Hi, good morning, everyone. We're kicking off our virtual ophthalmology forum this morning, and it's our pleasure to have to be hosting EyePoint here. With us are President and CEO, Jay Duker, CFO, George Elston, and CMO, Ramiro Ribeiro. EyePoint, as you know, is finalizing its phase III program DURAVYU, which is in the new class of tyrosine kinase inhibitors for the extended treatment of wet AMD and diabetic macular edema. The first of these wet AMD trials will report out in August, with the second to follow shortly in DME in 2027. A lot going on in this very dynamic space right now. Why don't I give you, Jay, a few minutes to give your overview and what gets you excited about your opportunity.
Great. Annabel, thanks for having us. Yeah, at EyePoint, we're really excited about where we are right now. As you mentioned, 2026 looks like it's going to be a transformative year for us, things couldn't be going better. We are on track to report top line from our phase III wet AMD trial, LUGANO, this summer, sometime in August. Far, things look good for that. Our second trial, which is exactly the same trial, LUCIA, should report out approximately two months later. Yes, really exciting and important times for us. Those trials, again, to just give a little more detail, they're identical non-inferiority primary endpoint wet AMD trials. We are up against on-label 2 mg EYLEA, the first trial enrolled about 432 patients, second trial about 475 patients.
Our drug is being dosed at a level of 2.7 mg every six months, and we hope to be able to get a label for every six-month dosing in wet AMD. I'm happy to also mention that just recently, we reported an update in the safety from those two trials. We have a DSMC that meets every six months. They get to look at both the masked safety combined from the two trials as well as the unmasked safety from each trial individually, and they have announced that no change in the protocol is necessary at this point. This is important because, at the time of the meeting, all of the patients in the EYP-1901 arms had received their second dose of our drug, and about a third of them had received the third dose of our drug.
In studies such as this, most of the safety issues come up around the time of injection. We've been able to look at the masked safety combined from the two trials, and as we've reported, it looks very similar from the safety that we've seen in the 190+ patients that we have dosed already and reported from the single phase I and the three phase II trials.
Great. Just wanted to talk about the DURAVYU profile itself. It's been backed by some pretty extensive early studies on the release profile. You've had some pretty good dose-finding studies and pretty consistent safety. What are the key profile characteristics that you've established so far, and what are you looking to bring out in these upcoming trial readouts in August and thereafter?
Sure. Again, DURAVYU EYP-1901 consists of a small molecule tyrosine kinase inhibitor that's called vorolanib, which is patent protected. It's in our Durasert E delivery system. The delivery system, as a non-erodible form, has been in four FDA-approved products. What we've been able to do with the delivery system is make it so that the inserts are 94% drug payload, only 6% matrix. One other big advantage that we have over potentially the competition is that we can be shipped and stored at room temperature. We don't have to be refrigerated, and we don't have to be frozen like gene therapy, for example. These inserts are fully bio-erodible, and they're designed so that the matrix holds the drug until the drug is fully eluted. The matrix should go away several months after that.
This enables the inserts to avoid any free-floating drug particles, and they do show in animals what we call zero-order kinetics. In animals, after initial burst of drug that is on the surface of the inserts, within a week or two, they settle into zero-order kinetics, which means a steady state release until about 90% of the drug has been eluted. We think this enables relatively lower doses of drug to give very good clinical results. Again, I use the example of the YUTIQ product, which contained a very small amount of corticosteroid, and it treated uveitis for three years rather successfully in about 60% of eyes. The zero-order kinetics allows relative microdosing to be successful. Animal studies and human PK studies suggest that the drug should last for six months minimum in just about every patient.
There is some variability, but by month nine, the drug should be fully eluted. Again, we're testing it as an every six-month drug in both DME and wet AMD. From an efficacy perspective, what we've been able to show in both the phase II DME, certainly in the larger phase II wet AMD trial, DAVIO 2. In DAVIO 2, we were non-inferior to on-label EYLEA control with a very small change in visual acuity, both at month eight and at month 12 of less than half of a letter at month eight. That is essentially equivalent statistically to EYLEA. That type of result, if we were to achieve that in phase III, would be outstanding.
I would add that from a success with regard to approval and certainly commercial success, we believe as long as we're statistically non-inferior, that would be a win for us and that the exact number probably doesn't matter because clinicians and patients can't tell the difference between, let's say, a half letter and one letter. From what we've learned so far and what we expect in the phase III would be non-inferiority change in visual acuity against that EYLEA control. I've already talked a little bit about safety.
Mm-hmm. Yeah.
Reduction in treatment burden, which means that the eyes that get our drug end up with fewer injections than EYLEA control. We were able to show that quite convincingly in phase II. In phase III, it's a statistical superiority test, which because of the large size of the trials, we actually only need about an 8% difference between us and control to show statistical superiority. That should be an easy bar to hit. Of course, from a commercial success, if we showed the same thing that we showed in the phase II, which was equivalent of about a 35% reduction in the way it's being measured in the phase III, that would be a really outstanding result.
Great. Can you just talk about some of the modifications that were made to LUGANO and LUCIA to essentially, hopefully, work in your favor for DURAVYU? I think there are some different rescue modifications. There are some different entry criteria. Maybe slightly different doses, how you arrived at that.
Yeah. Let me take a couple of those.
Okay.
I'll ask Ramiro, our Chief Medical Officer, to talk a little bit about the rescues. First of all, we enrolled 75% treatment-naive patients and 25% previously treated patients in both trials. That was by design. We wanted to have a more, I would say, real-world look at how our drug performs. I think more importantly, when you look at the DAVIO 2 population, it was a really tough-to-treat population. The previously treated eyes that we got had on average about 10 injections normalized over the previous year, where in the United States, it's more about six injections. We did well in that population. If you look at a naive population, a priori, perhaps up to a third of those eyes are what doctors would call easy to treat, meaning they can get out three months between injections with almost any agent.
Our hypothesis is that if those patients do well every three months with a ligand blocker, they should do very well with our drug. We think that de-risks the result and makes it more of a real-world type population that we're dealing with. With respect to the inserts themselves, again, I mentioned that we're 94% drug now. That's an improvement. Previous iterations of the inserts contained about 1 mg per insert, had considerably more matrix than what we have now. That improvement has enabled us to get 2.7 mg into two inserts. I might add, these inserts come in a sterile prepackaged, preloaded syringe injector, and we can inject up to three inserts simultaneously with one injection. For DME and wet AMD, we're testing two inserts.
I see.
Ramiro, I think, really is the person who did a lot of work around the rescue, and I'll let him take that question on.
Yeah. If you recall from our phase II study, we had five different supplemental criteria in that program. We look at what is very important, not just the rate of supplement injection, but what was the outcome of those supplement injections. Did the supplement injections improve patients' vision? Which is at the end of the day, the primary endpoint for these studies.
Out of those five supplemental criteria, we learned that two of those were the main ones, the important ones. That was patients that had vision loss and accumulation of fluid. Having both disease activity. Then the second one was the presence of hemorrhage. The other three criteria, just vision loss, just fluid, [audio distortion] discretion, didn't make a big difference in terms of visual outcomes. For the phase III study on the learnings of the phase II program, we decided to only have the two criteria: patients that lose vision and have fluid or have hemorrhage.
I see. Okay. I guess one issue that came up in the phase II trial was controlling for discretionary supplementation. How do you control for that in the phase III? How do you stop a physician from treating a patient that their instinct is to treat, right?
Yeah. Vascular discretion is not allowed per the protocol. We have a set of supplemental monitors that are retina specialists. They work with us, and they have conversations with the site to make sure that they understand the purpose of the protocol. Of course, if a site decided to supplement a patient, that is a major protocol deviation.
Okay. All right.
If I could add, though, this is actually an important kind of actually change in concept for some retina specialists. If you use a short-acting ligand blocker and the retina's dry, and two months later you see new fluid, you're going to say, "Well, the drug's run out. I better treat because the fluid's going to increase." What we've shown and seen in our phase II, and I have to say other sustained release are reporting this as well, is that there can be some fluctuations, especially in subretinal fluid, that can come and go from visit to visit and don't necessarily require a new treatment. I think that this will be some learnings that the retina community is starting to absorb, that not all fluid is the same, and subretinal fluid may not be that bad.
If you have sustained release, a little bit of fluid may go away at the next visit. It doesn't necessarily mean that the insert has run out.
Okay, I see. You had mentioned this earlier. How important is the mix of treatment-naive and treatment-experienced patients in this trial? I guess one of the questions we would have here is if treatment-naive helps DURAVYU, how does it not help EYLEA as well?
Well, it may. The argument, though, is because EYLEA is being dosed on-label, which is a three-injection monthly load followed by every other month, that we're over-treating some of those eyes in the study. We know that that's probably true because in the real world, not everybody gets every other month EYLEA. A couple of principles. First of all, we are treating on-label, and over-treatment isn't a problem. There's never been any kind of risk associated with that. Yeah, that is a logical conclusion that some of those control patients may not need every other month EYLEA. I'd also turn it around the other way. Some of those eyes, about 20%, require monthly EYLEA, and therefore, some of those patients are likely to be under-treated using on-label. As a result, we would expect some of those eyes to need rescue.
In fact, if you look at our phase II, about 6% of the EYLEA control arm, despite getting every other month EYLEA after a load, got rescued by month eight, and 13% got rescued by month 12. We would expect some of those rescues in this trial also.
Okay, got it. With regard to repeat dosing, is this something that FDA requested, or did you specifically design repeat treatment into the protocol to lock it into a six-month interval as I guess an optimal duration, a sweet spot duration that you're looking for?
Yes. The latter is what we started with. As we looked at our PK data and we looked at what doctors and patients want, the every six-month dosing made the most sense. The FDA, I don't think necessarily we had safety data from animals where you show that that type of dosing is safe in animals. Their contention is if you want to get a full label for re-dosing, you need to do it for two years. The first year, and the top-line result will be efficacy and safety. The second year that both trials go out will be for safety only. Of course, we'll be looking at the efficacy, and we would expect continued, if not better efficacy in the second year. From that second year is submitted to the FDA as a supplemental to get the full label for ongoing re-dosing every six months.
Okay. That would be four injections over the course of two years?
That's correct.
Okay. All right. Got it. As we noted earlier, the first of these trials we're going to report out in August. It's designed as a non-inferiority, as you've said, as is typical in wet AMD trials. I guess others have gone for superiority. What do you think you need to show in this competitive environment? There's a few obviously under development. There's gene therapy potentially. What do you think your profile needs to look like?
First of all, again, I think we talked about the three things that we need to hit. We need to be non-inferior, we need to show continued safety, and we need to have that reduction in treatment burden. I think beyond that, doctors will look for good control of the anatomy on OCT without the typical sawtooth pattern that you usually see in every other month EYLEA. I think doctors will be looking for a certain number of patients that are rescue-free. Remember, we had about 62%, 63% rescue-free up to six months after our drug went in DAVIO 2. We believe we should do better than that in the phase III. I think that if we do, I think that will be very helpful for commercial success. I want to reiterate, we're not another anti-VEGF. We work at the receptor level.
We block all the VEGF receptors, and we block PDGF, which should help with fibrosis. In addition, we've got significant preclinical data now to show that we block JAK1 at the doses we're using in humans, which means we should have a beneficial effect against activation of the IL-6 pathway. That's becoming increasingly important in both DME and wet AMD. We think altogether that is a potential advantage that if approved, we will have over virtually all the competitors.
Okay. Got it. Can you talk about filing plans here? I know that there's been obviously proposals by heads of FDA who are no longer doing single study filings. What is the most recent update on these guidelines?
Again, we're doing two trials in both wet AMD and DME, and we've taken from the start, what I would say is a de-risk approach. It's a risky business that we're in, and any time you can reduce the risk, you should. Ex-U.S., again, which we're also quite interested in, always has required two trials. If you take a step back and say, could you do one trial? You could always do one trial. There's actually FDA guidelines around that. Most companies, unless it's been a rare disease, I think really all companies have really taken the two-trial approach in retinal disease. That we believe is de-risked.
At the Retina World Congress just two weeks ago, the new head of the ophthalmic division, Dr. Boyd, was asked some questions about that, and his response was the standards for approval have not changed, and that when asked about how large a study would a company need to do to submit with one trial, his answer was generally several thousand. I think most companies, and us included, would rather do trials of, let's say, an N of 200, 300, 400, and do two of them, and then do several thousand trials to try to get an even lower p- value. It sounds like the standards at this point are the same. Regardless, we've taken a de-risk approach.
I want to give you a chance to speak about DME because this is where DURAVYU could be very well-suited because of the potential IL-6 impact or the blocking of IL-6. Why is it important specifically in DME and not necessarily in wet AMD, and should it help you on both fronts, essentially?
The quick answer is yes, it should help on both fronts, but IL-6 levels are highly correlated to the presence of DME. That's been shown in the direct DME specimens, and that's across the board. When you look at the wet AMD data, while there's good data to suggest that IL-6 plays a role, it seems to be limited, meaning not all patients have elevated IL-6, but the ones that do have elevated IL-6 seem to do much worse than the general population of wet AMD with anti-VEGFs. I think that the room for improvement in DME by blocking both VEGF and IL-6 is certainly higher, and we now have some pretty good clinical data from other companies that that's the case. The other companies, though, are not developing sustained-release anti-VEGF, anti-IL-6 blockage as we are.
If you go back and look at our phase II data, there's a couple of points to be made. The first is, if you look at our week four results from the VERONA trial, our 2.7 mg arm, which is our go-to-market dose, hopefully, was about four letters better than EYLEA as early as week four. We're about 40 - 50 microns drier as early as week four. We think that potentially is the IL-6 advantage. There also in the 11 patients who were in the high dose in that study, two of them had been on VABYSMO prior, and one could argue that they were suboptimally treated with VABYSMO, whereas when they got our drug, they did much better.
Again, that's a small N, but you can imagine in the real world, if it holds and there are eyes that are not necessarily doing well on the standard of care but do better with our drug, that would, I think, speak to very good commercial success. Going back to that early improvement at week four, if we can show that in the pivotal trials, I think we're going to capture a lot of the market. It's not just IL-6, it's also the sustained release, because this is another area where patients find it very hard to keep up with the right number of injections, especially in year one. That by using sustained release, I think that this forced compliance, in a sense, will give better visual results, and that's ultimately why we're doing this, which is better visual results.
Okay, great. I know that we're getting short on time here. I want to give George an opportunity to maybe talk to us about how you're thinking about commercialization. Obviously, well, George or anyone, frankly, this has obviously become a more crowded space. It's served by big pharma, as we all know. Do you have an intention of going it alone, and what would it take for you to service this market?
Yeah. I think importantly in the United States, retina in particular is very reachable by a company like EyePoint, and we're planning on launching the product in the United States ourselves. There are about 2,400 retinal doctors in the U.S., and you can address that with about 70 reps. We acknowledge there are certainly two big players. As Jay said earlier, we're not another anti-VEGF, and we think we've got a unique approach to the space. Part two of that is we've been way ahead of the curve on manufacturing. We built our own manufacturing facility, which is being scaled up for not just stability batches, but also for commercial launch. We're obviously focused on clinical data, but we do drug development at EyePoint, and CMC is just as important.
That's an important component of the NDA, and we're well ahead of the curve to be prepared for that as part of our filing. Yes, we've most recently hired a new Chief Commercial Officer, Mike Campbell, who's already started assembling a great team, and we will be ready to launch this product upon potential FDA approval as early as the end of next year.
Okay, great. Just to tie it all up, what is your cash position to be able to do this and build this infrastructure? Obviously, I realize you have this big plant that's quite a heavy lift.
Yes. Thank you for that question. Our cash guidance has actually been unchanged for some time, which is into Q4 of 2027, and that covers all the ongoing phase III trials for wet AMD and DME. When we have the readout of the LUGANO trial this summer, we should have at least a year of cash on hand. We have several value inflection points coming up between now and then, and are well positioned.
Just to recap the value inflection points that you have.
LUGANO trial will read out this August. With LUCIA, about two months later. We should have full enrollment in the DME trial sometime in Q3, the DME readout would be around Q4 of 2027. We have a value pack-
Hopefully NDA submission early next year.
Early next year. Okay. Great. We're out of time, unfortunately. This goes very quickly. Thank you for participating and telling us all about the program, and looking forward to seeing this data in August.
Thanks, Annabel.
Thanks very much, Annabel.
All right.
Bye-bye.
Thank you.