining us from right down the street is Yasha Modi. Yasha is at NYU, also practicing retina specialists. Yasha also does uveitis, which means he's a glutton for punishment for those of you who know that field. I used to describe Yasha as an up and comer, but he's up and here. He -- while Young has really made a terrific name for himself as a KOL and as a clinician and as a surgeon. So following the introductions, I'm going to give you a company overview. I'm then going to describe our lead asset DURAVYU, which is vorolanib intravitreal insert, formerly known as EYP-1901. Yasha is then going to come up and he's going to review the top line data, 8-month was the primary endpoint for the Phase II DAVIO 2 trial for DURAVYU in wet AMD. Following that, Carl is going to give the first public presentation of the 12-month data from the Phase II DAVIO 2 trial. And I think you're going to be very impressed with what you see. Ramiro and I will then talk about the pivotal programs. We have 2 pivotal Phase III trials planned, and we will describe the details around those pivotal programs. I'll briefly update you on the early pipeline. And then I'll ask Carl and Yasha to come up, and we're going to have what should be called a roundtable discussion, but it looks like it's going to be a rectangular table discussion about interesting topics concentrating on wet AMD. We will have time for Q&A at the end and I promise to get you out of here on time before 9:30. So company overview. EyePoint is committed to improving people's lives with serious retinal diseases through improved therapeutics. But at our essence, we are a drug delivery company to the back of the eye. We have patented drug release formulations that allow us to improve the outcomes in the intervals of treatment. Our lead asset, again, DURAVYU we'll be talking about in detail this morning. We're a Phase III clinical stage company at this point and DURAVYU the lead asset, that is a potential of a multibillion-dollar market opportunity along with a pipeline, which, again, if it comes to fruition could be a second drug of a multibillion-dollar market opportunity. This is based around the Durasert technology. Durasert has been around for several decades. And I think as most of you know, there are 4 FDA-approved products that have Durasert delivery technology. What we're using in DURAVYU EYP-1901 is Durasert E, which is fully bioerodible. We have a strong balance sheet. And as of the end of this month, we predict we'll be at least $280 million of cash, which gives us a cash runway well into 2026. And here's our pipeline. Wet AMD really is what this company is all about right now, entering Phase III with DURAVYU. As you know, and as you'll see, Yasha will present really, really strong Phase II data despite a relatively small study of only 160 patients. We were statistically noninferior to the standard of care, which is 2 milligrams Eylea. We also have a program in non-proliferative diabetic retinopathy. We reported top line data about 1 month ago and that data showed a biological effect for our drug and a very impressive continued safety profile. But based on the results, at this point, there's no plans to go forward with any continued studies of NPDR. We will have 12-month data for NPDR later on this summer. I'd also like to announce this morning that our DME trial, the VERONA trial is now fully enrolled. We've enrolled 27 patients in that trial randomized to either an Eylea control versus 1.3 milligrams of DURAVYU or 2.7 milligrams of DURAVYU. And we're on target to deliver top line results from that trial the first quarter of next year. EYP-2301, which is razuprotafib in Durasert E, that's a TIE-2 agonist. TIE-2 is important in VEGF-mediated diseases. You don't want to block TIE-2 because if you block TIE-2, you upregulate angiopoietin 2 and angiopoietin 2 leads to vascular instability. So there's a balance between angio 1 and angio 2. You want angio 1, you don't want angio 2 and by agonizing TIE-2, you keep that in balance. And we have a very potent molecule that could do that, and we've been able to formulate it into Durasert E to last at least 6 months with a single injection. We're also studying the potential of complement inhibition in sustained release and we are still in the preclinical phase of that study. So that's a picture of a Durasert insert next to a pencil. You can see they're tiny. It's delivered in a standard in-office intravitreal injection. Nothing to like to say really difficult about it. But for most retina specialists, it's something they do 40 or 50 times a day. Durasert comes in a self sterile package, the physician simply opens it, takes out the syringe injector, takes away a tab, pulls off a cap and injects it. And what's nice about this technology compared to all the other sustained release technologies out there is we're shipped and stored at ambient temperature. No refrigerator space. And unlike gene therapy doesn't have to be frozen at minus 60. The inserts provide a constant release of drug what's called zero-order kinetics. And what zero-order kinetics essentially means is after the small initial burst of drug that's on the surface of the inserts, you maintain a steady drug level and in animals for at least 9 months, and we believe perhaps a little shorter in humans, but that steady drug level applies constant pressure on the receptor. And this allows essentially micro dosing, where you might think if you had a drug, which you were giving intravitreally as an injection or orally, you have to get a big Cmax to make it last long. It's irrelevant with zero-order kinetics because of that constant release. So the drug is embedded in a bioerodible matrix and they're designed so that the matrix holds the drug together through the lifetime of drug release. And that's important because you want to be able to control drug release with this insert. You don't want to have your matrix go away before the drug is gone because then you have free drug in the eye. And with free drug in the eye, you really don't know what type of dose you're getting and the potential, if you had a free drug in the eye that the drug could be mobile and perhaps even block the vision. So there's no dispersion of the drug with these inserts. So on to DURAVYU, we believe we have the best and most advanced sustained-release program out there, and here are the reasons why. First of all, we've had great safety from our DURAVYU inserts across now 4 clinical trials. I'll talk about that in a little more detail but we've had no ocular or systemic SAEs related to the drug. And this is really important as those of you who follow the retinal space, that safety is really, really paramount to physicians and we have the best safety track record of any of the sustained release out there. We now have aligned with the FDA on the non-inferiority pathway, non-inferiority for our pivotal trials. That's the pathway that, frankly, the last 5 drugs have been approved with and we're comfortable and highly confident in this noninferiority approach. We have the most robust data set. I already talked briefly about the 160 patients in the Phase II trial but we've had along with that, the other Phase IIs and Phase I. So the largest data set out there for sustained release. And with back to the Phase III trial design, we're the only company that's looking at redosing and that's really important to patients and physicians the ability to redose the drug on an interval that is better than perhaps than what they're getting now. This both aligns with the FDA but it also aligns with again clinical practice. The Phase III trials really have to show the physicians how to use the drug. And our non-inferior trial decide against the standard of care 2-milligram Eylea will be able to do that. And finally, our molecule, vorolanib patented, very important. It's patented out to 2037, new mixes of action. We work at the receptor level, and really, again, best-in-class delivery system with those 4 FDA-approved products. So vorolanib is a small molecule tyrosine kinase inhibitor. It's highly selective. It blocks all the VEGF receptors and it blocks PDGF. By blocking all the VEGF receptors, we should block all isoforms of VEGF, VEGF A, B and C. And by blocking PDGF theoretically, you'll have reduced fibrosis. We'd like to be able to show that in a pivotal trial and that's one of the things we'll be looking for is the ability to reduce fibrosis with our drug. We've demonstrated in a preclinical model, neuroprotection. This is a preclinical rodent model of retinal detachment and the rodents that got vorolanib had less damage to their outer retina and had better visual function with vorolanib in this model. Again, this is something we'll be looking for in the Phase III trial to show perhaps, we hope additional benefits to not just the anti-VEGF and longevity of our DURAVYU. And we do not inhibit TIE-2. I think at everybody's table, you've got a paper reprint that is just about to be published, if it hasn't already, where we looked at the several different TKIs that are being developed or haven't developed for the back of the eye. And at the doses that we're using vorolanib does not block TIE-2, again, something that's important. Vorolanib, interestingly, was studied in both a Phase I and a Phase II trial orally. At that time, it was called X-82. The idea is that you could give an oral drug once a day and control wet macular degeneration. What you're seeing here, these are OCT images from the Phase I trial where patients would -- they were treatment naive. They were newly diagnosed with wet AMD, and they received only oral vorolanib. And you can see there is a really terrific anatomic response and visual response as well from oral vorolanib. Now the drug wasn't taken forward past Phase II because it had systemic toxicity, but there was no ocular toxicity reported. About 150 patients were dosed with oral vorolanib. And that, again, adds to our safety database, which makes us even more confident of the safety around vorolanib. The other interesting thing about this trial is that many of the eyes in the trial had wet AMD in just one eye, and they were receiving an oral medication. So naturally, the other eye would have received some vorolanib. During the length of the trial, the eyes that receive vorolanib, there was only 1% that converted the fellow eye to wet AMD. The eyes that were under control, it was a 12% conversion rate. Again, showing the ability of vorolanib to actually block conversion of wet AMD and showing really excellent biological activity. This is an image of one of the inserts. These inserts are cylinders, they look yellow because that's the color vorolanib. They're heavier than water, which means they sink down to the bottom of the vitreous cavity. And they basically stay there. We can inject multiple inserts with a single injection. We can inject up to 3 and we did that in several of the Phase II trials. But as you'll see in the Phase III trials, the number of inserts we're going to be using is 2 inserts to get the dose that we need. Controlled release for at least 6 months. Again, in animals, it's about 9 months. We think it's a little bit quicker in humans. You don't see any free floating drug done as again, routine in-office injection and shipped and stored at ambient temperature. Each of these inserts is actually just 1/5000 of the vitreous cavity. So they take up very little space in the eye. I want to go into a little detail about safety now. I mentioned the excellent safety track record that we have. And these list the 4 trials for which DURAVYU is delivered. And we've given it to 191 patients with a minimum of 1-month follow-up, we have a little bit more than that in the VERONA trial now. But the other trials, at least 10 months follow-up in some trials longer than that, and there are no ocular systemic SAEs associated with our drug. So really, really good safety record, both orally and delivered intravitreally. I'm going to now ask my colleague, Yasha Modi to come up, and Yasha is going to review the results of top line of the Phase II trial, the 8-month data. Yasha?

Yes. Thank you so much. All right. Good morning, everyone. Thank you for being here. Just as a background, I am a pure clinician and a clinical researcher. So if there's anything that I say, please feel free to that is sort of not clear, please feel free to interrupt me, and I'm happy to sort of answer any questions. Actually, to Jay's point, we do a ton of injections where every single week in clinical practice. And where we are in the landscape of AMD is we're blessed to have incredible performing anti-VEGF medications, what we call probably second, some called third generation anti-VEGF medications. And I've been treating patients for up to 8 years now and the stallworth patients who continue to show up always ask me 2 questions. Can we extend the interval and can we potentially stop the treatment? I think the latter question is pretty clear that we can't, but obviously, extension of the interval becomes important. When we think about where we are, when patients miss visits, that's when we lose vision. And Rishi Singh at the Cleveland Clinic had demonstrated in his patients, that patients who went larger than longer than 5 weeks lost vision and some of those patients lost vision irrevocably. So certainly, there's a need to get consistent therapy in these patients and incomes TKIs and the promise potentially of longer-acting medications. Now these are really designed to get a much more durable effect but not necessarily replace anti-VEGF medications. So the DAVIO 2 Phase trial -- clinical trial was randomized, it was double masked, and Aflibercept was the control arm. So there are 3 total arms. You have DURAVYU 2 milligrams, that's basically 2 inserts given by one injection. DURAVYU 3 milligrams, 3 inserts given by one injection versus aflibercept control. All of these patients were heavily pretreated. In the year prior to treatment, the average number of injections was about 10 and the average time of macular degeneration of conversion to exudative disease was over 2 years for these patients. So intensively treated patients throughout the clinical study, very different from our treatment-naive clinical studies. And so a day 1 at randomization, they receive an aflibercept loading injection. Week 4, they receive another one. And then at week 8, they receive another one. So 3 loading doses just to get all of these treatment previously treated patients on the same page. 30 minutes later, the DURAVYU 2-milligram and 3-milligram inserts are implanted or inserted into the eye. And then every 8 weeks, they're giving sham injections to maintain the masking of the Phase II study. These patients are followed monthly. So if there is a need to retreatment, they can get retreated every month if need be. And so the blended primary endpoint was at week 28 and week 32, effectively 6 months at the insertion of the DURAVYU implant per the FDA guidance. Now remember, we're going to be talking about 3 things. We're going to be talking about vision, we're going to be talking about reduction of supplemental therapy and then we're going to be talking about anatomy. And when we think about these patients, these patients should have all theoretically plateaued. They have all received their treatment and what we really want is to demonstrate stable visual acuity, stable anatomy and a reduction of supplemental therapy. So on the y-axis here, what I'm showing is change in ETDRS letters, change in visual acuity. And what we see is after the loading dose, which is sort of where they get the DURAVYU implants at month 2, we see incredible stability of their visual acuity all the way out through month 8. And so you can see that they sort of fluctuate a little bit, but they're all within a couple of lines of -- a couple of letters of each other indicating incredible stability. If I were to test probably anyone in the audience here on ETDR charting, we're all going to be probably within a 2 or 3 letter variation of one another as we get tested out in the absence of pathology. Now when you think about reductions in clinical treatment burden, we can do this in 1 of 2 ways. You can look back and say, well, what was the sort of number of injections people were receiving before they ended up getting into the clinical trial. And if you look at the mean number of injections 6 months prior to screening on average patients receive 5 injections. Now if you look at the mean number of injections after they get the DURAVYU implants, either 2 milligrams or 3 milligrams the number of supplemental therapies is less than 1. So you take that numerator on the top, divide that by the denominator, and you get the reduction in treatment burden of around 85% to 89%. Now you could say, well, maybe that's not fair. Maybe you're looking at data before they enroll in a protocol specified way. And you're looking at what clinicians didn't practice rather than in a protocol-driven way. But you can also do this analysis using the control arm within the protocol. So now let's add in the aflibercept. So these patients have to get injections every 8 weeks. And the mandate, the minimum number of injections is going to be 3. What you see is that number is 3.28, meaning that patients are also rescued and the aflibercept are needing injections every month potentially. And so the numbers of the DURAVYU implants are the same. So the reduction in the treatment burden within the clinical trial going out to 32 weeks is 78% in the 3-milligram arm and 83% in the 2-milligram arm. And so I think this curve really shows it nicely where after they get the DURAVYU implant, naturally in a population of individuals, you're going to see that patients over time are going to need more supplemental therapy, but what's really remarkable is when you get out to month 8, 60% of these patients, 63% of these patients did not require any supplemental therapy. Now that's incredible because we do not have any drugs in the market that will allow us to get 6 months out. And if you look at the aflibercept arm, noticed they're getting injections. They're getting injections at month 4, month 6 and month 8, and 6% of those patients also needed rescue treatment. So no matter which arm we're in, of course, naturally, the most intensive arm is aflibercept arm, but all of these patients at some level will need rescue treatment. And I love looking at the swim lanes. The swim lanes, I think, kind of give you the most visually impressive way of looking at data in a Phase II study. What you're seeing here on the left, all those black dots represent the number of injections that people are receiving before they're enrolled in the clinical study. You can see some are getting very intensive treatment. Some are relatively sort of like almost treatment-naive only had received 2 or 3 injections. And then there is going to be that run up. And so the blue dots represent the aflibercept loading doses, and the pink represents those who receive an aflibercept and 2 milligrams of DURAVYU. And what's abundantly obvious is the reduction in the number of supplemental treatments. So now I think as a clinician, I always like to look at very specific patients and say sort of what happened. So if you look at patients 32, 33, those patients received a ton of injections beforehand. And then after they get the DURAVYU implant, they really don't receive anything. But then you can take a look at the last patient, look at the last swim lane #53. This is the patient who's received a ton of injections, but then still need supplemental treatment every 8 weeks. Now certainly, we don't understand why some people will require that treatment. But even then, they still receive and patient 53 received less supplemental therapy after they received the DURAVYU 2-milligram implant relative to beforehand. This is the 3-milligram data also looks very similar, a lot of injections beforehand and less injection subsequently after they get the DURAVYU implant. Now let's talk about anatomy. Again, remember that concept, these patients are fully treated. Their anatomy should be remarkably stable throughout the window of this study. And at the time in which they get the DURAVYU implant, what you see or insert, I should say, what you see is that the CST it starts to look like maybe it's starting to creep up, but then there's incredible stability all the way out through month 8. And if you look at the aflibercept arm, it's sort of kind of moving like this. Again, the amount of fluctuation, you have to understand the y-axis. It's less than 25 microns. So when you think about the retreatment criteria, if you look at [indiscernible] the studies that approve faricimab. If you look at PULSAR, the studies that approved 8-milligram Eylea, you had to be somewhere between 50 at the most conservative to 75 microns of fluid fluctuation in order to get retreatment. So this demonstrates within 25 microns incredible stability across these arms. And I want to show you some cases. I don't know how many of you are accustomed to seeing OCTs, but this is the world that Carl and Jay, we live in. And when we look at OCTs, this is the qualitative way in which we determine retreatments. Now this is the patient who's had a lot of injections before they get treatment. They have no fluid at the time of their screening or the time in which they get their day 1 injection, but they have clearly what looks like there's a separation between the RP and Brooks memory. So that's a classic or sort of what we call a Type 1 neovascularization. And throughout the entirety of the study after they get the DURAVYU implant, they do not require treatment. This is a different patient. They look nearly identical to one another, but this patient has persistent amounts of subretinal fluid even after they're loading aflibercept injections and after the DURAVYU implant, they maintain that small persistent amounts of subretinal fluid. Now retinal physicians through something called a fluid study, our learning to basically tolerate some small amounts of subretinal fluid. And what's incredible here is that the CST is not rising and the vision is not falling. Here's the patient who did require retreatment. So here, this patient gets the DURAVYU implant and then when we get out to week 16, you can see that the amount of fluid is drastically worse, that triggers a retreatment. And what we would normally expect is if there's no therapeutic effect of the drug, then that patient should be getting injections every 8 weeks similar to that of the control arm, but ultimately does it require injections out to week 32. So in summary, the Phase II DAVIO trial hit its primary endpoint, which was non-inferior change in best corrected visual acuity. It had a favorable safety profile, as Jay had mentioned. And when we think about what's most clinically relevant to our patients is the reduction in treatment burden. You can look at the 6 months before relative to the window in the study. And you can also look at an intra study within the study looking at the aflibercept control arm, and there's a drastic reduction in the number of treatment burden. And what's most impressive to me as a clinician is 63% of these patients when supplemental free at 6 months. So before we move on, I want to talk a little bit about what would happen if you get rid of all of the supplemental therapy. So in other words, let's say you take all of the patients who never required aflibercept because aflibercept we already know, it's an excellent drug. It can prop up the results in terms of your visual acuity, in terms of your CSTs. So let's take all of those patients out and let's see what happens for those who never require supplemental therapy. And so what you're looking at is change in ETDRS letters again, and we can see that the curves are essentially all overlapping with some various changes throughout the window. At the primary endpoint, there's less than a one letter difference showing incredible visual acuity stability as well as this is CST data. Essentially, what we see as incredible stability in the patients who receive the DURAVYU, and of course, if you imagine aflibercept, remember, we're dosing them every 8 weeks. What you're starting to see is a little bit of sawtoothing, kind of at the subclinical level, probably not clinically meaningful to most retinal physicians but certainly doesn't have that stability that we see in the DURAVYU arm. So I want to turn this over to back to Jay.

Yes. Don't go for a second because I want to ask you one question. That was great. But that saw 2 thing that we're seeing in the aflibercept arm, what does that mean to you about the cohort that we enrolled.

Yes. I think it basically shows that there's incredible disease activity, right? Because if you imagine like let's go and see you're taking patients that are effectively [indiscernible]. Maybe they're just getting treated for the sort of conservative nature of maintaining stability. Well, then you would see that their sort of CSTs would be identical. There should be no increase in fluid. And here, what you're seeing is that in the time in which they're not getting an injection, they have an increase in fluid, then they get the injection and then the CST declines. Just tells you about disease activity.

So this was a group of patients that needed a lot of treatment.

And you can certainly see that through that data.

So Carl Regillo is now going to come up and present for the first time the 12-month data from the DAVIO 2 trial.

Good morning. It is a privilege to be here. Before I get started, I want to say a few words about Jay, Jay and I go way back. Jay was a retina fellow when I was a resident at Wills Eye Hospital. So he's a little older. But I'm going to say, I've looked up to Jay, my entire career. Jay is very humble and will not tell you on the podium here that he's probably among the most respected, most accomplished retina specialists internationally. And we're very proud at Wills. We only regret we weren't able to keep them or get them back to Wills Eye Hospital, but equally proud of all the work he's doing now with EyePoint. I also want to say in preparation for this meeting, Jay, Ramiro said, hey, how about presenting the 12-month data. And I said, "Well, that's a great privilege. Thank you. I'd love to. My first question is how does it look because through my career, I've been asked to present first to podium before, and it's not always a great data. In fact, I presented my share of failed studies. Lampalizumab, probably the most notable and most recently, KSI-301 Phase III. And it's always hard to dance around poor data, but that's not the case here. I'm glad to say. So we'll dive right into it. You've seen this, of course, Yasha did a great job presenting to you the 8-month data. Here is 4 more months, 12 months, so that represents 10 months after the last dosing or the only dose of DURAVYU in the last dose of aflibercept in the load. And so what you're seeing here is ongoing excellent, in fact, identical BCVA in all 3 arms, as shown here to within 1 letter at 12 months, again, 10 months from the DURAVYU insert. So impressive that's necessary. In fact, as you can see, ultimately, for Phase III, we're using a non-inferiority study design, and this is what has to be shown. And exactly what you would expect, these patients started with relatively good vision because they've been mostly previously treated here, right? And they end with good vision. I've spent my career talking about optimizing disease control and getting the best long-term vision outcomes in wet AMD. This also is reminiscent of the superb visual outcomes in disease control that we saw with the Port Delivery System, sustained delivery of anti-VEGF at an adequate level to control disease across the board. But here, of course, we don't deal with the surgery or device. We're dealing with an office-based bioerodible insert. So very impressive. And also very impressive here is very clinically meaningful supplemental free rates that continue on. You saw the 8 months, I'm showing you 4 more months to month 12. We're seeing now 10 months after DURAVYU half of the patients going supplemental free. So we're really seeing durability that's quite impressive. We sort of think of it as 6 months, but really quite a bit longer. Also noticed, as Yasha pointed out, that we have a very active group of wet AMD patients here. How can I say that? Because when you look at all 3 arms could be supplemented and that includes the standard of care every other month aflibercept. So we're seeing 5 more aflibercept injections after the loading phase, month 12, we're seeing 22% supplemental injection rate in the control arm. So every other month dosing with aflibercept, which is considered sort of gold standard of care and that's every controlled group going forward and going back, I should say, in our recent pivotal studies and that's with faricimab, that's with brolucizumab. We're still seeing lack of complete disease control with every other monthly aflibercept in this patient population. So that's, I think, particularly impressive. And then also a word about Jay. Jay is one of the world leader in OCT, in fact, came in the other OCT experts, call OCT VEGFOmeter, right? Because it really there's been studies that really well correlate disease control with VEGF suppression and what we're seeing in OCT. And that's what we're seeing here. As Yasha pointed out, ongoing sort of flat line here. And in fact, a little bit of a dose response here, too, the higher dose DURAVYU controlled disease as well as, in fact, identical to aflibercept despite that little sawtooth, which continues on, again, indicative of active disease in our patient population here and even the low dose to within 10 microns, which is essentially equivalent. And all this with regards to disease control and good outcomes with an excellent safety profile, so ongoing good safety. So now again, over the course of 12 months, and the 4 additional months and I'm now presenting no new SAEs or AEs of any significance. The safety profile looks the same. There has yet to be an SAE attributable to DURAVYU. And now with a pretty good sized Phase II and as Jay said, totality of all the studies and data that you're seeing here. There's always the potential when we do an insert because we see it with the OZURDEX dexamethasone implant, potential for anterior segment migration, which may or may not be a problem. It is with the Dex implant, but probably not here, but we're not seeing it at all in general here. So that's good. And in particular, safety is paramount, as mentioned before, we don't sacrifice safety for durability. That's why brolucizumab was a failure. That drug was a better drug. Brolucizumab was a better anti-VEGF in terms of drying and a variety of measures and outcomes in the clinical studies, but it's not as safe because it led to cases of excessive inflammation, vasculitis and vascular occlusions. We have that issue to some degree also, which is suppressed the use of SYFOVRE in practice. But here, there have been no cases of retinal vasculitis or vascular occlusions to date with this drug. And then more so, especially in the small study the impact could be great if there's high rates of discontinuation, which discontinuation rates in the study remain low all the way out through 1 year and no discontinuations have occurred related to DURAVYU. So in summary, this has been an easy presentation because the data is strong. I didn't have to dance around anything uncomfortable here, 12-month DAVIO 2 data looks excellent. Ongoing maintenance, excellent stability of visual acuity, very strong anatomical control, disease control as shown here. And we're seeing half of the patients going supplemental free out to 12 months or 10 months after the DURAVYU injection in both doses and safety remains excellent. Jay?

Thanks, Carl. I'm going to -- before you go down, I'm going to ask you a variety of variation rather of the same question that I asked Yasha. So when you look at this data and you look at the Saw-Toothing pattern and you look at the number of rescues in the Eylea arm, what do you think about the severity of disease that we enrolled.

Well, actually, the Saw-Tooth in the excursions of about 12 to 15 microns is actually identical to what we saw in view 12 and all the Phase III registration studies with the anti-VEGFs have been treatment-naive patient populations. So to me, it's reminiscent and reflects a similar patient population. There's always the concern and whether it's port delivery, whether it's gene therapy, all these sort of maintenance phase approaches, making sure that we recruit patients that are the types of patients we would want to use this drug in clinical practice.

Great. Thank you. Excellent. Ramiro come on up, and we're going to now talk about our Phase III program.

Thanks, Jay, and good morning, everybody. I just want to first start with saying how privileged I feel about joining EyePoint has been great first 3 months. So I'm going to give you an overview of our Phase III program. And I want to emphasize that the objective of the Phase III program is very clear, is to gain global regulatory approval, have a successful commercial launch and make sure we get the patients, the drug to patients and physicians as soon as possible. Our Phase III program was informed by multiple interactions with the FDA. We had a Type C meeting in 2022 to discuss key components of the pivotal study. We had the Phase III -- the Phase II results for DAVIO 2 in 2023. And as you know, recently, we had the end of Phase II meeting with the FDA, where we presented the results of our Phase II study and the details of the Phase III program. Our Phase III trials in LUGANO and LUCIA are going to be global, randomized, double-mask aflibercept control studies that are going to evaluate DURAVYU when given every 6 months, achieving a similar visual outcomes to own label of aflibercept while reducing the treatment burden. These 2 studies are designed as nonpriority trials. We will enroll approximately 400 patients per trial and we are going to have 2 treatment arms, DURAVYU 2.7 milligrams and aflibercept as the active control. The primary endpoint is the difference in mean change in BCVA from day 1 to the blended week 52 and 56 compared to Eylea. Secondary endpoints are safety, reduction in treatment burden, proportion of eyes supplemental free and anatomical stability. The secondary endpoints are very important for clinicians and patients. Here, the key elements for the Phase III program. First, as Jay mentioned, this is going to be the only sustained release wet AMD program that is going to evaluate reinjections for label purpose. We will enroll patients with active AMD, meaning that those patients would have fluid in the retina and vision loss because of wet AMD. And these are going to be either previously treated patients or treatment naive. Every single patient at the beginning of this study will receive 3 loading dose of aflibercept. We are using Sham injections for masking purpose. And as I mentioned, the primary endpoint is going to be at month 12, which will serve as the basis for the NDA submission. Both studies are going to last for 2 years and that's for proper safety monitoring. EyePoint is on track to be the first sustained release wet AMD program with 2 pivotal trials that enable the NDA submission to the FDA. Here is just a schematic of the Phase III program. Patients are going to be screened. If they're eligible, they come in day 1 and they get 3 loading doses, day 1, week 4 and week 8. At that point, they would have their disease under control. At week 8, after aflibercept, patients on DURAVYU get a DURAVYU injection through inserts and patients aflibercept arm get Sham injection. DURAVYU is going to be given every 6 months with Sham injections between, aflibercept every 2 months and the primary endpoint measured at month 12. Throughout the study, investigators are going to assess if the patient need supplemental therapy with anti-VEGF. Now we feel it's very important and we're very optimistic about having a very broad patient population in our study. This enriched the trial to have more supplemental free eyes, which had better outcome in DAVIO 2, and I'll go into that in the next slide. It also shows a broad label and global reimbursement. A broad patient population will speed enrollment, and I'm happy to share that we already have selected more than 80 sites to be part of our Phase III studies. The data that is going to be generated by a broad patient population is going to be very helpful for physicians and patients so that they know how to use the drug in the real world setting. And again, to remind yourself, we're going to have at the beginning of the study, 3 loading dose of aflibercept. So one patient gets DURAVYU, they will have their disease under control. Now why do you believe that treatment-naive patients are also ideal for our Phase III program. This comes from our Phase II data, the DAVIO 2, which is the largest wet AMD TKI to date. In that study, as shown by Dr. Modi Dr. Regillo, those patients where patients have to treat. They had on average 10 injections before being rolled into the study. And a typical naive patient, they get between 6 and 8 injections in the first few years, and 1/3 of those patients get even less of those injections. Also, the phenomenon of tough to treat was observed in aflibercept arm, where approximately 25% of them needed rescue therapy, supplemental therapy even getting aflibercept every 2 months. And as Dr. Modi presented, supplemental free eye in DAVIO 2 were the ones that has the best visual outcomes and patients DURAVYU numerically better than those on aflibercept arm. We also have data on what we call the pseudo naive patients in the DAVIO 2 data. So those are patients that had a diagnose of wet AMD less than 1 year and received 2 anti-VEGF or less injections. So those are the pseudo naive patients. And those patients had fewer supplement injections compared to the overall cohort. We believe that the inclusion of treatment-naive patients not only expands the potential population but also increase the probability of success. Again, to summarize, the purpose of the Phase III program is to share we have global regulatory approval. With that, I'll pass to Jay for other preparations for the Phase III study.

Thank you, Ramiro. Again, just to again reiterate back to the points about enrolling naive patients. The main issue, of course, is after 3 injections of aflibercept when DURAVYU goes in, they're not naive anymore. And it's very clear that the supplement free eyes do the best. And so we want to get more patients into the pivotal trial who are likely to be supplement free, which means the broadest population of wet AMD. I'm really excited about this other project that we've been doing, which is our manufacturing facility. We're planning for success. And in order to successfully commercialize this drug, we're going to need to make a lot of inserts. Right now, we make the clinical inserts in our headquarters in Watertown, which is fine for the pivotal trials, but we need to increase the ability to make the inserts for commercial success. So this facility is being built to our specifications in Northbridge, Massachusetts, which is about 45 minutes west of Watertown, it's a greenfield build, the developer and the landlord are building it exactly to what we want. And the deal that we have with the landlord is we don't pay anything for the building until we take occupancy, which should be probably later this year. This will be built to both FDA and EMA standards, and it's about a 40,000 square foot building. Just a quick word on the early pipeline now. EYP-2301, which is razuprotafib and Durasert E. This is a TIE-2 agonist. It actually works through blocking another receptor called VE-PTP. And when you block the VE-PTP, you antagonize TIE-2 -- sorry, you agonize TIE-2 that upregulating at 1, down-regulating at 2 and leads to vascular stability. This drug, razuprotafib was formerly known as AKB-9778 and you may be aware that it was tested as a subcutaneous injection in diabetic eye disease. And as a solo therapy, it actually did pretty well, especially anatomically as a combined therapy, it was modest visual improvement. But we believe the ability to sustain release it with zero-order kinetics will improve the ability to make -- get better visual outcomes and better durability than when delivered subcutaneously. So for the next part, I'm going to invite Carl and Yasha to come back up and we're going to have a little bit of a discussion about some of the topics we just covered.

So you both have really given us a nice background in your clinical practice. But Yasha, why don't we start with you and tell us how you treating wet AMD patients? How are you going to treat them this afternoon when you get back to your office.

Yes. So I think there's a number of different ways that we can treat that. There's something called like a mandated injection schedule, a treatment schedule where we sort of treat them every time but extend the time between visits and then an as-needed basis or PRN basis. So I basically do -- I don't think we have 1 size fits all, but probably 90% of my patients are on treatment extends to try and sort of maximize the efficacy but also given the most freedom away from our practice.

Carl, I know you're a treat and extend guy, too, right? You've written all the papers on it.

I spent my career, and I'm so glad you said you do that. I spent my career validating the treat and extend approach is the best way to balance efficacy and burden. There's PRN, which when you look at the CAD study actually didn't measure up because it's reactive. You wait to disease recurrence to inject. So if you were to follow a patient monthly with wet AMD and inject only when you saw signs of recurrent exidation, ultimately, it nibbles away at the vision over time. So the notion of continuous VEGF blockade by determining a specific patients disease-free or exudative free interval is the best way to maintain vision. And it's now been validated, prospectively controlled including against gold standard monthly ranibizumab. So that's why in the United States, Yasha and all of our colleagues pretty much do treat and extend across the board and even worldwide, I remember early on when I was talking about this and publishing on results, our international colleagues, we're still doing a whole hodgepodge of different things. But now the vast majority of retina specialists all over the world. That's what they do. And we know exactly how long our drugs last because when we do the treat and extend, you can then look at the distribution of intervals, how many patients get it every 4 weeks, 6 weeks, 10 weeks, 12 weeks. And in the first-generation drugs, on average, they last about 8 weeks in the maintenance phase. That's why aflibercept dosed every 8 weeks. But there's a range of 4 to 12 weeks. Very few can go more than 12 weeks. With the second-generation anti-VEGFs, which we've started to incorporate quite a bit in practice, I have to say that by study design, it exaggerates the durability of those drugs. You might see presentations that say, "Oh, look, some of these drugs, HD Eylea whatever can go 16 weeks or 20 weeks in practice, that won't happen. They're a little more durable for sure, but not to that degree.

So give us the range -- let's start with 2-milligram Eylea and how many patients would you say have to still be treated every 4 to 5 weeks on 2-milligram Eylea.

I can tell you because I did a prospective study to measure that. But it's about 25%, 28% of patients were being dosed more frequently than every 8 weeks.

Yes. So do you find a coincidental that 22% of RI's required rescue in the Eylea arm? .

It's exactly which you would predict.

What did you predict?

Based on something I published I don't know, now 6, 8 years ago.

How many in your practice or in your studies went 3 months and did well at a 3-month interval with 2-milligram Eylea.

37%.

That is the exact. So one of the points we made earlier in the discussion is we had very few patients in DAVIO 2 who came into the study peak-dose every 3 months, makes sense. If you're already being dosed every 3 months and your doctor says, "Hey, you want to be in a study where you have to come in monthly. Most patients are going to say, no. We got a few of them. And those patients actually did really, really well, no surprise supplement free. And so what we want to do again is get more of those patients into the pivotal trial to make our results even better than what we got in the Phase II. So Yasha, let's move on to the new drugs, high-dose Eylea [indiscernible] incremental improvement, game changer? How do you feel about them? And what's the evidence?

Yes. I think -- so I use a fair amount of faricimab. I use less aflibercept 8-milligram. With faricimab, I think there certainly is an efficacy benefit over that of aflibercept. And then when you look at the duration of the drug, I think what's really important to realize when you're looking at [indiscernible] those were effectively treatment naive [indiscernible] that were completely treatment naive. [indiscernible] , there had to be a 3-month washout of the patients that were previously treated. So effectively, they're all treatment-naive. And so that's how you get these results of patients going out to 16 weeks. Now the retina consultants of America is a large private equity-owned practice, something like 250 retina specialists. And actually, I think it was our about, they presented essentially all of their faricimab switch patients or those who were getting faricimab treatment-naive. 90% of the patients ultimately ended up being switched rather than being treatment-naive. And when you look at the incremental duration in neovascular AMD, how much extra time do you get between injections as I think about like just over 8 days. So that number is really important because in clinical practice, I was always sort of saying like, "Oh, maybe we'll switch you over to faricimab. We'll get you out another couple of weeks. And the reality is you don't even get out a couple of weeks on average. And so that paper is actually -- I believe it's a presentation. It's not published data yet, but because it's a presentation that's publicly available.

And so going to state the obvious. I hope you both agree that there's still room for additional ability of sustained release medications out there to lengthen treatment intervals.

What's amazing is that this is a previously treated population of individuals. A lot of the recent FDA approvals for our what we call third-generation anti-VEGFs were effectively treatment naive. So I love the fact that this study, the DAVIO 2 study is taken on some of our most difficult-to-treat patients.

And so Carl, I'll get right to that question for you. When jumping around a little bit, but -- do you have a problem enrolling the naive patient given the data that you just saw -- how are we going to do with naive patients?

No, no. Actually, I think this is a very easy study to enroll because patients are highly motivated to want to -- we say injections are well tolerated and they are very low risk, very well tolerated, but no one likes them. So in my experience with the Port Delivery System, for example, and that's even with going to the OR and with the device in the eye. It was pretty easy to recoup because patients would rather come in monthly and not have to get an injection and be monitored because they'd like this notion of sustained delivery and disease control of 6 months or so. And so although that was previously treated, it was recently diagnosed. So it was like a -- it was like a treatment-naive patient population. So in other words, I had a patient with new onset wet AMD and say, hey, we're going to start regular treatment and after 2 injections, we have the option to go into the Port Delivery System trial. And it's going to be very similar here. Patient presents to me, I'm going to say, hey, we're going to get you started on standard of care, standard injections, well proven, well tolerated. And then you have the option to be continue on in that way, get good outcome or the option to get a new product that's had a tremendous safety profile and shown very solid data that I'm comfortable and confident.

Does the idea of induction therapy and maintenance therapy, that's essentially what we're trying to do here. Is that -- Yasha, is that something that makes sense to you?

Absolutely. It's important to realize for somebody who treats uveitis. When you're talking about maintenance therapy for inflammatory disease, you're talking about a year's long process. And the analogy actually holds true to that of AMD as well. This is a year's long or decades-long disease process. Once we convert them to -- once they convert to exudative disease, we sort of think of it as a forever treatment. And so the idea of basically giving them induction therapy with sort of a hard hitting aflibercept injections, faricimab injections, whatever it is, and then maintaining them to get sort of a more durable anatomy makes a lot of sense. So I sort of see this in clinical practice as sort of a combination approach that they certainly won't get rid of anti-VEGF injections as we know it, but I think will be a really excellent supplement for the overwhelming majority of our patients.

And that leads really into my next question about supplements. Does the idea of supplementing maybe 1/3 of the eyes that are being treated with DURAVYU, does that bother you?

No, no, not at all. It's still the same thing. You're coming to the office. You're looking at disease control and the goal is to keep those vision gains that you got when you first did the induction phase and to do another injection or 2 for the patients, it's all watched, same thing. Going to get prepped in the same way. They're going to get an injection. And to get less injections is highly desirable to maintain the same disease control.

And Yasha, you showed patient 53 from the 2-milligram arm, which was the patient that arguably did the worst with 3 supplements, the only one that got 3. Yet if you look at the treatment burden, it was still reduced. And so in the real world, that patient who went from 10 injections in the prior year, they would have 6+2, 8 injections if that data holds with DURAVYU. They're happy, doctor is happy. Everybody is happy.

Yes. I want to add one more thing. Sometimes we do a lot on this supplemental free to be injection free. But obviously, you're still going to get an injection at 6 months or 8 months. And in practice, with a product like this, there are some patients that are going to get it every 8, 12 months or less, which is great. Patients will love that. But basically, I've been asked, what's more important, supplemental free or reduction in treatment burden. I say, yes, they're both important. Like you said, patient 53 would love the idea of getting 50% less injections instead of every visit, every other visit or something like that. It's still a value to that patient.

Can I ask you, Carl, what do you think the role of home OCT is going to be in the future. And then I'll ask you both, is that going to impact some of these longer-acting therapies.

I think it's going to be a useful technology. I don't think it's going to be necessarily widely adopted. I think it can be a little cumbersome. But I like it and I like it, especially for a sustained delivery platform, whatever that may be. A TKI here, gene therapy there, anything where it may be a little less predictable when a patient is going to recur, you could -- we will help to do is minimize the burden of coming to the office potentially. But I've heard a lot of colleagues and I too. I'm a little reluctant. It's a lot more work. And these dashboards I've seen a very cumbersome and such. And it's sort of like taking the blood pressure of your hypertensive patient every day. It's like a lot of data that may be overkill. But I do think it's going to play a role. I don't think it's going to get widespread adoption, and it's not necessary to adopt this product or a product like this in the field to have home OCT. We can do without it for sure.

Yasha, any different opinions.

I have a slightly different opinion on this. So one full disclosure, I did get to play around with the home OCT device, which I think was surprisingly cool. I think it's a new technology where clinicians don't know how to use the data right now. And I think you're absolutely right. It's sort of like think about the original iPhone. It was amazing, but compared to an iPhone 15, there are 2 totally separate levels of technological products. And so I think, yes, it will take a lot of time to slowly adopt it. Yes, we will have to learn how to use it. The clinical science is there, the regulatory pathways there. It's FDA approved now. They still need an economic model to make it worthwhile. But if they succeed in that venture, I think that when you start thinking about these really long-acting drugs, I think the play is a really important role exactly to what you said when you're thinking about going out 6 months without seeing them because ultimately, the panacea is not only just going out 6 months without an injection, but maybe going out 6 months and never seen you're retina doctor, right? So I think how do you do that if you have these patients who are recurring, I think we need some sort of imaging technology to help us get there.

Carl, you've obviously done a lot of clinical trials and pivotal trials, you just saw our trial design for Phase III noninferiority. What's your impression?

It's the exact type of study we'd want to see and do in practice in a clinical trial as a clinical investigator. It's pretty standard. It's the way we've done all our Phase III programs is noninferiority comparing to standard of care. All patients get good treatment that's going to happen with outcome. So I think there's really no other way to do it.

Any comment again on the ability to rescue in the Eylea arm. It's a bit of a unique aspect and one of the things, again, when we eventually submit the data, the supplemental rate that do review shows is not just going to be looked in isolation, it would be looked against the Eylea arm. And so that given the patient population that we talked about over a year, I think we'll get 22% supplemented in the Eylea arm in that patient population again.

Yes.

Yasha?

Yes, I think so. And what I love about the study design is it's safe. It's maximally safe for all patients in the study. So as clinicians, it's really easy for us to enroll these patients because there's so many outlets to maintain their safety and maintain excellent vision. And through the noninferiority study, you're de facto showing some level of value through a longer duration and less supplemental injections.

Yasha, in a naive patient, if you give them -- first of all, do you load everybody 3x? Is that your standard? .

I actually don't. I come from a camp of Bill Rosen from the PRONTO study, and that was I'm a descendant of the Baskin Palmer sort of mentality where it's probably not required. But the reality is, essentially, I treat them until there is the absence of fluid. So for patients with really active disease, they effectively get loaded. And maybe it's 6 loading injections or 8 loading injections. And for those with less disease activity, maybe they get 1 or 2 injections before they extend to longer intervals.

Carl, what do you do?

Yes, same. I treat to dry monthly with whatever agent it is. That's the way pretty standard. The CAD study also just had 1 dose and didn't have a SET 3 minimum loading. The 3 minimum loading is just because the curves on like this after 3 months, it's on average, dry. And the fact is 3 injections will get well over 75% of the patients, dry or effectively dry or under control. And that's where it comes from. It doesn't mean every individual patient needs 3, one patient may need only 1, as you indicated, and some may need 4. It's pretty rare though to need more than 4, 5 monthly injections to get the macular dry in wet AMD. You see that in DME. We may need more monthly intensive, longer induction.

And the one thing I'd like to point out is even in the rare patient who may still have a little bit of fluid after 3, DURAVYU doesn't have to do better than Eylea, we just have to tie them. And so if 3 shots of Eylea didn't get rid of the fluid and the Eylea arm goes into every other month, and they have persistent fluid in the Eylea arm too. And the case that you showed, Yasha, where there was even previously treated after a load, there was still a little bit of fluid, that's a case that illustrates. We actually, in some ways, did better because there were visits where there was no fluid in that eye. So if -- let's go to the future and say we've got an FDA-approved product with a label for every 6 months. And let's just say we replicate the data we did in DAVIO 2. Yasha, how are you going to use it in practice?

Yes. I think so for patients who want a longer duration of treatment who are essentially getting the standard of care of let's say faricimab or 8-milligram aflibercept and then are stuck. I think this is a really excellent supplemental medication. I sort of see this initially as a supplemental medication to try and get them longer durations of intervals. And that's also where I think we are, as a retina practice and as a society will have to learn how do we follow these patients? Do we continue to see them and maybe just avoid their treat and extend, do we use home technologies to help us. I love where this is going that kind of keeps us really creative and we have to be constantly evolving to think about how to maximize outcomes as well as decrease the number of treatment visits for patients.

Carl, how would you do it?

Exactly as the Phase III proposed study design, start the patient on monthly injections. And then after the maculas drive, that's 2, 3, 4 treatments tell them about this as an option, either continue to do an anti-VEGF biologic or transition to a longer, more durable approach and I could introduce, I don't have to introduce it at month 3 as in the study, I can introduce it as soon as the macula is dry, enter at any point thereafter. So it could be 1 year or 2 into therapy. And we have this huge patient population out there. 98% of my wet AMD patients, of course, are previously treated. And so any of those patients, this is potentially on the table as an option for them. Even if like you said, it may not always have to be a frequent flyer to consider this. It could take a 3-month or and extend them to a 6, 9 months.

Well, and again, the example Yasha, you gave of how we're doing with [indiscernible]. For 8 days, it's been a tremendously accepted new product to get us basically probably a week longer -- but yes, so let's go to treatment naive. Would you use it in only patients who are 8 weeks or less or 9 weeks or if you had somebody who's every 3 months would you offer it?

I think the natural tendency is to when we first have it in our hands to first offer to the more frequent flyers. They're going to be most motivated to make a change or to want to adopt something new and different. But that doesn't mean the 10-weeker, 12-weeker, they should hear about it as an option, too. And I think ultimately, when you get comfortable with the product, it's been on the market and such, you'll expand the patient population you'll treat. So I think really any of these patients potentially could benefit from that transition of trying the product.

And Yasha, let's just suppose we are antifibrotic and neuroprotective. And maybe we're not even that, but let's suppose our supplementation nonsupplemented eyes look like what you just went over, maybe 0.5 a letter or maybe even a letter better than Eylea. So maybe not statistically superior, but numerically superior. Do you think that would resonate?

I absolutely do. When we think about who loses vision and exudative AMD patients who are consistently getting treatment, those are patients who develop subrental fibrosis and those patients who develop geographic atrophy. So those are the patients who fall off the curves in the setting of showing up regularly and getting the best of care. So this is not a disease where we can stabilize their vision in the current error. There are always going to be people who will lose vision. So if you can demonstrate a decrease sort of incidence of fibrosis, that's going to be huge.

Terrific. Thank you very much, both of you.

Pleasure.

Oh, yes, we are going to -- I'm sorry, we did to keep you up for the question and answer. It's not just going to be me. I'm going to open it up to you guys as well. We start on the right side here. Thanks.

This is Eddie Hickman from Guggenheim. Thanks for the color on the Phase III design. Do you have a goal for the percentage of naive versus previously treated patients you're looking to enroll or the number of previous treatments that you said it was 10 in DAVIO 2. Do you have sort of a goal for what you want to see as baseline for these patients?

Not at present. It's something we will be monitoring and one or the other make it capped at some point, but we'll see how enrollment goes. I don't think that there's going to be any numbers or previously treated. Again, looking at the data, the eyes that came into the study previously treated but were already treatment extended out. Those are the eyes that we would like to try to enroll. But we're not going to be able to do that in priority. That's not going to be something that we're going to outside of the study be able to mature.

Got it. And then after that initial loading dose, is there any sort of control for excluding patients that don't have any response to those 3 early doses?

No. There's, again -- I touched on that. There's no reason to. So if we have a nonresponder to Eylea, the DURAVYU arm doesn't have to show a better response. It just has to maintain them. And in a smaller trial where you might get 1 or 2 bad patients into 1 of your treatment arms, and that can skew the results. In a larger trial with 2 arms and 200 patients in each arm, where we believe that randomization would take care of that and plus I can ask my panelists here, how many real nonresponders are out there? In other words, naive patients given 3 shots, give them 4 shots, 5 shots and they still have a lot of fluid. What's the percentage, Carl?

It's actually super rare. I'm not even sure you can say there's a nonresponder. There's a small segment, I'm going to say 5% that are suboptimal responders where you see some improvement, but there's some persistent fluid that you think is excessive that you would like to see get better. But even then, a lot of these poor nonresponder scenarios, I think are often patients that we have advanced disease at the time of diagnosis, have some fibrosis. And often, there is persistent fluid or thickening or cystic change over that fibrosis that you may not get dry -- but nonetheless, they all seem to derive at least some benefit because even if they don't improve, they don't worsen in the vast majority of cases. Occasionally, you get some breakthrough hemorrhage that sets a patient back, but that's really rare -- and like you said, with randomization, it's going to occur occasionally and with the big numbers that shouldn't impact.

And once again, the point is we don't have to do better. We just need to tie it. Yasha, any other thoughts there about nonresponse.

Completely agree.

Yes, keep in mind, a lot of frequent players or these patients, I said 25% are aflibercept, every 4, 5, 6 weeks. Many of them are actually good responders, just need drug frequently, can't extend them or else significant fluid comes back. So it's good disease control, but it doesn't last very long. And the durability of any product in the anti-VEGF in the eyes partly related to maybe disease activity and VEGF levels, but also on how fast the patient clears a drug. We know, for example, in an eye that's vitrectomy, the vitreous gel acts like a depot. When we do a vitrectomy, all these drugs, all the biologics that we inject last a lot last. The durability goes way down. So more liquefied vitreous in one patient could account for why the drugs don't last as well. And the nice thing about zero-order kinetics and sustained release technology is that it doesn't matter anymore.

It's about the 12-month data was going to be pretty exciting. Regarding the Phase III [indiscernible], the inclusion of male patients is interesting. It makes a lot of sense from a commercial standpoint. On one of the slides, I think you guys mentioned that DURAVYU performed numerically better envision than aflibercept in supplement free or in pseudo-naive patients in DURAVYU hypothesis to why that occurred as we think about the Phase III and if you had to estimate also getting some client questions on just how the BCVA and CST baseline criteria might differ given the inclusion of those patients.

So first of all, if you look at what it is a continuum, there's easy to treat and hard to treat. In DAVIO 2, we were way over here in the hard to treats. What became clear as we went through the data is that the supplement free eyes did best in the prediction about supplement free. It wasn't how long they had the disease at all. It was the eyes that seem to be less VEGF need were more likely to be supplementary. And in fact, those pseudo naive eyes, we did enroll some patients who only had the disease for 3 months and they got 2 shots. And from a supplement perspective in the high dose, 87% are supplementary. That's the kind of results, especially if we want to see if we're actually numerically superior to Eylea. That's the type of result we will be looking for. Now back to how the naive patients are going to do, we already heard, you load them. First of all, they're not naive anymore after 3 and once you load them, most of them are dry. And even the ones who may have persistent fluid, we can do pretty well with them. There was a patient, in fact, you can go back to the old decks from the Phase I trial that had been previously treated, had got in Eylea and still had about 80 microns of several fluid. Never went away, never got supplemented and DURAVYU was able to keep stable at 80 microns through 8 months. So that's the kind of eye where you might say, well, you didn't try out, but my response is, well, neither did EYLEA. And we don't have to dry out everybody because all we need to do is keep their vision stable.

Okay. And just a follow-up. As we think about probability of success for the Phase III is the rescue criteria, the same as DAVIO 2?

The rescue criteria, the #1 rescue criteria that's important was a 5-letter loss of best on study with 75 microns of fluid, and that one, it will be the same. The other rescue criteria is in Ramiro has done a pretty deep analysis on them. Some of the rescues frankly didn't meet any criteria, and we're going to try to really rein that in if we can. We want to eyes that need to be rescued are going to get rescued. That's going to be mandate but the eyes a don't bet criteria, we're going to really see if we have medical monitors discuss it with the sites. And some of the rescue criteria that we used actually didn't result in any improvement in the vision, and that's the purpose of rescue. But Ramiro, I don't know if you want to -- you want to add any...

Yes, I think when we evaluated data in detail, we saw that there were actually some sort of criteria that some injections that didn't meet the criteria and didn't bring any outcomes for that patient. So we discussed with some of the investigators and try to understand the reasons behind it. And then on the Phase III study, where we want to make sure is that supplemental injections are given for patients that met the criteria, so that we don't have unnecessary supplement injections.

This is Colleen Kusy from Robert Baird. Can you talk about the decision to go with just 1 dose in the Phase III and what you think some of the benefits of that are. And then with the inclusion of the naive patients in the Phase III, would you expect the label to include naive patients? Or to your point on those naive patients will be previously treated when they get the drug, would you not expect naive patients?

They will be enrolled as naive, and we would anticipate that it would be a naive patients or previously treated as maintenance. The one dose route, actually, in some ways, was easy, we talked earlier about using 2 doses. The masking that we are proposing will work with 1 dose, and so it's not a masking issue. And by looking at the results, while there was no clear dose response. I think Carl referred to the OCT data. And as you look deeper into it, it does appear anatomically consistently the higher dose work better. And some other statistical analysis, the Ramiro's group does, again, points to the higher dose performing a little bit better. It doesn't mean the lower dose wouldn't be noninferior, but now we can actually get the end of the study, the power of the study even higher by just having one treatment arm and that's really the goal is that the approximately 400 patients were increasing the power by not having 75 or 100 in a lower dose because we don't need to.

This is Jennifer from Cantor Fitzgerald. I mean I was especially encouraged by the 12-month BCBA curves, especially taking into account the number of rescues in the Eylea arm. I'm getting a couple of questions just thinking about the differences in some of the design aspects of the pivotal trials. Can you talk about maybe what the screening conditions would be for treatment-naive patients after the 3 loading doses. And how do you expect that to impact the nonverity margin and expected standard deviation? Maybe I'll start there.

Yes. So the screening occurs prior to the load, patients get randomized at day 1. And so there's no exclusion after the load. Everybody's in provided there's not a problem and they have to be removed. So there's -- there'll be screening kind of the standard screening stuff that we used in DAVIO 2 to screen out the large lesions or hemorrhagic lesions or fibrotic lesions. But after day 1, they're randomized day 1 and they're in.

Can I ask that in this treatment naive patients, the inclusion criteria to get them into the trial, are there any differences in terms of OCT or baselines that might affect standard deviation compared to some of the other treatment naive trials that we've seen?

There may be, I would answer. I mean I'm not quite sure that the standard deviation would likely with the inclusion of naive patients, be a little bit higher, we would anticipate that. Is that the question?

Yes. I guess it would be the average between previously treated and treatment-naive patients, but also within the treatment-naive patients. Is there a way to screen for them before -- there isn't a screening period, but is there a way to selectively...

The answer is -- I say. The answer is yes. So that there are studies that have looked at what are the parameters of a CNV that suggests they're going to need a lot of therapy. And we'll be using some of that data to -- at the beginning to screen out those patients -- that's -- again, that's no different than what we did in DAVIO 2 to a degree in what every other study has done. There's visual acuity range. It's not every visual acuity. Fibrosis gets included, large averages get excluded.

Okay. And my last question is someone is asking in terms of the regulatory back and forth, I just want to clarify what's been signed off on? And are there any aspects that you're still waiting on? Or anything there?

No, we're good. We're waiting for nothing. We're full speed ahead. The protocol that you just saw is getting submitted to the RVs and this is our protocol. So we're aligned with the FDA, and we're not waiting for anything.

This is [ Caroline Poucher ] on for Tessa Romero at JPMorgan. So were there any common characteristics across the 50% of patients were anti-VEGF supplement for you at 12 months. And then I just have a follow-up.

Yes. So this data is really fresh. That analysis is not complete yet. Ramiro, you may want to comment on that. But we will be presenting the data at various places over the next several months. And we should be able to have that data by the fall when we are presenting at Retina Society and Carl is presenting at the AAO.

Okay. Great. And then can you just outline your powering assumptions for the Phase IIIs?

We're really not making that public. Our discussions with the FDA based on what other companies are saying. We've been very clear, and they've been very clear the responses. And so we're comfortable with the powering assumptions using the 400 patients and knowing that we're a mix of naive and previously treated. But we're actually not -- proprietary reasons talking about exactly what they are.

Graig Suvannavejh at Mizuho. I was curious now that you've shared with us the plans for the pivotal Phase III trial designs. Will you be in a position to comment on when you expect to kick off LUGANO in terms of more specific timing just more granular time lines around like enrollment times and maybe...?

You will have that in the future. I think when we get first patient into the study, I think that will all kind of lay out pretty nicely. We're still guiding to second half of this year, and we'll be honing in on that soon. But as of today, second half of this year, we're on target.

Great. I just wanted to follow up on some comments around use of Sham and in the context of FDA draft guidance and whether there was a consideration of other potential mechanisms? And also did you consider perhaps an SPA as perhaps a competitor has?

So use Sham is interesting. Ramiro outlined all the interactions we've had with the FDA. And at no point did they ever say to us, we don't like the use of Sham the way you have it designed. The draft guidelines, which I remind everybody, our draft guidelines for public commentary. They are not things that have to be adhered to at this point. Although our study adheres to every single one, when you read them, there's nothing in there about masking. This well-designed trial, 2 of them. No. There's no reason to think about an SPA because we're not a special protocol. We are a vanilla non-inferiority trial that's been run 5x successfully. In fact, in some ways, we're more vanilla than faricimab in high-dose Eylea because they were varying their treatment intervals. We're not doing that. We're in every -- we're going to be in every 6-month drug. There's no reason to get an SBA. If at some point, an advantage pops up, we might consider it. But as of now, we're not getting an SBA, we don't need an SBA. I think we have time for on more because I promise that get you out of here on time.

I-Eh Jen from Laidlaw & Company. Just 2 questions here. The first one is in terms of the naive versus treatment experienced patients, what if the trial doesn't balance the 2 groups into 2 arms. What might be the possible sort of shortcoming or shortfall? Or was there any impact at all?

Yes. So if they're not balanced in the 2 arms, we won't anticipate that these 2 are going to act any differently. Again, we would expect the naive population to actually do better than the population that we enrolled in DAVIO 2 for the reasons that we've already given. It's a broader expense of the population more of those eyes are not going to be needed. They're not going to be eyes that need 10 shots a year. So we wouldn't expect that there would be a big difference based on what we're seeing in DAVIO 2 with the way our drug performed in the Phase II.

So if they move more into the control arm that would there be a little bit issue there?

It shouldn't be.

Okay. And just a follow-up here just for the doctors here. In terms of if the drug is approved over time, would you consider patients still visiting you routinely, but their visit will be -- or feel that we experience whether they need another injection or it could be without for that particular visit, would that be a scenario you envision over times if this drug gets approved.

I think it's going to benefit patients in 2 ways, definitely decrease treatment burden and could also decrease ultimately as we get comfortable, especially with a given patient of the durability of the product and the performance for a given patient, even decreased their office visit burden too with or without, as we talked about the OCT home OCT technology. Part of the reason why we see patients somewhat frequently in general, that we don't extend much in practice beyond 3 months, even with second-generation drugs is because we're also monitoring the fellow line and such. And so some of that will still be at play here.

I just want to say one thing about the -- any of you have ever been to get a standard eye exam, essentially, it's -- you get your vision checked. You oftentimes we get your pressure checked, they'll dilate your eyes. You'll then wait a little bit of time. You'll get your imaging, you'll then go see somebody who'll clinically examine you, and that's about sort of the whole process of somewhere around 2 to 3 hours from when you're in the door to out the door, which maybe you realize is a little slower. But I think what we're going to have to do is sort of recalibrate how we do these visits because I think, to your point, are you just going to be -- are you still going to have to see them the same number of times, right, because that's relevant to patients. And I think the answer is we're going to have to be creative. And I think there's one paper by Phil Rosenfeld who essentially, he sees like 100 people, all AMD at every clinic day that he's at Basket Power. And so he essentially does vision and OCT, then he got rid of vision and just uses OCT and injection. So he's creating a streamlined process to get people out the door in 30 minutes. And I can very easily conceive of a strategy where we at NYU would maybe just have them come in for OCT visits, walk in and out on their way to work, no dilation and then we can make sort of real-time decisions on whether or not they need treatment. So we will have to get creative on this.

How about an OCT kiosk...

Basically, yes, we just sort of build the OCT visit and I think -- when you start talking about longer-acting drugs, the whole goal is to not only decrease the number of injections, but to decrease the time that they spend with us.

So on this slide, you have a listing of upcoming presentations of the DAVIO 2 data and further discussion about the Phase III program. And we've got 2 publications. Links are right there and you've got one of the copies on your table. So again, to close, we believe we have the best sustained release program out there. We've got excellent safety through both the oral and the intravitreal routes. We've got a clear noninferiority pathway that's aligned with the FDA. Robust data set from the Phase II that now up to 12 months really continues to look excellent with essentially no change in vision against the Eylea control despite 22% of the Eylea control getting extra shots. We've got a Phase III trial design that includes redosing. We're the only ones going to be looking at redosing, which is really important for patients and practitioners. It does align with the FDA and also aligns with clinical use. And finally, our molecule is patented, and we have a best-in-class delivery system. Thank you very much, and thanks to our panelists and our KOLs for coming. Really appreciate your attention.