EyePoint Pharmaceuticals, Inc. Aktie

Ladies and gentlemen, thank you for standing by. Welcome to EyePoint's LUCIA Topline Data Readout. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to turn the conference over to Dr. Jay S. Duker, President and Chief Executive Officer of EyePoint. Please go ahead.

Thank you. Good morning, everyone, and thank you for joining us. Earlier this morning, we issued a press release announcing topline results from our Phase III LUCIA trial evaluating DURAVYU in wet age-related macular degeneration. As a reminder, DURAVYU was designed as a differentiated sustained release multi-MOA TKI to improve the current standard of care in wet AMD, the largest retinal disease market that has been dominated by monotherapy anti-VEGF biologics. Across its clinical development program, DURAVYU has consistently demonstrated meaningful visual and anatomic outcomes along with a favorable safety and tolerability profile, representing a compelling value proposition for retinal disease physicians and patients.

Before we get into the data, I want to first acknowledge what I'm sure is top of mind for many of you. As we disclosed in today's announcement, the LUCIA trial did not meet the primary endpoint despite demonstrating visual improvement through week 56. We are deeply disappointed by this outcome, given the promising scientific rationale and prior clinical program. We sincerely thank the patients, caregivers, clinicians and study teams who participated.

LUCIA is a randomized, double-masked, aflibercept-controlled, non-inferiority Phase III trial that randomized over 400 patients 1:1 to receive either DURAVYU 2.7 milligrams or an on-label 2-milligram aflibercept control. The trial enrolled both previously treated and treatment-naive patients with active wet AMD and along with LUGANO, is the only sustained release wet AMD pivotal Phase III study designed to evaluate 6-month redosing over 2 years against the gold standard of care, on-label aflibercept.

Patients in the DURAVYU 2.7 milligram treatment arm received an intravitreal dose of DURAVYU every 6 months, while patients in the control label arm received on-label aflibercept every 2 months after the loading phase. DURAVYU is delivered via standard intravitreal injection in the physician's office similar to current standard practice with FDA-approved anti-VEGF treatments. The primary endpoint of LUCIA is the average change in best-corrected visual acuity at weeks 52 and 56 blended versus baseline vision. Secondary endpoints include safety, reduction in treatment burden, percentage of eyes free of supplemental aflibercept injections and anatomical results as measured by optical coherence tomography.

With that, let's discuss the topline results in further detail. These are our legal disclaimers. And this slide represents the overview of the DURAVYU development program. We have active Phase III programs in wet AMD, LUGANO and LUCIA. And in DME or diabetic macular edema, we have 2 active Phase III studies, COMO and CAPRI. Today, we will be discussing the results of the LUCIA program.

As a reminder, DURAVYU has many potential advantages, favorable safety profile, clinically relevant to trial design against on-label standard of care dosing, a potential multi-MOA advantage with the only TKI that combines VEGF receptor blockage and IL-6/JAK1 anti-inflammatory results as well as PDGF potential antifibrotic benefit.

Durasert is a proven delivery technology with 4 FDA prior approved products using similar sustained release. Each DURAVYU insert is 94% drug. There's no PEG or PLGA and it features room temperature storage.

This slide summarizes the results of the LUCIA trial. LUCIA did not meet the primary endpoint of mean change in best corrected visual acuity despite visual improvements. There was a meaningful reduction in treatment burden with strong anatomic control demonstrating activity of DURAVYU. We showed continued favorable safety profile with redosing, and we will be doing additional analyses that are ongoing to assess the next steps for DURAVYU as a potential treatment for wet AMD. EyePoint is now focused on our DME program with ongoing pivotal trials that feature a topline data readout in the fourth quarter of next year.

Both LUGANO and LUCIA followed an established non-inferiority regulatory pathway for wet AMD. There were a total of 432 patients enrolled in LUGANO and 475 in LUCIA. And in each study, there was a 1:1 randomization between DURAVYU 2.7 milligrams and on-label aflibercept. DURAVYU was dosed every 6 months, and the primary endpoint was at approximately 1 year for both safety and efficacy and potential NDA submission. Once again, the primary endpoint was non-inferiority in mean change in best corrected visual acuity from day 1 to a blend of week 52 and week 56 with a noninferiority margin of minus 4.5 letters. There were key secondary endpoints to be evaluated as well.

This schematic slide shows the outline of both LUGANO and LUCIA trials, highlighting the every 6-month dosing of DURAVYU and the blended endpoint.

The baseline characteristics for this study were well matched. As you can see on this slide, the best corrected visual acuities were approximately 65 letters, central subfield thickness on OCT was approximately 315 microns in both trials and the total area of the [ choroidal neovascularization ] on fluorescein angiography was 5.8 millimeters squared versus 5.4 millimeters squared in the control arm.

This slide shows the topline result of the primary endpoint, mean change in best corrected visual acuity. And you can see at the end of the trial, the DURAVYU arm on average gained 2.5 letters, but the difference was minus 3.7 letters, and that was outside of the non-inferiority margin.

With respect to reduction in treatment burden, on average, after the load, the DURAVYU eyes received 3.3 injections, which included 2 DURAVYU and 1.3 supplements. The aflibercept arm on average after the load received 5.3 injections. This represents a 38% reduction in treatment burden. And if approved, could potentially result in 2 fewer injections on average against Eylea.

For supplement free up to week 32, which is approximately 6 months after the first DURAVYU was delivered, 70% of the DURAVYU patients were supplement-free. 94% had received 0 or 1 supplement and over 99% had 2 or fewer supplements. At the primary endpoint, the supplement-free rate was 52% with 71% patients receiving 0 or 1 supplement and 83% of the patients had 4 injections or less at the end of the trial.

The anatomic control was good. As you can see in this graph, against aflibercept at the end of the trial, there was approximately 16-micron difference, which in clinical practice would likely not be felt to be significant at all. If you recall, the difference in the first trial, the LUGANO trial was approximately 4 microns. So overall, in both trials, DURAVYU showed quite strong anatomic control.

From a safety perspective, there were no reported cases of insert migration into the anterior chamber, anterior chamber opacities, free floating drug particles or retinal vasculitis. There were AEs of particular interest that occurred in less than 1% in both arms, including intraocular inflammation and endophthalmitis. There was more floaters in the DURAVYU arm than the control arm, but the majority of these cases were mild. There was a low patient discontinuation rate in both arms of approximately 8% and none of the discontinuations were due to study or treatment.

This slide shows the AEs that occurred greater than equal to 2%, again, highlighting that there were an increased number of vitreous floaters in the DURAVYU arm, similar to what was seen in the LUGANO trial.

The pooled results of the reduction in treatment burden showed an overall 40% reduction when the LUGANO and LUCIA trial were pooled together. And again, this could show a potential for 2 fewer injections per year in wet AMD patients.

This slide shows the pooled anatomic data between the 2 trials, showing a difference of about 10 microns and relatively stable control of the fluid by DURAVYU. And this slide is the pooled safety, a total of 443 patients treated with DURAVYU, showing no safety concerns.

I'd now like to review our diabetic macular edema or DME program. COMO and CAPRI are identical Phase III DME trials. This was informed by a positive Phase II VERONA trial and aligned with both the FDA and EMA on an established non-inferiority regulatory pathway. There was very high physician enthusiasm for participation in the trial and over 550 patients were enrolled across both trials. The first patients were dosed in both trials in February of this year and full enrollment was achieved by July. We expect topline data in the fourth quarter of 2027.

This is the schematic for the COMO and CAPRI trial, similar to LUGANO and LUCIA with 2 notable exceptions. The first being that on-label aflibercept for diabetic macular edema includes 5 monthly loading injections. In addition, in this trial, we dosed DURAVYU on day 1 in order to show a potential more rapid reduction in fluid and improvement in vision by week 4.

That decision was influenced by the results of the VERONA Phase II trial in DME. And as you can see, the purple line representing the DURAVYU arm at week 4 had increased improvement in vision versus aflibercept with a concomitant reduction in fluid noted as early as week 4. At the end of the trial, without a single outlier patient that missed visits, there was approximately 10 letter improvement in vision in the DURAVYU arm versus 7.3 letters in the control arm, and this was also matched by increased reduction in fluid.

Macular leakage on fluorescein angiography is a biomarker of vascular instability, and there was a dose-dependent reduction in vascular leakage as determined by the reading center on fluorescein angiography with the DURAVYU arm showing significantly less leakage at the end of the study.

This is one of the patients from the 2.7 milligram arm in the Phase II DME trial. This patient had been treated with monthly injections leading into the trial, first with bevacizumab and later with faricimab. After the washout period, the patient had residual fluid in the macula with a CST of 336 microns and the best corrected visual acuity of 72 letters. This patient received a single injection of aflibercept along with DURAVYU on day 1 and received no supplements. And at the end of the trial, 6 months later, the best-corrected visual acuity had improved to 80 letters and the CST was stable.

So in summary, LUCIA did not meet the primary endpoint of mean change in best-corrected visual acuity despite visual improvement. There was a meaningful reduction in treatment burden with strong anatomic control and a continued favorable safety profile with redosing. We will be doing additional analyses to assess the next step for DURAVYU as a potential treatment. However, the company is now fully focused on our DME program with data readout in 4Q of 2027.

To close, I want to reiterate that we continue to believe TKIs have the potential to be the next phase of retinal disease innovation. And today's data reinforces our fundamental conviction in DURAVYU. Today's results are supportive of DURAVYU's activity in controlling fluid and reducing treatment burden for patients as well as the safety of DURAVYU with redosing. We plan on continuing to review the data from LUGANO and LUCIA to determine the appropriate next steps for DURAVYU in wet AMD. We remain focused on advancing DURAVYU in the Phase III program for the treatment of diabetic macular edema, which represents the second largest retinal disease market and where DURAVYU still remains the only TKI in Phase III development.

With the multifactorial and inflammatory nature of DME, the potential anti-IL-6 properties of DURAVYU as well as compelling results in our Phase II VERONA study make us confident that DURAVYU is positioned well to deliver potentially earlier benefits with fewer injections versus the standard of care. We are on track to deliver topline data for our Phase III DME program in the fourth quarter of 2027.

Most importantly, our commitment to patients in the retina community remains unchanged. We will continue to follow the data and advance our development programs with the goal of delivering meaningful new treatment options for patients with serious retinal diseases.

I'd like to thank the entire EyePoint team for your unwavering commitment to improving the quality of retinal care for the patients we serve. I also want to express our sincere gratitude to the patients, study coordinators and clinical investigators who have been part of LUCIA and whose partnership has been vital to our growth and success as a company. Thank you for your attention.

Ladies and gentlemen, this concludes this call for the EyePoint Phase III LUCIA Topline Data Readout. You may now disconnect from the call.

I'm very happy to be kicking off day 2 of our healthcare conference with the EyePoint team. I'm joined here by EyePoint President and CEO Jay Duker, CFO George Elston, and CMO Ramiro Ribeiro. So thank you, all three of you, for joining us early on a Tuesday morning. Just a quick note on our research disclaimer. Please feel free to visit morganstanley.com/researchdisclosures for our disclaimer. So let's get into it.

It's been an eventful few months for the EyePoint team. Maybe we can start on the recent LUGANO trial readout, the Phase III readout, the first of two Phase IIIs that you're going to have this year. When we look at the data headline, the study didn't technically meet the primary endpoint in the full intent-to-treat population, but there were a number of encouraging findings underneath that headline. So we'd love to hear you guys walk through your interpretation of the data and importantly, what may have the market missed?

Sure. Thank you very much for the invitation. Thank you for the question. So the LUGANO trial was a Phase III trial, which studied our vorolanib intravitreal insert, 2.7 milligrams per dose. Vorolanib is a small molecule tyrosine kinase inhibitor that has activity against the VEGF receptors, PDGF, and JAK1. The control arm in this study was on label 2 milligram of aflibercept -- we're studying it in wet age-related macular degeneration. And the patient population, 75% of them were treatment naive, and 25% had been previously treated.

The primary endpoint of the study was non-inferiority change in visual acuity from day 1 to the average between week 52 and week 56. So as you mentioned, in the full analysis set, we did not meet the primary endpoint. But there was some really encouraging data that came out of the study, including the important secondary endpoints. First of all, safety. In the prior Phase II, Phase I trials that we've run with the insert, we really had no safety concerns, and that was really backed up in the Phase III, the safety looked quite clean. We also showed really good anatomic control of wet AMD. That's measured in the office by an instrument called optical coherence tomography or OCT. And at the end of the trial, there was only a negligible difference in retinal thickening between the study arm and the control arm. We were able to reduce the treatment burden by over 40%, which if approved and in the real world, could mean two fewer injections per year on average. And over half of the wet AMD patients went the full year under control with our drug alone.

And in that group of patients, we were statistically not inferior in change in visual acuity. In the overall population, however, one of the things that really stood out as highly unusual is the number of eyes in the control arm that lost 15 or more letters. Historically, that occurs because some eyes just don't respond to anti-VEGFs. And remember, this is an elderly population, so some of these patients will lose vision for other reasons, like cataract or glaucoma or dry AMD. Typically, in the 2 milligram Eylea arm, at the end of a 1-year trial, you expect between 4% and 5% of the eyes to lose 15 or more letters. In the LUGANO trial, it was only a half a percent, and that, again, is statistically highly unusual. And we believe that was the primary reason for the miss. It certainly wasn't that our drug wasn't active.

Again, looking at the secondary endpoints, our drug was durable and potent and safe, but there appeared to be a significant mismatch in these 15-letter losers. And if you go back and look at our Phase II trial, the DAVIO 2 trial, 7.7% of the control arm, the same control arm, 2 milligram Eylea, lost 15 or more letters. So it went from 7.7% to a half a percent. And in the Phase II, in our high-dose arm, it was under 4% lost 15 or more letters. When we really broke it down, we ended up with nine patients in the DURAVYU arm that lost 15 or more letters for something other than wet AMD. In those eyes, when we looked at the visual acuities and, of course, the anatomic control and the overall clinical findings, six of them lost vision due to geographic atrophy, the severe form of dry AMD, versus none in the control arm. Again, highly asymmetric and unusual. Two lost vision due to glaucoma, and one from successfully repaired retinal detachment, where the patient developed a severe cataract after the successful surgery. So we believe that this asymmetry in the 15-letter losers was the primary reason that we missed the endpoint.

Okay, that's really clear. I mean, it sounds like, the control arm simply just performed a lot better than you would have expected based on historical trials. In terms of the nine DURAVYU patients that actually experienced a 15-letter or greater vision loss, can you help us understand what you think happened in those nine patients? I know you mentioned geographic atrophy.

So the geographic atrophy patients, I think, again, at the end of the trial, if you looked at their anatomic control of their wet AMD, it was quite good. And in fact, of those nine patients, three of them never received a supplemental injection. And the reason they didn't receive it is the treating physician felt that there was no active wet AMD and there was no reason to give them another anti-VEGF. So we then did some further analysis to look at the possibility of our drug speeding the growth of geographic atrophy.

Now, we certainly hadn't seen that in any of the prior studies, and there's no preclinical data to suggest that. And in fact, the analysis that we've done, I think pretty shows I think quite clear that not only do we not cause new geographic atrophy but in pre-existing geographic atrophy the rate of progression was no different than the fellow eye, for example, which is a nice internal control and was actually less than what's been reported as the usual progression of geographic atrophy.

What we did find is the eyes in the DURAVYU arm started with geographic atrophy closer to the center of the fovea and that means that even if they progress at the same rate obviously if you start closer you're more likely to have visual loss from that. So we think, again, it was just an asymmetric distribution. The two patients that had loss from glaucoma. One of them, unfortunately, every time they got an Eylea shot, which was part of the trial for them to get Eylea at the beginning, they spiked their pressure very high due to the Eylea shot. And clearly, if that patient had been randomized into the other arm, they would have received Eylea and had the same pressure spikes. So, again, it appears so, certainly just a little bit of bad luck with the randomization in those cases.

Okay, that's helpful context. And then when you think about the 42% reduction in the treatment burden that you highlighted, how do physicians think about that magnitude of reduction in the context of real-world treatment burden in the disease?

So I think, again, overall, the physicians we spoke to and we've spoken to a lot of retinal specialists and shown them the data. They're quite enthusiastic about the secondary endpoints, including that reduction in treatment burden. The expectation or hope going into the trial from retinal specialists was that we would have at least a 20% reduction in treatment burden. And when you look at the real world analysis of medications like high-dose Eylea and VABYSMO, which have been very successful, these second generation anti-VEGFs. They appear to reduce treatment burden less than 20%, about one injection less per year on average, yet they're quite successful. So we think that overall success of the reduction in treatment burden, if approved, would be very enthusiastically accepted by the retinal community.

Okay. And then just going back to the safety profile for a moment, it looked quite clean, as you mentioned, including after repeat dosing. So no meaningful imbalance in intraocular inflammation, no observed retinal vasculitis or severe IOI. So how important is sort of the repeat dosing safety experience when you think about the differentiation of your drug?

Well, again, these patients on average who are diagnosed with wet AMD live for over another 10 years. And so you want to be able to treat them successfully and safely for the rest of their lives. So the important thing in wet AMD when you look at the long-term success, patients, despite our very good short-acting anti-VEGF, still lose vision. And so the ability to retreat and have long-term suppression of VEGF appears to be associated with much better outcomes in the long term. So obviously you have to show the safety and efficacy in your trials, so we're certainly able to show safety with repeat dosing, and again, we expected that animal data in the previous safety from single injection really gave us confidence that we would be safe. But if a drug can't be repeated, and obviously if it's even a long-acting that might last 6 months or a year, it doesn't really help us retina specialists treat patients in the long term. You need to have repeat dosing.

Okay. And then is there, just thinking about the takeaways from the study, I mean, is there anything you learned from LUGANO about sort of patient selection or baseline patient characteristics that could influence how patients would use, or how physicians, rather, would use DURAVYU commercially?

So we've looked quite a bit at the outcomes to see if there was any indication that, for example, the drug worked better in eyes that were previously treated or eyes that were treatment naive, and we didn't find a difference. We've broken it down by some other parameters, and we'll continue to do that, certainly, because that's something, if approved, is very important. You want to be able to tell the treating physicians which are the eyes that are going to do really well. And especially that 54% that went the full year with our drug alone.

As I think I've emphasized over and over, we have these supplement criteria in the trial, but that's not how doctors treat in the real world. They don't supplement per se, but given that we're a different mechanism of action, I think in the real world, if we're approved, doctors wouldn't hesitate to use both a biologic ligand blocker and a long acting TKI together to get, hopefully, a synergistic effect. So, again, when we look at those eyes that were made it through the full year stable on our drug alone, we're hoping to find some biologic marker early on that might indicate that subgroup of patients. But as of yet, when we looked in the Phase II, we were not able to discern it, and we'll be doing further studies to try to elucidate that.

Okay, great. Just given the totality of the data and the outcome, what conversations have you had or are you expecting to have with the FDA around this study?

So I think, again, putting it in context, the FDA has seen a lot of aflibercept 2 milligram arms and how they do. And I think we have a very solid clinical explanation as to why we missed the primary endpoint. And there are certainly examples in retina of drugs that hit one Phase III and missed a second Phase III being approved, and there are plenty of examples outside of ophthalmology of that as well. And so if the second trial, the LUCIA trial is positive, we're quite optimistic that the FDA will accept our NDA and review it.

Okay, that's a good segue to LUCIA, which I know is coming up next quarter. On Q4, you've guided the street. This is obviously an extremely important readout for the company. So can you remind us how similar the trial is to LUGANO and whether there are any meaningful differences in sort of the patient population that we should be thinking about?

Ramiro, do you want to answer that?

Yes. So in terms of study design, LUGANO and LUCIA are identical, exactly the same type of study design. In terms of the patient population, the only difference is that LUGANO was 100% U.S. patients, and LUCIA is 80% U.S., 20% international. We published the masked baseline characteristics earlier this year in a medical conference, and the baseline characteristics on a masked fashion was pretty similar. The way that we are analyzing the data also, of course, pretty similar. We are amending the analysis plan for LUCIA based on the learnings from LUGANO. So one new analysis that we're going to be doing is looking at patients that lost 15 letters for reasons not related to wet AMD. And similar to what we did for LUGANO on a post-hoc manner removing those patients, in LUCIA, we're going to pre-specify that and as a pre-specified sensitivity analysis. The primary endpoint, it's still the same, takes into account all the patients. But for the sensitivity analysis, we will remove those patients.

Okay. Ramiro, just going a little bit further on the geographic mix, how do you think that could influence either the control arm performance in LUCIA or maybe just the underlying variability in visual acuity outcomes?

Yes, I think if you look at recent Phase III studies in wet AMD and when they broke down by geographic region, there was no meaningful difference between U.S. and international patients. In the end of the day, wet AMD is a relatively genetic disease, so you see mainly Caucasian patients. The sites that we use outside of the U.S., of course, are sites that have experience in Phase III studies. They are located in big cities. So we should not expect any difference in terms of geographic region between U.S. patients and international patients.

Okay. So the timeline you've outlined is Q4 for LUCIA data and then potential NDA filing in the first half of '27, right? So what would you really need to see in LUCIA to feel comfortable moving forward with the planned NDA?

I think it's actually quite binary. If we have a positive primary endpoint, we intend to move forward with the NDA filing in the first half of next year. And so from the perspective of acceptance in the retina community and use, I don't think the retinal physicians will care very much about the actual numerical difference, if there is one, between our drug and the control arm, as long as we're approved and safe. So we would expect to see similar secondary endpoints in LUCIA that we saw. And if we do and we hit the primary endpoint, then I think we intend to file, and I think we'll have a good chance of having the drug accepted.

I guess in your conversations with retinal specialists, do you feel like there's still a lot of enthusiasm around the program and kind of belief that you guys have an active drug here?

I think there's a lot of enthusiasm, yes. In that, again, when they look at the secondary endpoints, in particular the anatomic control, which is what retinal physicians use on a daily basis to decide how well their drug of choice or their interval is working, I think they're very enthusiastic about it. What a drug like the vorolanib insert can do for them and their patients is, first of all, the most important thing is it will really help long-term visual acuity. Because in the long term right now, patients are undertreated.

And by having an insert that lasts 6 months or longer, the ability to treat in the long term and have patients come back for visits, I think is going to improve. And retina specialists clearly understand that. It also gives them flexibility to change their dosing frequency longer if they choose to, and depending on the patient in this situation. And so I think the enthusiasm is there, and I think that in general, the secondary endpoints, we did better than expected in the retina community. And that's what's really going to make us commercially successful. We have a hurdle we need to get over, which is we need to hit the primary endpoint in the next trial and obviously get approved.

Of course, yes. Maybe just on the commercial opportunity and sort of the competitive backdrop, the competitive bar has certainly been raised by increasingly durable agents like Eylea HD and VABYSMO that are on market. What would DURAVYU need to offer just in practice to drive actual switching from those agents?

Well, I think the obvious thing is, again, further length of time between injections. If you really look at the real-world data, whatever agent we use, about 20% of wet AMD patients still have to be treated monthly. And about half have to be treated every 2 months or more frequently. And so there's a huge need out there, even with these newer agents, to try to extend those patients out further. And so, again, I alluded to this earlier. If you have a patient that you're treating 12 times a year, and let's hypothesize that the DURAVYU is safe, effective, tolerable, approved every 6 months and you use it in that patient and you still need to or choose to use a ligand-blocking biologic in between and say your total 4 times a year injections. That's those 2 -- what we called in the trial supplements, those wouldn't be considered supplements in the real world because in the real world you've gone from 12 injections a year to 4 injections a year, which is terrific for everybody.

And if you go back and look at the data from LUGANO, almost 90% of the eyes were controlled with four injections or less per year. And again, going back to the real world, if you ask the question, well, how many high-dose Eylea patients or VABYSMO patients are treated at a 3-month interval or longer? It's not 88%, it's probably a third of that. So that ability to get many patients out to that 3-month or longer mark I think is something that's going to be very attractive to everybody, patients, physicians, payers.

Yes, if I can add to that, I think, because the topic switching comes up frequently and that's been the history of how wet AMD is treated. The most recent drugs say we last longer use us, stop using the other programs. And our message is quite different. Our message is it's no longer either/or, it's both because we're bringing a new MOA, we're going to be that background foundational medicine and if the anti-VEGF biologics are needed in between, doctors will use them. And so it's really a different commercial mind shift in that space.

To your point, George, that means that flexibility to actually, give supplemental anti-VEGF injections on top of DURAVYU when necessary. That kind of lowers the bar to entry, when it comes to practice or.

Yes, I think it totally does. And I think even though we showed over half the patients could go 6 months on our drug alone, it doesn't mean that, that's what the majority of doctors will do. Certainly at the beginning, they're going to want to see how the drug performs. And remember, many of these patients do not have wet AMD in the fellow eye yet, and they're susceptible. So I think the idea of going 6 months or longer between visits is not something most physicians are going to be comfortable with. They're going to bring the patients back to see how they're doing and check the fellow eye. And I think that some patients would be very happy to come back for a check to hear they don't need an injection. Or, as I think I've already mentioned, some doctors, even if the eye's under control, may choose to use the assumption that the two MOAs are going to be synergistic and choose to do that. That's the flexibility that our drug may offer.

Okay. Makes a lot of sense. I'm going to just switch gears for a moment to your diabetic macular edema program. Maybe you could, Jay, remind us why you believe DME could be an attractive setting for DURAVYU.

Well, I think first of all, the diabetics, it's a different population from wet AMD patients, they're younger, they're often working because they're diabetics, they have multiple doctor visits, and it's really hard for them to have the number of injections that they need. The study suggests in the first year of DME treatment, patients should receive about 11 injections, and in the real world, they receive about three. And some of that is that because DME is a multifactorial disease, it's not just VEGF-mediated, there's clearly an inflammatory component as well, that it can take multiple injections before the patients realize that they're actually getting better. So if you're a diabetic and the physician says, look, I've got to give you these monthly injections, you have three, four, five of them, and you don't perceive the benefit, it's very easy to stop coming back.

And we think that's a real problem in this population. So the things that really gives us really enthusiasm about drug in DME was the results of the Phase III trial, the VERONA trial, we looked at patients who were previously treated but all of them had active DME which means they had decreased vision and they had fluid on OCT and if you look at the initial data point after treatment, all patients received treatment on day 1, and at week 4, the eyes and the DURAVYU arm were already seeing about four letters better than the eyes and the Eylea arm, and there were also 40 to 50 microns drier on OCT. We can show that in the Phase III. Even if the end of the trial were non-inferior, were the same vision, but we can show we can get patients drier and seeing better faster. Who wouldn't want to have better vision with fewer injections? I think everybody would, and I think that ability to capture market share in the DME market, which is currently about a $3 billion market. I think it's wide open for a drug like ours.

So you mentioned the Phase III that are ongoing, Phase III COMO and CAPRI trials, they're now both fully enrolled. More than 480 patients on in the trial. And I know you're expecting top line data from that trial, those trials, I think it's Q4 2027, if I'm not mistaken. So, can you walk us through the design of those trials and kind of sort of what you learned from VERONA that may have informed some of that planning?

Go ahead, Ramiro.

Yes, so similar to our wet AMD, COMO and CAPRI are two identical studies. The main difference first on the control arm, we're using on label aflibercept, which means five monthly injections in the beginning, and then after that is aflibercept every 8 weeks. On DURAVYU based on what we saw in our Phase II study with the benefit of DURAVYU starting from day 1. We are dosing DURAVYU day 1 together with aflibercept. And then after that we have two additional monthly aflibercept.

And then DURAVYU is every 6 months. So day 1, 24 and then 48. The primary endpoint is chang from baseline to average week 52 and 56. So this is similar to our Phase III program. And then the secondary endpoints, we also have treatment burden, anatomic control, and safety. We also have supplement injections for patients that meet a certain criteria. And then we have both naive patients as well as previously treated. Most of the sites that are part of COMO and CAPRI were also part of our wet AMD study. So those sites, they have experience with Phase III studies and they have experience with DURAVYU, which of course, from an operation perspective, help us a lot.

Okay. Ramiro, maybe you can just give some context. I know it's a year away, but what do you think would constitute a compelling clinical profile in DME beyond just non-inferiority, what would we want to see in those Phase III trials?

I think the key components are, of course, the non-inferiority, which we have agreement with the FDA to use a non-inferiority margin of 4.5 letters, followed by a reduction in treatment burden, which also is important for DME. Safety, we have a good understanding of safety. We should see the same type of safety profile in DME patients. And then in addition to that, as Jay mentioned, it's going to be very interesting to assess the effect of the JAK1, IL-6 inhibition that we have with vorolanib in the DME patient. This can translate to first either a gain in visual acuity earlier than just aflibercept, and then second, which is very important for physicians is a reduction in the leakage on the fluorescein angiography. We know that long-term patients that have leakage either on the OCT or on the FA, but have worse outcomes than patients that have dry retina.

Okay, that's helpful context. George, I'm going to turn to you. Just thinking about the balance sheet, you ended the second quarter with about $180 million in cash, and you've got runway into Q4 '27, so you're well-funded here. But how do you think about cash utilization following LUGANO? And, I know you've been investing ahead of the launch, but how do you think about cash spend going forward?

Yes, great question. And I think we've got a pretty good track record at EyePoint of managing and controlling our burn. Our cash guidance has been unchanged for over a year. Obviously with LUGANO missing, a number of things have pushed out. And so we're still very confident in that cash runway is probably a little bit better, but clearly between now and then we'll need to add the balance sheet, we've got a number of catalysts, including LUCIA, including the potential NDA filing and acceptance, and as you mentioned, COMO CAPRI next year. And so I think with success in LUCIA we'll have a number of levers we can pull, including potential synthetic structures on top of equity and other mechanisms like that.

And just on the point of the sort of investment ahead of launch, I know you've been bringing in commercial leadership and kind of building out your manufacturing capacity. Can you talk about sort of the prep work that's going into that?

Yes, so I think what gets lost out there, obviously there's a lot of focus on the clinical outcomes and that's clearly important, but when you file an NDA, CMC is just as important, if not more important, in the sense that most CRLs happen on the CMC level. And so we've been in front of manufacturing for several years. We had a state-of-the-art facility built for us by our landlord in Massachusetts. And so that has been under scale up and we now have batches under stability, we have four registration batches, and we're in the process of scale up to support that CMC, and the team's just done a remarkable job out there. And then on the commercial side, it's never too early to get in front of your customers, start talking to payers, and we've built a very small but important team in preparation for launch. And I think the bigger spend on the commercial side will obviously come after NDA acceptance and approval where we'll start to build that organization out.

Okay. One more comment, if I may, about the manufacturing. So these inserts, there's a lot of technical know-how that goes into making them. And the other big effort we needed to do at our facility in Northbridge, Massachusetts, was automate the process in order to really meet the demands of successful launch. The inserts really need to be made not by hand but by machines. And again, George said it and I'll re-emphasize, our team has done a remarkable job to automate and semi-automate the process from the beginning right straight through to the inspection of the inserts. Formally the inserts were inspected individually by hand. A person picked them up with tweezers and weighed them and measured them and looked at them under magnification for impurities. That's obviously not something that you can scale successfully commercially and we knew that and that's one of the reasons we built this facility in and brought in the type of automation that's necessary and we've been able to do that successfully.

Okay just to give you the last word, Jay, I mean, LUCIA's around the corner, a lot to be excited for. What do you think investors will understand with a positive LUCIA data that they may not appreciate today?

So again, I like to emphasize the secondary endpoints because that's what's going to make this drug commercially successful. What we're trying to do here is really improve patients' lives by giving them better long-term vision. And the pathway to do that is through those secondary endpoints. So that, I mean it's obvious, we need to hit a primary to get approval, but we are quite optimistic that with the primary endpoint being hit in LUCIA, in the strong secondaries and the clinical explanation for the miss, I think the agency is going to look quite favorably at the application.

Terrific. Well, thank you. We're wishing you success in LUCIA, both for the EyePoint team and for patients. So we'll stay tuned and thanks for joining us today. Thank you. Appreciate your time.

All right. So welcome, everyone, to Day 1 of Citi's Back-to-School Biopharma Conference here in New York City. Great to be back in New York. I'm Yigal Nochomovitz, one of the biotech analysts here at Citi.

So our first session, it's my great pleasure to welcome the management of EyePoint Inc. We have Jay Duker, President and CEO; George Elston, EVP and CFO; and Ramiro Ribeiro, the CMO of the company. So welcome all of you. Thank you very, very much.

Thanks for having us.

Of course. So obviously, a lot has happened. You've had some Phase III data. You have another important -- very important Phase III result coming up soon in the fall. So Jay, maybe just to level set, if you could just introduce the company, introduce the goals of your lead program. And then I know we're going to have an important discussion about the LUGANO results and then what to expect, of course, for LUCIA in a few weeks.

Sure. Thanks for the introduction, and thanks for the invitation. So at EyePoint, we are a company that specializes in drug delivery to the back of the eye. Our lead product is called DURAVYU. It is the vorolanib intravitreal insert. Vorolanib is a small molecule tyrosine kinase inhibitor, which has activity against all the VEGF receptors, PDGF, and JAK1, giving it an anti-inflammatory component.

It's in our proprietary delivery system that allows it to have therapeutic levels in humans for at least 6 months with a single injection. And as you mentioned, we are currently in 2 Phase III programs, wet AMD and diabetic macular edema, or DME. So we have 4 Phase III trials ongoing.

And the first trial, the LUGANO trial in wet AMD, read out several weeks ago. The second trial, the LUCIA trial, started about 2 months after LUGANO. And so we expect to read out about 2 months after the LUGANO readout. And then we have 2 fully enrolled DME trials, COMO and CAPRI, which fully enrolled approximately a month ago, and those will have readout in Q4 of 2027.

Okay. So let's start with LUGANO. I think it would be a good idea to sort of summarize what the results were there, what you observed, and of course, some of the asymmetry that you saw in the results that led to just missing on the primary endpoint, but there were certainly some mitigating factors there in terms of the way the randomization played out.

Sure. So the trial enrolled 432 patients with wet age-related macular degeneration. Approximately 75% were treatment naive and 25% were treatment experienced. They were randomized on Day 1 to 2 groups. They either received 2.7 milligrams of DURAVYU every 6 months or EYLEA on-label control. Both arms were treated with monthly EYLEA at the start of the trial.

Then all the patients were seen monthly, and every other month, the EYLEA arm received another EYLEA injection on schedule. And every 6 months, the DURAVYU arm received another DURAVYU on schedule. Both arms could qualify for a supplemental injection if they met specific criteria for disease activity. And the trial execution was quite good, thanks to Ramiro and his team. We had overall about a 6% dropout rate in both arms, and none of the dropouts in the DURAVYU arm were due to the drug itself.

So as you noted, the top line, which was non-inferiority change in visual acuity between Day 1 and weeks 52 and 56 averaged. The top line result for all patients was that we were not non-inferior. However, the most glaring unusual aspect of the trial was the behavior of the control group at what I'm referring to as the low end of vision. In all previous studies of 2-milligram EYLEA on label in Phase III, approximately 4% to 5% of the EYLEA eyes lost 15 or more letters, either due to wet AMD activity or due to other things.

Remember, these are elderly patients, and they can lose vision for things like cataract, glaucoma, retinal detachment, geographic atrophy. So the expectation is 4% to 5%. It's varied between 3% to as high as 6%. And if you look at our Phase II data, in Phase II, 4.3% of the DURAVYU eyes lost 15 or more letters and about 7% actually of the EYLEA eyes lost 15 or more letters. So that gave us quite a bit of confidence going into Phase III.

But when we looked at the results, only 0.5% of the control eyes lost 15 or more letters. It's a very, very unusual result. Of course, that result really had nothing to do with our drug. Those eyes, obviously, they were controlled. They didn't receive our drug. They received EYLEA on label. And if you look at our inclusion and exclusion criteria, they really weren't that much different than prior trials. So other than, hate to say it, but bad luck, it looks like a series of eyes that lost vision due to other things were randomized into our arm and none of them got randomized into the EYLEA arm.

So specifically, when we looked at overall the 15-letter losers in the LUGANO trial, it was about 4%, which is what one would expect. But virtually all of them except one was in our arm. Now some of them were due to wet AMD that still had activity. But we had 3 retina specialists independently take a look at the eyes, and they all agreed that the primary loss of vision in 9 of them was not wet AMD.

And in fact, those 9 eyes, this is what we call this asymmetric cohort, they actually had good control of their wet AMD at the end of the trial. There was no wet AMD activity...

Based on the CST?

Based on OCT, CST, color photographs, fluorescein angiography, all those tests we do to determine is there active wet AMD or not. One of them lost vision due to retinal detachment. Retinal detachment was successfully repaired, but that patient had not had cataract surgery. And if you repair retinal detachment in an elderly patient using a vitrectomy technique, you get a cataract very rapidly, and that patient did get the cataract.

Easily, easily.

Yes, it had nothing to do with our drug. And of course, when you look at the rate of retinal detachment, there was one in each arm, which is actually a little bit lower than one would expect. So 6 of the patients lost vision due to geographic atrophy. And we've now done some extensive analysis of the geographic atrophy in the trial. And the conclusion is we have no evidence that our drug causes new geographic atrophy or speeds the growth of preexisting geographic atrophy.

And this is something we will show publicly shortly. But we looked at things like the rate of new GA. And of course, geographic atrophy was allowed in the trial to a certain degree. And at the beginning of the trial, there was 10% of the eyes in the control group had GA according to the reading center, 8% in the DURAVYU arm. And at the end of the trial, it was 29% versus 24%. So at least statistically...

It's almost identical...

Yes, it was equivalent, but numerically higher in the control arm. The rate of growth, again, if you look at the rate of growth of GA untreated, studies will say anywhere from 2 to 2.2 millimeters squared per year. The rate in our arm was less than that. And you can also use the other eye as a comparison. And for the eyes that started with GA in both eyes, if you hypothesize that somehow we sped GA up, then it should show up as a difference between the 2 eyes. And there wasn't a difference between the 2 eyes.

That's interesting. So that's data you're going to...

Yes, we'll be showing that.

I don't think that specific statement was in the original.

No, we're going to be showing that publicly shortly.

That's quite compelling.

Yes. And finally, the location of the GA overall started closer to the fovea. But so to summarize, again, not looking at all at our drug, just looking at the performance of the control arm, it would be hard to believe that we're going to see that lower rate of 15-letter losers in the next trial.

So I guess -- okay, that makes a lot of sense. Aside from just sort of having bad luck again, which one shouldn't expect, is there anything else -- what else would give us confidence in LUCIA delivering sort of a normal result? Is it a little bit of a larger trial?

So it is. It is. But I'd like to just mention how well we did with the secondary endpoints because when you really think about it, the secondary endpoints are what will make this drug commercially successful if approved. And you may recall and others may recall, we've been saying this for years. When you talk to retina specialists, and you ask them, what if you have a new drug that's safe and effective and can be delivered every 6 months, but results in a 1-or 2-letter decrease in vision or even 3-letter decrease in vision?

The majority of retina specialists say, well, I don't care about that because the patients don't notice it. And it's such a small amount. So we need to hit, obviously, the primary endpoint to get approval. But when we look at the secondaries, we're really confident that this drug is going to be commercially successful. So first of all, safety. We were never worried about safety. We never had a safety issue in the prior trials. And preclinically, the safety looked excellent.

And again, as expected, there were really no safety issues. Things like cataract, elevated intraocular pressure, no difference between the groups. I mentioned retinal detachment, no difference between the 2 groups. There were no cases of severe inflammation. And in fact, any intraocular inflammation, there was only one in our arm and one in the control arm. So IOI was very low as expected. No insert migration, no anterior chamber opacities.

There was a higher rate of floaters, but none of the floaters really were -- they were mild to moderate, and they didn't affect the vision. And patients, obviously, they didn't ask for the inserts to be removed or anything like that. That was really the only mismatch worth noting. So from a safety perspective, it's great. What we really did well also is anatomically. Anatomically is the measurement of CST on OCT, and that's what the doctors really look at to see if things are controlled.

So a normal foveal thickness is, let's say, 300 to 325 microns. At the end of the trial, we were 4 microns different than the control arm, virtually identical to the control arm. So we had really good wet AMD control. So that's the other thing that when you -- if you looked at the secondary endpoints first, you'd say, boy, this drug worked great, should have hit the primary. Why didn't we? Well, we believe we didn't hit the primary, not because we didn't control wet AMD well. We did.

So what about other things like supplements? Supplement-free rate up to 6 months was over 70%, at 1 year over 50%. And 1 supplement, almost 80% of the patients at the end of the year had 0 or 1 supplements. The other our really great statistic here is 88% of the DURAVYU eyes got between 2 and 4 injections for the year, which means theoretically, one could control almost 90% of the wet AMD population using 4 injections or less.

So if you really ask the question, well, how many eyes get treatment extended to every 3 months now, even with the new second-generation drugs we have, it's not 88%. It may be 1/3 of that. So again, that really gives us confidence that we can be commercially successful. It does actually amount to approximately 2 fewer injections per year, hopefully, in the real world. So all of those secondary endpoints gives us confidence in LUCIA.

And we did another ad hoc analysis where we said, okay, let's just assume for a second that all the 16 eyes in the LUGANO trial that lost 15 or more letters. Let's just assume the randomization didn't work and let's randomly assign them 8 and 8 to each arm. And we did that 10 times. And every time we did that, we were non-inferior to the control and the difference was between 1.3 and 2.0 letters...

So sort of like rerandomizing the thing...

Yes, exactly. If you make the assumption that this just we got really bad luck, and let's divide the 15-letter losers in half. And remember, in DAVIO 2, there were more 15-letter losers in the control arm, but divide them in half, and we were non-inferior.

You said that the point estimate was in the 1.?

1.3 to 2.0.

Okay, 1.3 is essentially what you had at DAVIO.

A little bit more, but well in the non-inferiority range. And so that type of analysis, if one assumes that the control group is going to revert back to what it usually does and the actual numbers of letters lost is about the same for all these 15-letter losers, then we are quite confident we will be non-inferior. I have to say also, we've taken a look at the 10 to 15-letter losers. There were 6 in each arm. So there wasn't a big mismatch in the milder levels of visual acuity. It was only in the 15-letter losers.

Okay. And then did you want to mention the injection burden reduction, too, just the number?

Yes, it was a 42% reduction in treatment burden, which, again, better than expected. And that, again, is equivalent to about 2 fewer injections per year.

Right. Okay. And as far as the LUCIA data, that's the expectation is in a few weeks, I gather, or mid...

I would say -- yes, we're talking -- still we're saying publicly Q4. But again, if you add 2 months on to when we posted the LUGANO data, we'll be in that ballpark. Obviously, we need to accomplish the database lock and then do the statistical analysis, but we expect it relatively soon.

Okay. And as far as the -- like you mentioned the historical standards, I mean, this -- what you saw here in terms of the asymmetry was just very unexpected...

Unheard of. Yes, between 6x and 10x less 15-letter losers than had ever been seen in a 2-milligram EYLEA Phase III.

And since you just mentioned that there was -- it was balanced in the 10 to 15, that really that kind of further illustrates that perhaps there was just...

That's all we've got right now. That's all we can come up with. And certainly, the preclinical data doesn't point to any type of toxicity. We -- in rabbits, we dosed about 10x the dose equivalent that we've had in humans, and we never found a maximally tolerated dose. So it doesn't, again, appear to be related to the inserts or the drugs per se.

We had, again, 6 cases of GA that progressed into or near the fovea that caused some visual loss. But when you look at the overall group, no higher percentage of new GA. The rate of progression of the GA was less than what's been reported on average and essentially the same as the fellow eye.

And the LUCIA study is sort of identical in most, if not all respects to LUGANO, except there's a little bit of an ex-U.S. component.

Correct. We did end up recruiting more patients, 475 in the end. Dropout rate, again, Ramiro, similar, correct? Yes. So similar dropout at this point. The LUGANO trial was 100% recruited in the U.S. LUCIA is 80% U.S., 20% international.

Okay. So assuming you have a good result on LUCIA, which would be the expectation, how are you thinking about the submission? You have one positive study, one study that -- there were certain -- a lot of mitigants, although it didn't hit the primary. How -- what is the ophthalmology division going to do with that situation?

Ramiro, why don't you take that question?

Yes. So as soon as we would have the results from LUCIA, of course, we would engage with the agency for a discussion about our package. In ophthalmology, there are several precedents of submissions and drugs that got approved with one study being negative and then the other study being positive. And recent examples are Apellis with SYFOVRE and Outlook Therapeutics with a drug for wet AMD, so the same indication.

What is important for us is that the secondary endpoints go in the same direction. The safety profile is pretty good. So if we combine that with the LUCIA positive results, I think we are very confident that the agency would see this with good eyes, right? Because they don't look at this as a black and white thing. They look at the totality of the data, what is the unmet need for the patient. I think they do appreciate the unmet need of treatment burden, a therapy that brings similar visual outcomes with less injection. And I think they're going to see with good eyes our overall package.

And should we be anticipating any sort of combined/pooled work on LUCIA plus LUGANO or that's just something that you do later?

So for every single submission that you have 2 studies, it is very common to pool the 2 studies together. You don't necessarily need to show positive results on the pooled data, right? You have to show that the trend is similar. So we are going to pool for the submission, but we don't think that necessarily needs to be positive.

Okay. And if I could add, we don't know exactly where the numbers of difference in visual acuity would have to be for the pooled data to hit because we don't know the standard deviation, obviously, at this point. But the ad hoc analysis, which I mentioned, where we randomly assigned the...

The rerandomization.

Yes, the minus 1.3 to 2.0, I can tell you if we're in that range, we'll hit the combined almost definitely.

I would agree, considering I tried to run -- I ran some of these simulations in my...

What'd you get?

Very similar. Very similar. Okay. And then as far as -- so LUCIA later in the fall and the filing timelines, can you just reiterate what those are, please?

Yes. So I think, of course, with the results from LUCIA, we're going to have to discuss with the agency the overall package. Of course, now it becomes a little bit more just in terms of detail, the amount of data we have to include in the submission takes a little bit longer, but we're confident that we should be able to submit by first half of next year.

Okay. So you mentioned, of course, the very important data in terms of the treatment burden reduction, 2 to 4, essentially quarterly at worst, potentially even less. So just talk a bit about how you're going to position this to the retina community in terms of the ways in which -- because everyone is going to use it in a different way. There's going to be different strategies. People do different things, as we know, in the retina world. So just kind of maybe just enumerate how you see this playing out commercially in terms of the use cases or the types of patients that could be treated and just kind of go through that.

Sure. Of course, there was some -- obviously, whatever the label says is going to provide some limitation in the sense that if we're approved, we would expect a label something like wet AMD previously treated or treatment-naive after 3 injections of an anti-VEGF every 6 months. So I don't think doctors will use it more frequently than every 6 months because it won't be on the label and therefore, it would be unlikely that payers would cover it.

On the other hand, I think the way that doctors generally approach wet AMD schedule of injections, there's 3 ways we've done it for years. On label or let's call it, on a schedule, which is rare nowadays and has been from the start, frankly, we've individualized therapy from the start. PRN or as needed, that means you see the patient quite frequently, but you only inject when they're active. That's really kind of fallen by the wayside. There's not a lot of people who do that. And then, of course, treat and extend, which means you treat every visit, but you extend the time between the visits until you find what we refer to as the fluid-free interval and then generally you stick to it.

So I think those 3 methods will probably be the way doctors adopt it at least at the beginning. But it may be given that 88% figure of 4 injections per year or less, it wouldn't surprise me if doctors say, look, I want to take advantage of 2 MOAs, an extracellular ligand blocker and an intracellular receptor blocker and just put patients on a schedule. That may be the way it's done.

On the other hand, one could see it, an easy type of treat and extend where you're using both drugs and extending out the visits and injecting as kind of as you would in any kind of treat and extend type of program till you get out to 6 months between the DURAVYUs. And if the patient is doing well, some of those patients may stay at every 6 months. Of course, most retina specialists will tell you they like to see the patients more frequently. And then certainly, at the beginning, I think there won't be a lot of doctors who are going to be comfortable going every 6 months right out of the bat. I think they're going to want to see how the patient responds and get used to it.

But I think at the beginning, the surveys we've done and others have done suggests that most retina specialists are saying about 1/3 of their patients, they would use a sustained-release tyrosine kinase inhibitor on. And that probably will grow as they get confidence in the safety and how it works. And the low-hanging fruit, let's say, would be these patients who are being treated every 4 or 5 weeks, about 20% of the wet AMD population needs monthly treatment regardless of the drug.

So one could see even under the situations where you have a monthly patient 12 times a year and you put them on DURAVYU and at month 3 or month 4, there's a recurrence and you give them another anti-VEGF at that point. Well, all of a sudden, you've gone from 12 injections a year to 4 -- so even though that -- you might call it a supplement or rescue whatever an additional injection is given or 2 might be given, that's a big win for everybody. So that whole idea that supplementation means failure, not at all in the real world because what doctors and patients want is confidence in their vision and their anatomic control, but with fewer injections and visits. And we believe DURAVYU, if approved, can provide that.

Let's make sure we talk a little bit about DME too. So tell us about why -- DME is obviously a very different disease in terms of versus wet AMD. So maybe just discuss how the TKI works in DME, when we expect that data, how those trials are structured? And also a question that we've gotten quite a lot is -- which I think is pretty straightforward to answer is the risk related to DME given what we saw with LUGANO, but I imagine that's easy to be answered.

Well, let me start with, first of all, DME is a multifactorial disease, and we've known that for years. And if the disease is purely VEGF-mediated, like, for example, proliferative diabetic retinopathy, if you give an anti-VEGF and you see the patient back in 48 hours, that disease has stopped. And with DME, it can take multiple anti-VEGF injections to get it under control. And of course, corticosteroids work in DME, really work in wet AMD, another indirect evidence that's multifactorial.

So we believe that the JAK1 inhibition that our drug provides will provide additional benefit, especially in DME, where IL-6, which is activated through the JAK1 receptor, the IL-6 pathway has been implicated in DME by quite a bit of evidence, both indirect and direct at this point. So we think that, that potential advantage what is really going to help our DME results. And in fact, if you look at our Phase II DME trial, the VERONA trial, at day 1, the eyes were randomized and they either received an EYLEA or they received an EYLEA and 30 minutes later, they received our drug.

At week 4 at the first visit, the eyes that received our drug were already about 4 to 5 letters better than the EYLEA eyes, and they're about 40 to 50 microns drier. So that's our drug. And whether you say, well, it was a combination with the EYLEA, that's fine. I don't think doctors or patients will care. But if we can show that to be true in the Phase III, I think we're going to be able to capture quite a bit of the DME market, which is currently about a $3 billion market in the United States.

So our view is that the DME is further derisked by the LUGANO results and basically because 2 things: safety and anatomic control. Things like geographic atrophy obviously doesn't occur in DME. Sure, eyes can get a detached retina from any type of injection. But things -- other things that can happen in the DME population, remember, cataracts are twice as likely. We had no increase in the rate of cataracts and the safety of the wet AMD trials. So that the safety and the anatomic results give us increased confidence in the DME result. And we think that the market penetration in DME, if we're approved in both indications, is probably going to be higher.

And can you just sort of review the endpoints there for both...

Yes, Ramiro, do you want to talk about the DME trials?

Yes. So we have 2 Phase III studies fully enrolled for DME, COMO and CAPRI. They are also identical studies, U.S. and international. The design is that on the control arm, patients get the 5 loading dose, which is only aflibercept and then every 8 weeks. For DURAVYU, they get DURAVYU at day 1 because we want to show the benefit of JAK1 inhibition starting day 1. And then they get 3 loading dose and then DURAVYU every 24 weeks. The primary endpoint is change from baseline in BCVA to week 52 and 56, which is the same time point for wet AMD study. Again, the studies are fully enrolled. We expect the results sometime end of next year.

And just so everyone is clear, this is also a non-inferiority trial or...

Right, so non-inferiority with the same non-inferiority margin of 4.5...

That's right.

4.5 letters.

Okay. And is it also going to be -- I don't know if you've discussed this yet, but is it going to be a staggered readout COMO and CAPRI are they coming together?

So the enrollment was done simultaneously. So the results will likely come together.

Okay. By the way, going back to what you were saying before about some of these downstream analyses you were doing on LUGANO. Should we be expecting those -- to see those before we see the LUCIA results? Or just so we have some sense of timing that we know?

Yes, yes. Shortly.

Okay. Very good. Why don't we spend a little bit of time talking about your manufacturing because obviously, that's an important piece of the puzzle, a very important piece of the puzzle, and you're in very good shape there. So it would be good to understand how that's going along.

Yes we are. George, do you want to talk about the rationale behind us doing our own manufacturing and where we stand with it?

Sure. So just to remind everyone, we actually had our state-of-the-art facility built to our spec several years ago. We've been in the facility for almost 2 years now. And if you look at NDA submission as an example, everyone is focused on clinical data, obviously, but CMC is just as important. And I'll remind the audience that most CRLs happen with CMC, and we know that our team knows that. So that facility has been in motion, in process of scale-up to support a potential commercial launch. And so we have production batches on stability, registration batches on stability and the team is now gearing up for the commercial production at scale. So it's been quite a remarkable process. And just from a competitive and an IP perspective. So while we -- yes, we do have very good IP around DURAVYU, know-how is just as important. And so we were very focused on making sure we control the production of those inserts, and that's all done at our facility in Massachusetts.

I will add, obviously, the scale is really, really important. If you need to make 10,000 inserts a year for a Phase III trial, you need to make 20 or 30x that for commercial success. So in order to do that, our manufacturing operations and our R&D folks have been working really, really hard to essentially automate and semi-automate the entire process. So the example I've talked about is in the past, we hand inspected every insert. A human picked them up with tweezers under a microscope, weighed them, measured them, visually inspected them. It's all done by robot now, much faster, much less breakage.

And so the lot size have increased tremendously and the yields have increased tremendously. And we're quite confident that should we be approved, we -- even under the best circumstances, we're going to be able to supply DURAVYU with this facility, at least for several years after launch, although we've got plans, again, if launch is successful, we will probably in a few years, need to build a second facility.

Okay. Just in the last few minutes, just give us a quick snapshot on the cash, please. And also, we're asking all the companies this now with the world of AI, just to what extent are you using AI tools in your processes either with regard to FDA submissions or analyzing data or any ways that you're more efficient internally? Just any sort of just brief perspective there would be helpful.

Yes. So from a cash perspective, so our cash guidance has actually been unchanged for probably a year now, which is into Q4 of '27 when we ended June with $180 million of cash. Obviously, that gets us through all 4 data readouts. But clearly, we'll have a number of catalysts between now and then to potentially top off our cash. From an AI perspective, I think we are, like most companies our size, looking at it cautiously. I think we're very protective to ensure that none of our data gets into the public domain to train any of these programs. But I think from an efficiency perspective, we -- it's being used in certain corners, but not wholesale yet as a company.

Okay. All right, Jay. So any closing comments just overall in terms of how you want to position things and just reiterate the confidence ahead as we look to the LUCIA results?

Yes. So again, while obviously, we were disappointed in missing the primary endpoint, the ad hoc analyses all point to strong activity, safety and durability of our drug, along with the secondary endpoints. And so again, looking at the control arm and the likelihood that we should revert back to the average rate of 15-letter loss in the control arm strongly suggests to us that LUCIA is likely to be positive. And if it is positive, we believe we have a clear pathway to approval and then a very clear pathway to commercial success.

All right. Well, that's great. We're looking forward to seeing those results maybe around Halloween, something like that. All right. Okay. Well, thank you very much.

Thank you.

Ladies and gentlemen, thank you for standing by. Welcome to EyePoint LUGANO Top Line Data Readout. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to Dr. Jay Duker, President and Chief Executive Officer of EyePoint. Please go ahead.

Thank you very much. Good morning, everybody. Thanks for giving us your time this morning. I'm pleased to report the Top Line Data from the first of our two Wet AMD pivotal trials for DURAVYU, the vorolanib intravitreal insert.

These are our legal disclaimers, and this is the agenda for today's meeting. EyePoint is a leader in sustained drug delivery for retinal disease. We are currently in two Phase III programs in the two largest retinal disease markets, Wet AMD and Diabetic Macular Edema.

Beyond today's discussion, we also have multiple potential catalysts over the next 16 months, including LUCIA Phase III data, a potential Wet AMD NDA filing, DME Top Line Data expected in about a year. We have had excellent execution in our four Phase III trials with rapid enrollment and a commercial cGMP facility in place for our U.S. launch.

DURAVYU has significant advantages, and we believe it represents a differentiated program. We have broad clinical programs, as I've already mentioned, Wet AMD and DME. We show a very favorable safety profile. Our trial design is clinically relevant. And one potential advantage is this multi-MOA mechanistic edge that RTKI may show in clinical trials. We not only block all the VEGF receptors in PDGF, but we also block the JAK1 receptor, which gives us the ability to block the downstream effects of IL-6. Our Durasert technology has been approved in four prior FDA products.

This slide shows you at the top, our Wet AMD program, at the bottom, the DME program. And today's focus is on LUGANO, the first of two Phase III Wet AMD programs. This is the design of both LUGANO and LUCIA trials. In LUGANO, we enrolled 432 patients. They were randomized to two arms 1:1 DURAVYU 2.7 milligrams or on-label Aflibercept control. This is the first study that looked at repeat dosing of DURAVYU. It was given every 6 months. The primary endpoint is 1-year efficacy and safety. The studies are planned to go on for 2 years for safety.

The primary endpoint of both studies is non-inferiority mean change in vision from day 1 to average week 52, week 56 versus the Aflibercept control and the non-inferiority margin is minus 4.5 letters. Key secondary endpoints are listed on this slide as well.

This is the schematic of the study. A couple of things I'd like to highlight. First of all, all of the eyes in the trial were loaded with monthly Eylea. At week 8, the eyes that were randomized to DURAVYU got a DURAVYU injection about 30 minutes after their third Eylea. DURAVYU was then redosed every 6 months, while the Eylea control was redosed every other month.

The reduction in treatment burden calculation is performed after the Eylea load. And note that the week 56 injections don't count. They're in the second year. And therefore, by design, the DURAVYU eyes each will receive two DURAVYU in the first year after the load, and the Eylea eyes should receive five Eylea after the load.

And here are the results. First of all, baseline demographics, nothing really to note here. As is true in most Wet AMD trials, it's predominantly a female population. We enrolled both treatment-naive and previously treated eyes in about a 75:25 ratio.

And the previously treated eyes were a heavily pretreated group with, on average, over seven injections a year leading into the trial. For those of you who recall the DAVIO 2 previously treated cohort, they came in with more injections. But remember, in DAVIO 2, injections were given right up until the time of randomization. In this trial, none of the eyes could have been treated with an anti-VEGF within 8 weeks of screening.

Further baseline characteristics, best corrected visual acuity, DURAVYU eyes started about 11.5 better and the total CNV areas was a little bit larger in DURAVYU. The larger the CNV in general, the worse the eyes will do, but analysis so far do not suggest either of those factors played into the results.

I have highlighted a couple of things in the medical history. First of all, about 25% of the DURAVYU eyes gave a history of having Dry AMD going into the study versus about 22% of the Aflibercept arm, but almost twice the number of patients in the DURAVYU arm gave a history of having Glaucoma.

This slide shows the top line results. We believe that LUGANO demonstrated clinically meaningful results that reinforce its potential of DURAVYU to improve the treatment paradigm in Wet AMD. When DURAVYU was studied for non-inferiority, by excluding an asymmetric cohort of only nine eyes or 4%, DURAVYU was non-inferior. However, in the full data set, confounded by these nine asymmetric patients who experienced visual loss greater than 15 letters from non-Wet AMD etiologies, DURAVYU was not non-inferior.

When looking at the secondary endpoints, 42% reduction in treatment burden through week 56. Remember, the ceiling was 60%, and this was highly statistically superior to standard of care. About 76% of the eyes in DURAVYU were supplement free up to week 32. That was 6 months after the first DURAVYU went in. 54% remained supplement free through the end of the first year, meaning over half of the eyes in the DURAVYU arm were controlled exclusively by DURAVYU. Anatomic control was excellent. The CST difference at week 56 was only 4 microns, and we showed continued favorable safety profile.

So let's look at the visual acuities first. What you're seeing on this slide is the graph of the visual acuities, the top gray being the control arm and DURAVYU is in purple. And you'll see when we excluded this asymmetric cohort of nine eyes, DURAVYU was non-inferior to on-label Eylea.

So who are these asymmetric cohorts? Remember, these are elderly patients, and they can lose vision for reasons other than Wet Age-related Macular Degeneration. That is to be expected. In the DURAVYU arm, however, nine patients lost greater than 15 letters of vision due to non Wet AMD etiologies. That included six patients who lost significant vision from Geographic Atrophy, Dry AMD, two patients lost vision from Glaucoma and one lost vision following a retinal detachment.

Interestingly, all nine showed good anatomic control of their Wet AMD, and six of these nine eyes received a supplement at some point in the study, but none of the supplementation improved their vision. These nine eyes accounted for a total of 258 total losses of letters.

Why are we calling this asymmetric? Because in the Aflibercept control group, surprisingly, none of these eyes lost more than 15 letters due to a non-Wet AMD diagnosis. So looking at the graph up right, the dotted line is the DURAVYU eye's visual acuity results when the nine asymmetric eyes are removed. Notice about 5-letter improvement that is maintained throughout the trial.

The solid purple line is the visual acuities of the nine patients who lost vision due to non-Wet AMD diagnoses. Notice they never really gained vision, and they steadily lost vision throughout the trial.

When looking at their anatomy, what's surprising at first glance is that their OCTs were actually thinner than the rest of the cohort. The cohort overall showed good control of fluid. But when you think about it, Geographic Atrophy is atrophy. And it's no surprise that those nine eyes were actually had thinner maculas than the rest of the cohort. This was not due to active Wet AMD, however.

This slide shows the full data set showing that the primary endpoint was not achieved. There was approximately 3.8 letter difference between the two groups. Recall, if the nine eyes were removed, it dropped to a 2.4 letter difference. The bottom graph is the CST on OCT central subfield thickness and notice again, at the end of the trial, there was only a 4-micron difference.

So why are we calling this asymmetric? This slide shows you the number of 15 letter losers that occurred in prior studies that involve 2-milligram Eylea. And you can see looking at the right side of this chart, it covers around 4% to 5% and averages about 4%. In LUGANO, at the bottom, it was only 0.5%. So this was highly unusual in an elderly population that there weren't additional patients who lost significant vision due to non-Wet AMD diagnosis.

So what did our preliminary evaluation conclude about this? So the first question is, was this asymmetries in adverse events? Is that what resulted in the visual outcome result? And the answer appears to be no. Cataracts were evenly balanced between the two arms. Intraocular pressure increase evenly balanced. We had very little intraocular inflammation or IOI, only one patient in each group and the IOI was not severe. These are investigator-reported percentages of Dry Age-related Macular Degeneration. And you can see while no statistical difference, there was a trend for more Dry AMD overall in the Aflibercept arm.

There was one patient in each arm that had a detached retina and that percentage is typical for this type of trial. However, the eye that had the detached retina in the Aflibercept arm gained a letter. The eye in the DURAVYU arm lost 40 letters that appears to be due to the onset of a cataract in an epiretinal membrane unrelated to wet AMD.

The second question might be, were these eyes undersupplemented? Did our supplement criteria cause the result? And the answer appears to be no. Supplementation worked as expected. The top line of this graph on this slide represents the visual acuities of DURAVYU patients who received a supplement, without the nine asymmetric patients. You can see at top left, the visit prior to supplement, these patients had about a 3-letter gain in their vision. But at the supplement visit, they were minus 2 letters in their vision, which is about a 5-letter difference, which is exactly what we tried to capture in our supplement criteria. By the second visit post supplement, the eyes were back to where they were a month prior to supplementation.

The bottom graph is the patients in the nine cohort who got supplemented. It was only six. And presumably, the other three did not get supplemented because the investigator deemed that the visual loss was not due to a VEGF-mediated disease, not due to Wet AMD, and therefore, supplement wouldn't help. And in fact, the visual acuities that the supplement visit in these eyes were already down 14 letters. You notice what happened post supplement, essentially no change in the visual acuity, confirming that this visual loss was not due to Wet AMD.

How about Geographic Atrophy? Well, I already showed you the investigator's assessment of Geographic Atrophy. What you're seeing here is the reading center assessment in a masked fashion. At baseline, the two groups were evenly matched with geographic atrophy, 8% in DURAVYU versus 10% in control. At the end of the trial, no surprise, this happens in Wet AMD eyes. There was progression of geographic atrophy.

Numerically, however, it was higher in the control arm and therefore, suggesting that DURAVYU showed no trend of worsening of Geographic Atrophy. So we conclude that neither the supplement criteria or any DURAVYU-induced AEs drove the primary result.

How about the secondary endpoints? So let's talk about reduction in treatment burden first. And again, we had a 42% reduction in treatment burden. This averages to about 1.1 supplement injections per year in the DURAVYU eyes. But from a clinical perspective, if this drug is approved and available to clinicians, they might expect two fewer injections per year in their DURAVYU patients, which we believe would be an outstanding result for patients with Wet AMD.

The supplement-free rates demonstrate our potency and durability. Up to week 32, that is 6 months after the first DURAVYU, 76% of the patients were supplement free and 96% had received only 1 or 0 supplements with 99% getting 2 or fewer supplements. At the end of the first year, it was 54% supplement free with almost 80% getting either 0 or 1 supplement. At week 56, almost 90% of the Wet AMD eyes that were treated with DURAVYU were stable with 2 or fewer supplements. That is four injections annually or fewer controlled almost 90% of the Wet AMD eyes.

This slide shows you the subgroup analysis for the unsupplemented eyes in both DURAVYU and control. This was over half the population, 54%. And you can see in this subgroup, DURAVYU was non-inferior to on-label Aflibercept with only a minus 1.8 letter difference. And again, looking at the anatomic control, it was excellent with only a 3-micron difference at week 56. So this slide also helped to show that our supplement criteria appeared to be adequate.

If you believe that some of these unsupplemented eyes were losing control on DURAVYU, then you would have expected the OCTs to get worse as the study progressed. And you can see that they didn't do that. They remain stable. So both stability in vision and stability in anatomy in over half the eyes with our drug alone.

So anatomic control, you've seen these graphs already, but just to reiterate, a 4-micron difference at week 56 with the typical sawtooth pattern that we see with every other month Eylea and lack of a sawtooth pattern in DURAVYU.

Safety. AE profile, we believe, confirms a favorable safety profile with repeat dosing. We had no cases of insert migration into the anterior chamber, no anterior chamber opacities, no free floating drug particles were observed, no cases of retinal vasculitis, no cases of severe IOI. And in fact, as I already mentioned, there was only one case in each arm of IOI. And in the DURAVYU arm, it was treated for 2 weeks with topical medications and got better. Less than 1% rate of retinal detachment in endophthalmitis in each arm.

There was a mismatch in floaters, but all cases of floaters were mild or moderate and didn't require treatment or have any impact on vision. And as we previously reported, there was a low discontinuation rate of about 6% in each arm. This is the entire AE chart for all adverse events that occurred over 2%. As I mentioned, we had about 2.5x the rate of floaters as Aflibercept, but they really didn't cause any visual decrease. None of the patients reported wanting to have the inserts removed, really didn't seem to be an issue with repeat dosing. We will be digging into that a little bit more. But based on the temporal association, we think that some of these floaters were probably visualization of the insert.

Neovascular age-related degeneration, you'd expect with more supplements, we would have a higher rate, and that accounts also for the Retinal Hemorrhages, the Retinal Edema and the Subretinal Fluid. Those are all events that one would see with active Wet AMD. Notice again, no cataract intraocular pressure, Dry Age-related Macular Degeneration, no difference.

So what are our conclusions? First of all, we believe these results are clinically meaningful and potentially impactful commercially if approved. While we didn't hit the non-inferior margin in the total population, we were non-inferior when we excluded this asymmetric cohort of nine eyes who experienced severe visual loss unrelated to Wet AMD. We believe this study shows favorable safety profile with redosing, 42% statistically superior to standard of care reduction in treatment burden. 80% of the eyes could go up to week 56 with 0 or 1 supplement and the anatomic stability was excellent with only a 4-micron difference, confirming both our potency and our durability.

So why do we have confidence? Well, first of all, we showed that half the patients could be supplement free at 1 year with stable vision and OCT, which potentially means 50% of the Wet AMD patients out there could receive just two injections a year of our drug showing stable vision and anatomy. This evidence gives strong potency data and durability data based on the OCTs.

This is the first TKI to show a vision gain in Phase III. And in the totality of the results, we believe we have demonstrated the potential to change the treatment paradigm.

We also have a lot of confidence in LUCIA. The strength of the ad hoc analysis and the secondary endpoints gives us confidence in hitting the primary endpoint and the secondary endpoints in the upcoming LUCIA trial. We expect to show that data in the fourth quarter of this year.

So if positive, we expect to engage the FDA in a discussion of our Wet AMD data package, and we hope to submit that in the first half of 2027, and we look forward to advancement of the DME program with both pivotal trials reading out in Q4 of '27.

Thank you very much, and happy to entertain any questions that you may have.

[Operator Instructions] Our first question will come from Tessa Romero with JPMorgan.

So I wanted to ask a regulatory question here. What are the pushes and pulls that we should be thinking about around approvability potential as we think ahead and your expectation to file in the fourth quarter. Isn't it the case that you will need two positive non-inferiority trials to file? And then I have one follow-up.

Yes. We don't believe that, that will be necessary. As I'm sure many of you are aware, there are at least two instances that we're aware of in the ophthalmic division of the FDA, where there were approvals of a drug with one Phase III that was positive and one Phase III that was negative, the Apellis drug and Outlook.

And there are a myriad of other studies like this outside of ophthalmology with approval. Also, remember that just a few months ago, the agency updated their guidelines around single trial approval. And what was important with a single trial is supportive results on distinct prespecified secondary endpoints. I think we showed that. Consistency among the subsets, I think we showed that, high-quality conduct with missing minimal data and a mechanistic MOA that directly targets the major driver of the pathophysiology. So I think if LUCIA is positive, we're going to have a strong package to submit to the FDA, and we are confident that if LUCIA is positive, that the FDA will look very favorably on the package.

Okay. And just as a follow-up here, what gives you confidence that you won't have a confounding cohort in LUCIA as well?

Well, I think, again, looking at the data, having eyes in an elderly population that lose vision from Geographic Atrophy, which is unrelated to Wet AMD therapy or other diagnosis is not unusual. Having none of them in the control group is highly unusual. And so again, those type of diagnoses, additional anti-VEGFs don't stop glaucoma. They don't stop the cataract after retinal detachment repair. And so what we would expect is not that these would not occur at all in LUCIA, but they would be balanced.

And had they been balanced, then we would have hit the primary. Now I didn't show a slide on this, but we've already done an analysis like that, where if we had taken all the 15 letter losers and just split them evenly between the two arms. And did that randomly, and we did that over 10x randomly and each time we were non-inferior. So we believe that it's likely that this was due to chance alone and that we won't see a similar split in LUCIA.

But beyond that, if you just look at the efficacy and you look at things like the control of the anatomy, our drug did a great job controlling it. If you look at the supplement free, 54% were treated with our drug alone with non-inferiority change in visual acuity and excellent control of the anatomy. We have a highly potent drug that is durable. And that if approved, we believe doctors will welcome its use, and we believe this can really help a lot of patients if approved. So we're going into LUCIA with a lot of confidence.

And the next question will come from Faisal Khurshid with Jefferies.

Can you just confirm the outcome on the primary endpoint, including what the bottom range of the confidence interval was for BCVA in the ITT population?

I'm going to ask our Chief Medical Officer, Ramiro Ribeiro, who's here with me to comment on those numbers.

Faisal, so when we look at the full analysis set, including all patients, the difference in BCVA was about 3.8 letters and the confidence interval crossed the 4.5 letter at about 5.7. What is very interesting is that when we remove the nine patients, again, this is only 4% of the patient population, then the difference between the groups is 2.4 letters. So those nine patients represent 1.4 letters. And then we are below the 4.5 confidence interval for the non-inferiority.

So again, I think this represents compelling evidence that the effect of those 4% patients driving the results. And then one very interesting analysis that we have done also instead of looking at the mean change, we look at the median change. And again, with that type of analysis, we also observed the impact of these extreme values. And then with the median analysis, we also show non-inferiority against only Aflibercept.

Got it. And then just as a follow-up. So does that mean that like for that 2.4 number that the bottom end of the confidence interval for that was like pretty close to 4.5. And if so, how should we think about that going into LUCIA considering that like past precedent and what AMD has shown variability between identical trials?

Yes. So I wouldn't call it very close. It was around -- I think our limit was around 4. And so I don't think that's very close. And so obviously, if we get that result in LUCIA, that would be favorable.

The next question will come from Sun -- I'm sorry, Yatin Suneja with Guggenheim.

Thank you, Jay, for walking us through in details. I mean, definitely, those nine patients, a little bit unlucky on those nine. I mean remarkable control on OCT. So the question I have for you is maybe just repeat, if you could. When physicians treat, how do they -- like what is more relevant to them? Is it the OCT or the BCVA?

And then with regard to the FDA, are you going to have an interaction with them before the next study reads out just to get a sense of how they might be handling these nine patients? If at all, would love to sort of get some clarity on the FDA front, how they will treat this study in terms of those nine patients?

And then what about the previous DAVIO studies, right? Could those be used as a supporting evidence even though the patient population was different? If you can maybe just sort of frame the full package for us.

Sure. Let me work my way backwards. Yes, the full package will get submitted and so DAVIO 2 will be confirming evidence, especially vis-a-vis the safety.

So the second question you had was about regulatory interaction. It's too early to really have a clear pathway. Obviously, we've been working diligently over the last few days since the study was unmasked to understand the results. And we will, in the future, have a more clear path and discussions with the FDA, but it's too soon to know that.

As for how we treat in the real world, I think Tarek Hassan, Tarek, if you're here, can you say hello? Are you on the call?

Yes, I am, absolutely.

Tarek, so you're obviously still a highly regarded, very busy practicing retina specialist. The question was, when a patient comes in for a visit with Wet AMD, what's more relevant to you, anatomic control or visual acuity?

Well, it's obviously both. When we think about the things that we can control within the bounds of a treatment that we may have in our hands, it's ultimately really the anatomy that we have the most impact upon that. So we deliver the drug to do the best we can with the disease at play, in this case, Wet AMD. So we want to dry the eye as much as possible. We want to control the growth of the wet AMD lesion. We hope it translates into a visual improvement, which it does in most cases, when the primary driver of vision loss is that.

Of course, we care about vision. It's just that so many other confounding things like we saw in this trial, for example, can affect the vision, and that's out of our hands. We wish we had more drugs and more therapies for these other things. But in short, we care about both, but we have in our hands, something that we can try to fix anatomy, and we hope the vision correlates.

And the next question is going to come from Steve Seedhouse with Cantor.

I had two. The first one is just are you planning to amend or update the statistical analysis plan in LUCIA just to prespecify this type of secondary analysis, excluding these etiology patients just to build some perspective sort of credibility for the case that you'll ultimately make to the FDA?

I'm going to ask Ramiro to answer that question.

Yes. Thanks, Steve. I think it's very fair to take some learnings from the Phase III study and then apply for an upcoming Phase III study readout. So we're typically going to spend the next 2 months looking into the LUGANO data, trying to learn as much as possible so that we can apply any learnings into the LUCIA readout.

Okay. And then, Jay, I think I heard you mention in response to a prior question that the cost margin for the confidence interval was about 4 letters associated with that 2.4 letter difference in that ad hoc analysis.

But when you exclude the nine patients, obviously, that are outliers, presumably that reduces the variance quite a lot in that subgroup. So how much did that affect sort of that 4-letter outcome? And when you did that simulation, I think you mentioned splitting up those nine patients across the two arms. In that -- in those 10 simulations, how close does the non-inferiority margin get to the 4.5 letter threshold?

Yes. Good question, Steven. And again, I'm going to ask Ramiro to address them.

Yes. So let me just recap the first. On the full analysis set with all patients, the difference between DURAVYU and Aflibercept was 3.8 letters and the lower bound of the confidence interval was 5.7. Once we remove those nine patients that lost vision not because of wet AMD, then the difference between DURAVYU and Aflibercept was 2.4 letters and the confidence interval, the lower bound was 4 letters.

Once we did all those simulations that Jay referred to, where we split in half the patients that lost 15 letters, of course, varies a little bit, but then the confidence interval for all those 10 simulations was less than 4.5 letters as low as 3.7. But of course, on those 10 simulations, it varies a little bit.

And our next question will come from Yigal Nochomovitz with Citigroup.

I wonder if you could spend a little more time just explaining the mechanics of how you came to identify these nine patients that contributed to the highly asymmetric analysis. Can you just kind of walk through what the process was there to find them?

And then can you also talk about what you plan to do with respect to any pooling of data for these two studies, assuming LUCIA is positive, what types of pooled analysis might we expect when LUCIA reads out? Or would that only be later?

Sure, Yigal. No, happy to address both. So when we first took a look at database lock of the masked data, overall, the group showed about a 3% or so rate of 15-letter loss, which is right in line with what we would have expected and maybe even a little lower than what we saw historically in these trials.

When we unmasked, of course, we realized that the 15-letter losers were highly asymmetric and mostly in our arm. So then we did an analysis of them, including the 15-letter loser in the Eylea arm, which was, first of all, was this 15-letter loss due to continued activity of Wet AMD? And the answer was very few.

The second group was, did these patients lose vision due to Wet AMD, even though the control was good. And the answer was, again, very few. That happens. You can control the anatomy, win the war -- win the battle and lose the war because of various reasons. But in those small number of eyes, I believe it was three, the anatomy was well controlled, but the visual loss was due to Wet AMD.

Then the other nine eyes, of which there were none in the control arm lost vision with well-controlled Wet AMD due to other things. Six, again, geographic atrophy, two due to glaucoma and due to the detached retina that while was reattached, had significant decreased vision due to cataract and epiretinal membrane.

Looking at the GA patients, and we've showed them to some KOLs now already, and I think they agreed that all of them had GA at the beginning of the trial. And we will be looking more closely at the progression and the progression of GA, not in the 15-letter losers, but in the other patients to try to determine was there asymmetry or not.

But at least on a population basis, based on the reading center assessment of Geographic Atrophy and the investigator's assessment of dry AMD, there does not appear to be a difference between the groups. And in fact, on a numerical basis, we noted higher numbers in the control arm. I think your second question was about pooling, correct? Ramiro, do you want to answer that one?

Yigal. So as part of any NDA submission with two Phase III studies, one of the ask is always to pull the two studies together to again show the consistency of the results and then you submit to the FDA.

I think when we think about LUGANO, as Jay mentioned, we unfortunately have those nine patients. But other than that, the data looks very consistent. It makes sense clinically on how those nine patients behave and how they affect the data. So if LUCIA is successful, then we would certainly pull the data to show the overall benefit of DURAVYU.

Okay. And I'm just curious, have you done sort of the downstream calculation figure out what you would have to show from a lower bound of the non-inferiority confidence interval and the point estimate for BCVA in LUCIA such that when you take the ITT populations for both studies, pool on a pool basis, you would generate an overall positive result globally for both trials. Is that a calculation you've done or plan to do?

I think we need to look into that a little bit more. We don't have that precise calculation at the moment. I think you can look at kind of a range, which would be positive, but we don't have those exact numbers right now.

And our next question is going to come from Graig Suvannavejh with Mizuho.

I don't believe we've touched upon the debate around the contribution of treatment-naive patients versus treatment-experienced patients? And were you able to see anything within those nine patients that could be attributed to this difference? If you just comment on that dynamic?

And then the second question is probably a bigger picture question, which is given this data set and maybe given the data set from your rival competitor with their first Phase III data, how should we be thinking about overall the TKI class? Any thoughts on how maybe differently or not you're thinking about this class in general?

Sure. So the second question, I think I'll take first, which is TKIs work in Wet AMD. This is now, I believe, the ninth trial that has confirmed that there's biologic activity, durability and the ability to control the anatomy using TKIs. If there are multiple TKIs that are approved, I think that there's certainly room in the market for that, but I would think that label and safety are going to be the things that would set us apart. I think that based on the safety that we've shown and the potential for label since -- obviously, we went up against on-label Eylea, I think that, that would have the ability to set us apart.

Your first question about the breakdown. In the nine patients, six of them were naive and three of them were previously treated, which is obviously consistent with the whole cohort. When we did subgroup analysis of the whole cohort, we -- there was not a big difference in the result between the naive or the previously treated. So we don't think that one group necessarily drove the Top Line results.

And the next question will come from Annabel Samimy with Stifel.

I want to clarify one point. Can you just tell us the treatment burden reductions in the rescue-free rates? This is based on the total population or also excluding the asymmetry?

And separately, given, I guess, there's always been a little bit of subjectivity in BCVA related to various reasons. To what extent does FDA weigh anatomical control of Wet AMD more so than BCVA? And are there examples of this in past wet AMD studies beyond the TKIs? I know that KOLs value OCT tremendously, but I'm just curious to know how FDA treats OCT and weighs it against BCVA in this kind of scenario.

Sure. So the first question was the secondary endpoints. All of those secondary endpoints that we showed you included the nine eyes, including the supplement-free subgroup analysis. The nine eyes were included. Of course, only six of them -- I'm sorry, three of them had not been supplemented.

So that 1.4 letter difference you saw in the non-supplemented eyes between us and the control group would have been 1.1 letters if those three outliers were not included. But to answer your question directly, all the subgroup analysis was the entire population, including the nine.

So the FDA really since the beginning of OCT 30 years ago has said that anatomic endpoint for diseases like DME and Wet AMD is the secondary, it's not the primary endpoint. But it needs to corroborate things.

I mean the FDA understands what the anatomy control means. There isn't a direct necessarily correlation between visual acuity and anatomy. There is a correlation, but it isn't 1:1. And therefore, it's strong corroborating evidence that we have potency and durability to show this type of an anatomic result. But that in and of itself doesn't get us to approval.

And the next question will come from Debanjana Chatterjee with Jones.

I have a couple. So were there any additional DURAVYU-arm patients with sub 15 letter losses, I mean, like between 8 to 14 letters that can be attributed to the same non-Wet AMD etiologies who fell below the cohort threshold and remain inside the -- like the 202 patients that -- excluding the asymmetric cohort comparator line?

Thanks for the question. Excellent question. We haven't had time to analyze that yet, but we certainly will.

Sure. And can you also confirm the six patients who did receive supplemental injections with no visual acuity improvement, was the OCT fluid confirmed fully resolved and stable at the visit immediately preceding each of the patient's vision decline or only at some point during the follow-up?

I don't know the answer to that off the top of my head about the presence or absence of fluid before. I believe in the geographic atrophy patients, at least some of them did get a supplement. And early in the trial, it may have been due to active Wet AMD, but not at the end of the trial.

And so that is, again, I don't want to -- we're going to need to go through carefully and look at each of those cases. So to answer the question, I think what you're getting at is, were some of those nine supplemented from Wet AMD. And I think the answer is probably yes. But that didn't lead to the visual loss because the control was excellent.

And I have one last follow-up. Do you see any read-throughs to COMO and CAPRI trials in DME? Is there any changes you would implement to the trial design there?

Well, certainly no trial design changes. I don't think the trial design played any role here. But I'm even more optimistic about our role in DME. There's no Geographic Atrophy in DME. That doesn't happen. And so you don't expect to see any kind of asymmetry there. And our Phase II DME visual results were even stronger and OCT results are even stronger.

So that I think this really derisks the DME diagnosis even more because look at the safety, look at the efficacy with respect to treatment burden, look at the efficacy with respect to anatomic control. All of this points to a potent drug with durability that's safe. And so all of that, in my mind, in our mind, really derisks the DME program as well, frankly, as we've said already, derisks the LUCIA result.

And the next question will come from Yale Jen with Laidlaw & Company.

I'd just like to get some sense of any difference in terms of patient baseline or other characteristics, for example, where the patient was enrolled and treatment naive versus treatment experience between the LUCIA and LUGANO study, so we get a better sense of any expectation or handicap.

I'm going to let Ramiro talk a little bit about baseline imbalances and whether there's anything necessarily that might be gleaned about LUGANO.

Yes. So first, on the LUGANO study, as Jay mentioned, we saw some small imbalances at baseline on BCVA, but those get adjusted in the model and didn't have an impact on the primary endpoint.

The LUCIA study in comparison to LUGANO, the study design is very similar, exactly the same. The only difference is that we had in LUGANO 100% of the patients coming from the U.S. LUCIA, 80% U.S. and then 20% outside of the U.S. So in terms of baseline characteristics, and we presented this at a conference earlier this year, we should expect them to be similar between the two studies.

And the next question is going to come from Lisa Walter with RBC Capital.

Maybe a couple here on LUCIA. Jay, if you plan to file with LUCIA alone, could the FDA require a more stringent non-inferiority margin for one trial versus two?

And then just on the rescues, wondering if you can give us a little bit more color here and give us a sense of the cadence of rescues, if they are occurring closer to the start of the trial or maybe closer towards the end -- towards the primary endpoint. Any color here would be helpful.

Yes. So first of all, I don't think there's anything to suggest that one trial versus two changes in non-inferiority margin. statistically, that wouldn't make any sense. And I don't think there's any data that would suggest that.

As for the cadence of the rescues, we talked about this going into the trial that the top line primary endpoint was going to be total patient population, but the FDA has asked us to do sensitivity analysis around the rescue eyes. And none of the sensitivity analysis was there a higher penalty paid for late rescue versus early rescue. So we haven't done a real analysis on that yet.

And frankly, I'm not sure it's really going to be helpful to do so. I think you can glean from the number of eyes that only received one rescue at 8 months versus the number of eyes that only received one rescue at 56 weeks, that there wasn't a lot more rescues weighted towards the end. But again, not sure that, that data is anything that either the agency or anybody should make any deal about.

If there are no further questions, then I'd like to conclude with just a few more remarks. First of all, obviously, the totality of the result was not exactly what we hoped for. DURAVYU showed that it's got the potential to change the treatment paradigm in Wet AMD. The safety is strong. The anatomic control was terrific and over half the eyes were controlled through the end of the first year exclusively by DURAVYU. In those non-supplemented patients, they were non-inferior to on-label Eylea.

As we really look closely to all of these results, we remain highly confident that DURAVYU has the potential to evolve into tomorrow's standard of care. And I want to thank all the LUGANO investigators and the patients who entrusted us to preserve their vision.

I also need to thank our team here at EyePoint. They are extremely talented and hard-working, but I especially want to mention Ramiro's clinical team, Robin's IR team, our IT team and our entire executive committee who really performed at the highest level with the unmasking of the data. We have a lot more to come, and we're really optimistic about the future. Thanks, everybody.

This concludes today's conference call. Thank you for participating, and you may now disconnect.

Great. First, welcome to Jay Duker and George Elston from EyePoint Pharmaceuticals here at the 47th Annual Goldman Sachs Healthcare Conference. Welcome, gentlemen.

Thank you very much.

For those in the audience and listening who may be newer to the story, can you start at a high-level overview of EyePoint say, core clinical programs that are advancing and key milestones that you have investors.

Sure. Happy to answer that question. And again, we really appreciate the invitation. So EyePoint is a drug delivery company for the back of the eye. We hope to improve patients' lives who have serious retinal diseases. Our lead product is called DURAVYU or EYP-1901. It's a combination of a small molecule tyrosine kinase inhibitor called vorolanib and our proprietary bioerodible delivery system. Vorolanib is a bit unique because it has activity against all the VEGF receptors. Again, it is a receptor-based treatment as well as PDGF.

And we also block the JAK1 receptor, which means we have an anti-inflammatory effect, which does appear to be important in retinal diseases. We are currently in Phase III in the 2 largest retinal indications, wet age-related macular degeneration and diabetic macular edema. The wet AMD trials are called LUGANO and LUCIA. They are traditional non-inferiority trial endpoints. And the first trial LUGANO is on target to read out sometime in August of this year.

The LUCIA trial is about 2 months behind and therefore, will read out approximately 2 months after that. The diabetic macular edema trials are still currently enrolling. And as of last week, they were 2/3 enrolled. They are simultaneous identical non-inferiority trials called COMO and CAPRI, and they should be fully enrolled in the third quarter of this year. Given that their endpoint is 56 weeks, the top line data should be out in the fourth quarter of 2027. So we have some really exciting milestones coming up in the next 1.5 years.

Great. Maybe dig in a little bit deeper in terms of kind of your view of the differentiation. So at a high level, where do you see the key differentiation versus standard of care from both standard of care as well as other emerging clinical agents?

Sure. So at a high level, what we can provide is sustained release anti-VEGF effect for 6 months or longer with a single injection. We have some excellent biologics that are direct ligand blockers that are approved. We have multiple biologics. And while some of them have extended duration, they really don't have sustained release.

My opinion, the only true sustained release that's approved is the port delivery system, but the differentiator there is port delivery requires surgery for placement. And our medications are injected in the office with a standard intravitreal injection procedure. And I might add, we do come in a prefilled sterile syringe injector shipped and stored at room temperature, which is not a major differentiator, but we believe commercially, the fact that we don't need to be refrigerated or frozen will prove to be an advantage should we be approved.

So I think the durability, obviously, is the big high-level differentiator. Now the next issue around durability, of course, people talk about reduction in treatment burden, how many fewer injections or visits will that provide? And while that's important, what we believe, and I think the retina community is coming to believe that durability with sustained release means in the long term, patients will get better vision. And that's really what we're trying to accomplish.

The reduction in treatment burden, let's call it a beneficial side effect of that, but that's not our true value. We believe the true potential value here is better vision in the long term. So that's the high level. I think also I mentioned that we do appear to have activity against the JAK1 receptor, which means we should reduce the downstream effects of IL-6 which is an inflammatory pathway that's been implicated in both DME and in wet AMD. That, again, can prove to be a differentiator for us. If we're approved with an every 6-month label, and we provide both anti-VEGF activity and anti-inflammation activity, I think that has the potential to set us apart from the current therapies and frankly, from the other therapies that are currently in study.

Yes. Let's dig a little bit deeper there. When you talk about especially some of your recent ARVO work around IL-6, JAK1, et cetera. Can you talk a little bit more detail on why you see the anti-inflammatory potential benefit as differentiated? -- specifically, how is that going to translate to meaningful clinical benefit and eventually commercial?

Sure. Great question. And let me kind of start at the beginning and what prompted this discovery that we were not only anti-VEGF, but we were anti-inflammatory. I'd like to go back and review a little bit of our Phase II DME trial, which is called the VERONA trial. And in the VERONA trial, we recruited active DME. It meant that they had fluid and they had decreased vision -- either to receive a single Eylea injection or an Eylea injection 30 minutes later with EYP-1901.

If you look at the week 4 result, the earliest time point, the eyes that received our drug were already 4 to 5 letters better than the eyes that received a single dose of Eylea, and they're about 40 to 50 microns drier on OCT. Now we believe we have a very good anti-VEGF drug. When we looked at that data, I said to the R&D team, I don't think we're that much better than Eylea. There must be something else active here.

And that's when we went back and did a further kind of analysis and discovered that the IC50 for vorolanib in the JAK1 receptor is about 80 nM, which means that the doses we're using in humans, we should be active against the receptor. Subsequently, we did some cell-based studies, including a study where IL-6 was applied in to cells and vorolanib was able at doses that were equivalent to what we're using in humans, reduce the downstream activity of the IL-6 by about 50%.

At ARVO, just recently, we reported another trial cell-based, which essentially looked at leakage from cells. If you add VEGF and IL-6 to cells, they will leak. If you then add an anti-VEGF, they leak less. If you add an anti-IL-6, they'll leak less. If you add both, you get minimal leakage. We then added vorolanib at approximately the dose we can get into humans, and we were essentially the same in leakage reduction as the IL-6 blocker and the anti-VEGF.

So as additional data to suggest that the anti-VEGF but we have do want to mention a couple of other things from the VERONA trial. I mentioned the rapidity of onset and also the rapidity of the dryness. But if you look at the eyes in Verona, and it was over 70% in the high dose that did not get rescued. They just received our dose our drug for 6 months. Those eyes improved over 10 letters.

Now again, cross-trial comparison is difficult. But if you look at the improvement in a previously treated population in patients receiving Eylea, it was less than that. In the Phase III, we've designed the trial to show this difference at week 4. We're dosing our drug at day 1. And at week 4, we can replicate the findings that we had in the Phase II. I think that even in the end, if we're noninferior to Eylea, but we can get the patients to see better faster and get them dryer faster, that means, I think, potentially a huge commercial success.

Back to VERONA, one other data point here, leakage in eyes can be measured quantitatively by fluorescein angiography and a reading center that's independent can rate the leakage, and that's a sign of inflammation. And in a dose-dependent fashion, EYP-1901 reduced the leakage more than Eylea did, another data point that suggests that this anti-inflammatory effect is real.

Great. We're going to -- we'll get into wet AMD and DME in a little bit more detail shortly. But before doing so, can you talk about the delivery platform and kind of how that is part of the story in addition to active.

Sure. Again, a great question. Just to remind people, EyePoint has been in the sustained drug delivery to the back of the eye space for almost 30 years. We've had 4 FDA-approved products with sustained delivery. All of them, however, prior were not bioerodible. The way they were designed is you had the drug had mixed with the matrix -- and then the drug disc or cylinder was then surrounded by an impermeable plastic that was inert. And the plastic was open. There was essentially pores at either end, and that allowed the drug to diffuse out.

And the reason you needed that is if you had a very soluble drug like a corticosteroid or ganciclovir, for example, without that reduction in the surface area, the inserts wouldn't last very long. So that matrix, though, is very similar to the matrix that we're using in the current version of EYP-1901, and it's been in tens of thousands of patients safely. The difference here is we removed that impermeable plastic. We want the whole surface area of the inserts to be able to release the drug because we wanted to get higher levels, number one.

And number two, we didn't want any residual long-term plastic to be remaining in the eye, given that on average, wet AMD patients can live over a decade requiring treatment. And so we really didn't think there was any reason to keep that design. So in effect, the current inserts are -- have less excipients than the 4 that were FDA approved.

In addition, what our scientists were able to do with the latest version is increase the payload of the drug. Our inserts are now 94% vorolanib. -- only about 6% matrix. That gives each insert payload of about 1.34 milligrams of drug, which means we're able to achieve high tissue levels with 2 inserts in a single injection. And our injector actually can hold up to 3 inserts, which, again, down the road, one could then potentially see the possibility of using multiple drugs in a single injection, which is something that we look forward to studying in the future.

Great. Very helpful. Moving on to, I guess, digging in a little bit deeper on wet AMD. Talk a little bit about VERONA and some of the prior data there. Can you talk about DAVIO 2 and how that underpins and plans within wet AMD?

Sure. So DAVIO 2 is our Phase II study in wet AMD. It enrolled approximately 160 patients, and they were randomized to either receive 3 milligrams of our drug versus 2 milligrams versus on-label Eylea control 2-milligram Eylea. The patients all were previously treated. And in order to enter the study, we only wanted to enroll patients that had responsive to an anti-VEGF. So they had to receive an anti-VEGF 2 weeks to 5 weeks prior to screening, and they had to show a response and then they were enrolled.

The primary endpoint was at month 8 in eyes were not reinjected with our drug. So they only received a single injection. And at month 8, we were statistically noninferior to Eylea and the actual numerical difference in the vision was only 0.3 in the 2-milligram arm and 0.4 in the 3-milligram arm. So that's 0.3 letters. And those of you who've been to the eye doctor, you read a line, that's 5 letters on a line. So it's less than half a letter difference, which is, again, statistically equivalent.

Equally important is we found that the safety was quite good. And we really had no safety signals that were identified in that trial. There were no ocular or systemic SAEs that are attributed to our drug or inserts. So we're quite pleased with the safety, and we've reported safety on over 190 patients from the Phase II and Phase I trials. And again, the safety has been quite good. From the perspective of, for example, the anatomic results, we measure anatomy using the device called the OCT, normal anatomy on OCT is up to 325 microns of thickness.

And anatomic control is important because in wet AMD, what's been shown is if you allow patients to gain fluid and have more leakage, even if you get it back under control, if that cycle continues, you can lose vision and get fibrosis as a result. So our maintenance of the anatomy was quite good in DAVIO 2. In the higher dose, the 3-milligram dose, there was about a 5-micron difference in the end between us and Eylea, which is really, really small. More importantly, to the doctors, having the fluid go up and down in a sawtooth pattern is something that they really don't like to see. And our fluid control is quite good through the whole study. And that's again important.

If you look at the eyes in DAVIO 2 that were unrescued, meaning they only got our drug, there was straight anatomic control all the way through. What that tells you is that the drug was working till the end because you would expect if the drug started to run out at month 7 or 8 or 9, you would start to see an increase in fluid, and we didn't see that.

So it gives us confidence that we truly have a 6-month or longer drug. Reduction in treatment burden was about 80% and about 2/3 of the eyes were free of a rescue up to month 6. And even though we didn't reinject the drug at 1 year, about 50% of the eyes in the DURAVYU arms were unrescued. So we had quite a good durability even with a single injection. So that gives us quite a lot of confidence going into the Phase III about the results. And we've obviously used what we learned in the Phase II to model the Phase III.

Great. So good transition to Phase III. Can you remind investors of study design and in particular, why you chose non-inferiority versus there's certainly other approaches out there? And then additionally, kind of the current status, you mentioned it earlier, but...

Sure. Sure. So noninferiority, the way the last 5 approvals have been in wet AMD have been using a noninferior approach. So it's a derisked approach. There's a lot of risk in this business. And our belief is that any time you can reduce the risk without harm to patients or harm to your label, you should. And so obviously, we're taking a derisked approach. Non-inferiority, again, the doctors understand it. They've seen it before. And our control arm 2-milligram Eylea is that's still the treatment of choice of a lot of doctors out there. And so when the data comes in, if we're noninferior to that 2-milligram on label, I think the doctors are going to understand very well where we fit into their paradigm. So noninferiority, again, to us is a derisking and it's the way to get to FDA approval, we believe, the fastest. So the study design is very similar to DAVIO 2, except in a few ways.

First of all, we enrolled the majority of patients who were actually treatment naive, about 75% treatment naive, about 25% previously treated. And we believe the addition of the treatment-naive patients, if approved, will not only help us on the label, but also derisk the trial. And what I mean by that is in DAVIO 2, we had a very tough-to-treat population. On average, in the United States, patients get about 6 injections a year. In DAVIO 2, if you looked at the prior year and normalized the number of injections, it was about 10.

And that makes sense because those are the patients we call frequent flyers who need a lot of treatment. We got very few easy-to-treat patients in DAVIO 2. And our hypothesis is if you have a patient who can go 3 or 4 months on any of the anti-VEGFs between injections, they should do really well with our drug. And we think the addition of the naive patients allows us to get a proportion of those easy-to-treat patients. So we think that's going to actually improve the end result.

The second difference, I mentioned already is we're reinjecting every 6 months over 2 years because we like an every 6-month label. We didn't reinject in DAVIO 2 at all. The third difference is we altered the supplement criteria -- we studied the supplement criteria in DAVIO 2 and found out that 3 of the criteria that we used did not result in an improvement in vision after supplementation. And therefore, you could call it a waste and supplement. And so we didn't include those in the pivotal trial. So ultimately, we think with positive data, doctors will know exactly how to use this and our label should be very straightforward.

When you think about what does good look like, how should investors frame BCVA in the context of non-inferiority?

Sure. That's a really good question and one that's very pertinent given that our data is coming soon. So I think the way to look at our data from the top line from the Phase III is really quite simple. The first is we need to hit noninferiority. We need to be statistically noninferiority. That's obvious. That's the primary endpoint.

But I'd also argue that the exact numerical difference probably doesn't matter. This is, again, a piece of data to share. But if you look at the wet AMD study of high-dose Eylea that got it approved, the high-dose Eylea arm was 1.4 letters worse than the 2-milligram arm. It doesn't stop us retina specialists from using it at all. It's a great drug because that amount of vision, we believe, is inconsequential to the patient. And frankly, the agency believes that, too. That's why the non-inferior margin letter or 2 or even 3 is in -- most of the physicians don't really care.

So I would argue that the exact numerical difference probably doesn't matter. We need to hit the primary endpoint. I'm going to reverse myself though and say, there's a chance we could be superior. And we're able to test for that without penalty if we hit the non-inferiority margin. Obviously, not guiding to this, but we could be statistically superior, even numerically superior. And I think, obviously, either of those, if we hit it, would be very beneficial to us commercially.

Now the second piece of data you should look for at the top line is safety. And those of you who follow retina companies, you know safety is of paramount importance. The good news for us is I've already mentioned the safety in the prior studies. And we've talked about this publicly. A few weeks ago, we had the DSMC meet, and they see not only the masked safety from the trials, they see the unmasked safety, and they didn't recommend any changes in the protocol of the trials, which is of a relief. We see a masked safety. And as we've reported publicly, the masked safety looks very similar to what we have seen in the prior 190-plus patients that we've already reported on.

So while the studies are not over, anything can happen, but I also like to remind everybody that most of the safety events occur at or just after the time of injection. And this last look at the safety, all the patients in LUGANO and LUCIA had received their second dose of our drug and about 1/3 of them had received the third dose. The third thing to look for at the top line is reduction in treatment burden. And we believe this may be the easiest bar for us to hit. And the reason is that it's a statistical superiority test for the FDA. And we only need to be 8% less than the control arm to be statistically superior.

Now the way treatment burden is going to be measured in this trial was a little different than prior. And I do want to go into a little detail about it so investors and analysts can understand because both arms of the trial get the 3-injection Eylea load at the beginning, those injections don't count for treatment burden.

In the DURAVYU arms, all eyes will receive 2 DURAVYUs mandated. In the Eylea arms, all patients will receive 5 Eyleas. So if there were no supplements and everybody follows protocol, the most reduction in treatment burden you could possibly see would be 60% -- we know there's going to be some supplements probably in both arms. But if you then look at DAVIO 2 and you say, what if you had the same supplement rate in DAVIO 2 as you do in the Phase IIIs, it'd be about a 35% reduction in treatment burden, which we believe would be excellent.

If you talk to the KOLs, and we talked to a lot of them and you ask them, what's your floor for using a TKI, they'd like to see at least a 20% reduction, which, again, remember, in a real-world situation, using a supplement is not a failure for physicians, that the idea of using 2 MOAs may be beneficial to patients. And therefore, just the idea of using a ligand blocker with a TKI may be an acceptable way to go.

So that's really the 3 things that I think are most important. I think we will likely talk about the anatomy and also talk about the percentage of patients that are rescue-free through the entire first year. While I'd argue also, given that the agency's interest is -- seems to be more in reduction in treatment burden, that figure is probably not as important. But I would hope that we could do at least as well as we did in DAVIO 2, where we were 50% rescue-free through the first year.

Switching gears a little bit to the commercial side. Obviously, a little premature, still need to get to the data. But to the extent data plays out as you expect, where do you see it fitting into the current treatment paradigm, especially vis-a-vis VEGFs?

So I'm going to, first of all, say it's never too early to think about that. I think that companies need to start to think about it even when they're designing their Phase I trial because this is a large continuum. We're focused on the clinical outcome because that's coming up, and it's easy to get focused on it. But we haven't just been laser-focused on that. We're focused on CMC because we know that, that's where most of the CROs come from.

And we're focused on commercial success because ultimately, what we're trying to do is improve patients' lives, which means we need to be able to get the drug to them. So it's not just how it fits into the paradigm is we need to be able to make enough inserts to satisfy what we hope to be a demand. But how it fits in, I think our data will help dictate that. But if you just look at us as a reduction in treatment burden, I think that we will be used in the majority of eyes.

If we provide an additional benefit, a visual acuity benefit or let's say, we can show we're antifibrotic at the end of the trial. I think doctors will accept then that in the long term, if we can reduce fibrosis, we will reduce vision loss. And they may choose to use us in the vast majority of their patients. And this is backed up by what we've heard on the podium by KOLs recently, where they have said, if approved, effective, tolerable, we use a TKI in 80% of our patients.

So I think at the beginning, it will be most likely used in the patients who require very frequent treatment. But I think once doctors get comfortable with it, if our clinical profile is what we hope, I think it's going to be used in the majority of patients.

Switching gears to DME. Let's focus on COMO and [ CAPRI ]. Can you talk a little bit more detail or give a little bit more detail on study design, specifically learnings from VERONA, -- you already mentioned a few, but anything more specific there as well as what investors should be looking for on the balance of the year as you march towards full enrollment?

Sure. So I would say that the study design in the DME trials is very similar to the wet AMD trials, 75% naive, 25% previously treated. The end of the trials are less, only 240 patients in each trial. And the reason we were able to use a lower end is that we will have the results of the wet AMD trials when we submit DME. And the agency has allowed us to use the safety data provided it's good, obviously, to inform the safety of the DME trial.

So we don't need to hit the safety numbers in DME that we would have otherwise. So the 2 big differences in the DME trials versus the wet AMD trial is we are dosing our drug of day 1. And there is a secondary endpoint of vision anatomy at week 4. So we hope to replicate in the Phase III what we showed in the Phase II because if we do and we can show as early as week 4 that we're better than a single dose of Eylea, even in the end, if we're noninferior and we're the same as Eylea or even a half a letter, let's say, or letter worse, but we're noninferior.

But we achieve the vision faster and we achieve dryness faster, I think the majority of retina specialists will choose to use us in almost all their DME patients because what patient wouldn't want to see better faster, I think they would. So that's the first difference. The second difference is a little bit more subtle, which is the label for Eylea 2 milligrams in DME is a 5-injection load, which is what we're doing.

The agency really insists in a non-inferiority trial that you use on-label Lucentis or on-label 2-milligram Eylea as your control. That's mandated. So we're sticking to that. But we don't believe the 5-injection load is necessary with DURAVYU, and therefore, we're only doing a 3-injection load. So very similar studies to wet AMD, but those small differences that I mentioned.

In terms of mechanistic rationale in DME, anything additional that you think the profile fits DME specifically?

I think I mentioned this already that we do have preclinical data with some supporting clinical data from VERONA that we have an anti-inflammatory effect. And so we expect to see that in the Phase III trials. And if we can show it, the combination of an anti-VEGF that's anti-inflammatory that's given every 6 months, delivered in the office, shipped and stored at ambient temperature, I think that has the potential to have a stand heads of everybody else.

From a -- I guess, mentioned earlier, commercial and I guess, never too early to start thinking there. Can you talk a little bit about the commercial and medical affairs readiness as well as manufacturing readiness that you're doing in advance of hopefully, good data?

I'm going to let George answer that.

Sure. So let's start with manufacturing. We have our own state-of-the-art facility. So we do drug development at EyePoint. So this facility was started 4 years ago. We have registration batches already on stability, and we are scaling up and preparing not just for building commercial supply, but also being prepared for pre-approval inspection.

The team has really done a remarkable job there. And we are just as prepared for that section of the NDA as we are for clinical data. So that is well underway, and we will continue to push that, especially through 2027. Interestingly, on our medical affairs team, we have a robust MSL group that we actually retained. We had commercial products several years ago, which we transacted. But we kept the MSL team, and they were really instrumental in helping us get our trials enrolled quickly, building relationships with the KOL community, and we've continued to add to that.

So that group is already on the ground as part of a more robust medical affairs team, which we think is very important, not just for wet AMD and DME, but also for commercial readiness. And then on the commercial side, we have a new Chief Commercial Officer, Michael Campbell, who joined us probably 2 months ago now -- in place about patient access, and that's really going to be key and part of our launch. And so while we have a small footprint right now on a commercial team, they're doing a lot of the leg work to be prepared on the other side of our data release starting this summer.

And obviously, with positive data, we'll be looking to scale that team up. We are planning to launch this product in the United States ourselves, and we will be ready for that. From a payer perspective, we've had initial discussions and have gotten very good feedback from payers as we think about where does DURAVYU position versus the current standard of care. And I think importantly, we're not another anti-VEGF. We're actually bringing a new MOA. And so we're really looking to position this program commercially in that same effect.

And I think the other interesting thing, and Jay touched on this a little bit, our product shipped and stored at room temperatures and some of our interactions with the larger practice groups and the private equity groups, the messages don't slow us down. And I think what's really unique about this program is we're this shipped and stored at room temperature. We're not taking up refrigerator space. And because it's a prefilled syringe, there's really no change in practice. So there's a lot of work between now and a potential commercial launch, but we've got the right team and right infrastructure in place, and there'll be more to follow.

Great. Briefly on balance sheet, can you remind investors current cash runway? What does it fund? And what does that include?

Sure. So our cash guidance has been unchanged for quite some time, and it's into Q4 of 2027. That includes all 4 ongoing Phase III trials and their readouts along with commercial scale-up for our facility and NDA filing. Obviously, the commercial -- I touched on this earlier, the commercial launch and scale up would obviously come on the other side of data.

But as we look out over the horizon, we've got the 2 Phase IIIs reading out this year in wet AMD. We'll have the DME trials reading out next year, NDA filing. So we have a catalyst-rich upcoming 12 months that we're going to be in a position to transact and fund the company. And we suspect it's going to be some combination of equity structure, and there's been a lot of interest from all of those groups on the other side of our data.

In our final little bit of time, maybe just in closing, what do you think is the most underappreciated part of EyePoint that investors don't -- they don't appreciate as much as you think they should.

I don't think there's a single thing other than the whole story. We are a derisked asset with, we believe, very good Phase II data going into the 2 largest anti-VEGF markets, total of almost $13 billion in the United States alone with data readout coming very soon. We remain quite confident and quite optimistic in the results, and we think we can make a difference for patients. And so I think as people dig in and turn their attention to us, they're going to realize how underappreciated we are right now.

Fair enough. Good place to leave it. Well, thank you so much for your time, and best of luck.

Thanks so much for inviting us.

Good morning. My name is Brittany, and I'll be your conference operator today. At this time, I would like to welcome everyone to the EyePoint First Quarter 2026 Financial Results and Recent Corporate Development Conference Call. [Operator Instructions] Please be advised that this call is being recorded at the company's request.

I would now like to turn the call over to George Elston, Executive Vice President and Chief Financial Officer of EyePoint.

Thank you, and thank you all for joining us on today's conference call to discuss EyePoint's first quarter 2026 financial results and recent corporate developments. With me today is Dr. Jay Duker, President and Chief Executive Officer of EyePoint. Jay will begin with a review of recent corporate updates and discuss our ongoing clinical programs for DURAVYU in wet AMD and DME. I will close with commentary on the first quarter 2026 financial results. We will then open the call for your questions, where we will be joined by Dr. Ramiro Ribeiro, our Chief Medical Officer; and Mike Campbell, our Chief Commercial Officer.

Earlier this morning, we issued a press release detailing our financial results and recent corporate developments. A copy of the release can be found in the Investor Relations tab on the company website, www.yepoint.bio.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. These include statements about our future expectations, clinical developments and regulatory matters and time lines, the potential success of our products and product candidates, financial projections and our plans and prospects.

Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC and in other filings that we have made or may make with the SEC in the future.

Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today.

I'll now turn the call over to Dr. Jay Duker, President and Chief Executive Officer of EyePoint.

Thank you, George. Good morning, everyone, and thank you for joining us. The start of 2026 for EyePoint was marked by a strong quarter of consistent execution as we approach a pivotal inflection point for our lead program, DURAVYU. We have strong conviction that the upcoming LUGANO and LUCIA readouts will catalyze our future transition into a fully integrated biopharmaceutical company, furthering our mission of improving the lives of patients with serious retinal disease.

We remain on track to deliver these Phase III top line data in wet age-related macular degeneration or wet AMD, beginning mid-year, positioning us to potentially be the first to market among all current investigational sustained release programs. In Diabetic Macular Edema, or DME, we are seeing strong momentum in our Phase III program with enrollment rapidly progressing to support our ambitious goal of full enrollment in both pivotal trials in the third quarter of 2026.

As we advance towards these significant milestones, we are confident that our clinically-rigorous, derisked and patient-centric approach will continue to reinforce DURAVYU's best-in-class potential in the 2 largest retinal disease markets. The fundamental strength of the DURAVYU program lies in its robust and differentiated clinical data. In Phase II trials, a single dose of DURAVYU demonstrated durable efficacy with improved vision and tight anatomic control.

In over 190 patients across 4 completed clinical trials, DURAVYU has demonstrated a consistently favorable safety profile with no safety signals. That profile continues to hold in our ongoing Phase III LUGANO and LUCIA trials for wet AMD as observed on a mass basis, where our low discontinuation rate of about 5% remains well below the 10% yearly average typical for wet AMD trials.

Importantly, none of these discontinuations were related to treatment. At this stage, all patients across the LUGANO and LUCIA trials have reached the week-32 visit, during which patients in the DURAVYU arms received their second DURAVU dose. Over 35% of those patients have since received their third planned dose of DURAVU at week 56. As a reminder, we received 2 consecutive positive recommendations from the independent Data Safety Monitoring Committee with a third review scheduled for later this month. We are optimistic that the interim masked safety data will continue to remain consistent, further strengthening DURAVYU's clinical profile.

In addition, we believe the multi-mechanism of action or MOA of DURAVYU's active ingredient, vorolanib, will prove to be a key clinical differentiator. Along with blocking all VEGF isoforms and PDGF at the receptor level, preclinical data supports vorolanib's ability to inhibit IL-6 signaling via the JAK1 receptor. With this unique ability to not only address both the vascular leakage and inflammation that contributes to retinal disease pathogenesis, but also potentially provide sustained release efficacy, DURAVYU is uniquely designed to deliver wide-reaching therapeutic potential.

Earlier this week, we presented peer-reviewed data at the Association for Research in Vision and Ophthalmology, or ARVO meeting that reinforces these findings and further substantiate DURAVYU's potential to improve long-term outcomes for patients. A primary kinase screen and subsequent measure of IC50 levels identified vorolanib as a potent inhibitor of JAK1, which plays a critical role in IL-6 mediated inflammation. In addition, vorolanib proved to be a potent inhibitor of IL-6 leakage in an in vitro cellular model. This data further highlights the multi-MOA potential of DURAVYU with the opportunity to bring a synergistic anti-inflammatory effect in addition to established VEGF and PDGF inhibition to the treatment of wet AMD and DME.

As we near top line data for our Phase III wet AMD program, it's worth remembering the key elements underpinning its thoughtful design. Our approach is derisked, following an established non-inferiority regulatory pathway. Both pivotal trials are identical and compared DURAVYU to on-label 2-milligram aflibercept, which is intended to reflect real-world practice and generate clinically-relevant data to inform the retina community.

Additionally, both trials are evaluating 6-month redosing and statistical superiority in treatment burden reduction to support the potential for a compelling label that addresses the need for effective, durable disease control. Taken together, we believe our Phase III program is well positioned to deliver data that will build upon our positive clinical development track record and contribute to strong commercial positioning for DURAVYU, if approved. We look forward to reporting top line data from our Phase III wet AMD trial, LUGANO, this summer with our second trial, LUCIA to follow shortly thereafter.

We are applying the same derisked approach to our Phase III DME program, which leverages a non-inferiority design, an on-label 2-milligram aflibercept control, and redosing every 6 months. Similar to our wet AMD program, we designed our pivotal trials for DME based on impressive data from the Phase II VERONA study in which DURAVYU demonstrated rapid efficacy with 4 to 5 letters of vision improvement and approximately 50-micron improvement in anatomic control compared to aflibercept at week 4.

Both of our DME trials, COMO and CAPRI are now underway with over 1/3 of patients enrolled across both trials following first patient dosing at the end of February of this year. Our strong pace of enrollment is driven by our ability to leverage our pre-existing clinical trial infrastructure and investigator network as well as the significantly smaller trial size compared to our wet AMD program. We expect top line data in the second half of 2027.

Stepping back, both wet AMD and DME together represent the vast majority of the global branded retinal disease treatment market with a combined branded opportunity totaling nearly $15 billion in the U.S. and growing. Through exceptional clinical leadership and commitment to serving the retinal community, we are positioning DURAVYU to become a durable franchise with blockbuster potential.

With a unique multi-MOA, robust clinical data package, proven delivery technology, the ability to be shipped and stored at ambient temperatures and administration via standard in-office intravitreal injection, DURAVYU represents a compelling and truly innovative product profile that has the potential to reshape the treatment paradigm for serious retinal diseases. We continue to make significant strides in our commercial readiness while remaining disciplined in our investments as we prepare for regulatory submission.

We have thoughtfully grown our organization with the addition of Michael Campbell as Chief Commercial Officer last quarter. In addition to expansion across key areas such as marketing and market access, regulatory, compliance and medical affairs to build on our organizational capabilities as we advance our launch planning and strategy for DURAVYU in wet AMD.

In addition to progress on our commercial readiness activities, we continue to prioritize CMC readiness. Our cGMP facility in Northbridge, Massachusetts has been online for over a year, supporting our plans for an anticipated CMC submission for our potential new drug application or NDA as well as for commercial supply, if approved. We continue to prepare for pre-approval inspection, underscoring our growing independent commercial readiness that we believe will ensure our preparedness to deliver DURAVYU to patients upon potential approval.

Before passing it over to George to review the financials, I'd like to thank the entire EyePoint team for your unwavering commitment to improving the quality of retinal care. We are proud to support the retina community and grateful to the patients, study coordinators and clinical investigators who enable our research. We look forward to our upcoming Phase III wet AMD readouts together with continued progress in our DME program, which we believe sets the stage for meaningful value creation at EyePoint.

I will now turn the call over to George.

Thank you, Jay. As the financial results for the 3 months ended March 31, 2026, were included in the press release issued this morning, my comments today will be focused on a high-level review for the quarter. Importantly, we continued our disciplined financial management and good stewardship of our resources, ending the first quarter with $223 million in cash and investments.

For the quarter ended March 31, 2026, total net revenue was $0.7 million compared to $24.5 million for the quarter ended March 31, 2025. The decrease was primarily driven by the recognition of remaining deferred revenue related to the company's agreement in the second quarter of 2023 for the license of YUTIQ product rights.

Operating expenses for the quarter ended March 31, 2026, totaled $88 million compared to $73 million in the prior year period. This increase was primarily driven by the ongoing Phase III trials for DURAVYU in both wet AMD and DME and the scaleup of our Northbridge commercial manufacturing facility.

Net non-operating income totaled $2 million and net loss was $85 million or $0.99 per share compared to a net loss of $45 million or $0.65 per share for the prior year period. As I noted earlier, cash, cash equivalents and investments in marketable securities on March 31, 2026, totaled $223 million compared to $306 million as of December 31, 2025.

We continue to expect that our current cash position will enable us to fund operations into the fourth quarter of 2027 beyond key milestones for the Phase III wet AMD program expected later this year.

In conclusion, we're pleased with EyePoint's progress so far in 2026 and remain well capitalized to deliver DURAVYU through key value-driving milestones in the 2 largest retinal disease markets.

I will now turn the call back over to Jay for closing remarks.

Thank you, George. As we continue to deliver on our key priorities for 2026, our team is focused on advancing preparations for the pivotal Phase III top line data readout in wet AMD expected mid-year and completing enrollment of our Phase III DME program in the third quarter of this year.

We believe TKIs represent the next frontier in retinal disease innovation, and we are proud to be advancing DURAVYU as a potential first and best-in-class option in the 2 largest retinal disease markets.

Thank you all for your attention this morning. I will now turn the call back over to the operator for questions.

[Operator Instructions] Our first question comes from the line of Tess Romero with JPMorgan.

So just one from us, on the DME side, actually. So for your COMO and CAPRI trials, you talked a bit about your swift pace of enrollment here. Can you speak to what you're hearing from the investigators in terms of the level of interest from both patients and physicians around a TKI sustained delivery treatment option like DURAVYU? What are the key differences and similarities that you hear in the DME space versus maybe what you heard in the wet AMD space?

Thanks for the question, Tess. Given that our CMO, Ramiro Ribeiro, is really at the forefront of this, I'll ask him to answer your question.

Tess, thanks for the question. So first, as you mentioned, we are seeing a great excitement around our DME program, COMO and CAPRI with a quite quick enrollment so far. We are now leveraging all the infrastructure that we use for our wet AMD with our clinical sites and our CRO and vendor as well.

The feedback that we're getting from the investigators, very similar to our wet AMD, is that our study is a very patient-centric study, trying to address a very important unmet need, which is the treatment burden. So patients that are participating in this study are very excited for a therapy that can last for about 6 months.

In particular, for the DME indication, we know that the need for this patient population might be even greater than wet AMD. This is a patient population that is relatively younger, and they are still in the workplace. So a therapy that can reduce the number of visits like DURAVYU is, of course, of very interest for this patient population. Again, I think the excitement both from the investigators, the patient in clinical sites is being reflected in the pace of our enrollment.

And I'd like to add just one more thought to this. We invited 90 of our wet AMD investigators to be investigators in the DME trials and all 90 accepted. So we believe that continues to show investigators' enthusiasm for the potential of DURAVYU.

Our next question comes from the line of Yigal Nochomovitz with Citigroup.

I'm just wondering if you could comment on how the supplement trigger criteria are functioning in the Phase III trial relative to the Phase II trial, the DAVIO 2 trial? And if you could also comment on what you would expect to be a meaningful supplement rate in the Phase III trial that would be consistent with a strong commercial uptake.

Yigal, nice to hear from you. Thanks for the question. With respect to supplements, I'm going to have Ramiro comment in a moment about how that is working in the trial. But I think there's really 2 issues around the supplementation that people should understand. The first is that in the clinical trials, supplements will be handled statistically with sensitivity analyses that we will be doing when we submit the NDA.

So there is a rate of supplements, at least conceivably, above which the drug would not be considered to be working independently because of the high rate of supplements. In saying that, the FDA has never put a line in the sand as to what that level would be, because they want to see the totality of the data. They want to see the safety and the efficacy otherwise.

So, from a supplementation perspective, there is an important hurdle, which, of course, we need to get over, which is the non-inferior margin, which is the primary endpoint. If we are approved, then I think the commercial acceptance shifts to a very different place.

In the real world, a supplement is not a failure. Doctors, I believe, if we are approved, will enjoy taking advantage of using 2 MOAs to help a [indiscernible] across a lot of chronic diseases, where if 2 MOAs in treatment are available, using them synergistically is a potential advantage to patients. Now obviously, we haven't shown that yet in our trials, but we hope that, that would be the case for the benefit of patients.

But my point about supplements in the real world, I'll give you again an example. If I've got a patient that I have to inject every 2 months with a biologic anti-VEGF and let's hypothesize that DURAVYU is FDA approved, it's safe, it's tolerable. It has a label for every 6 months and the patient gets shifted to DURAVYU, for the next year with 2 injections. But in addition, they received 2 injections of a biologic.

Well, it's a great win for everyone. The patient can go from every 2 months to every 3 months from 6 injections to 4 injections and that presumably the advantages of DURAVYU will be aligned with the patient and the doctor's interest. So there is the regulatory hurdle that needs to be reached over supplements. And if that's reached, I believe that supplementation in the real world will have great latitude for acceptance.

Okay. And then if I could just ask one other follow-up on DME. Of course, you mentioned IL-6 as a potentially interesting biomarker. Are any of those IL-6 biomarker endpoints formally embedded in the Phase III DME program as sort of secondary endpoints that could help differentiate the product?

I would say yes, but indirectly. Given that there is no way to measure in a patient in a clinical trial, the direct effects on IL-6 or JAK1, we would be measuring the indirect effects. The indirect effects, of course, number one is visual acuity. What we hope to be doing in the long term is provide better visual acuity for patients. But in DME, we may be able to provide it in the short term.

Again, looking at the VERONA data at week 4, the patients who received DURAVYU had better vision and drier retinas as early as week 4 compared to a single dose of aflibercept. We have set up the COMO and CAPRI trials to try to show that. And there is a secondary endpoint of visual acuity and OCT at week 4, given our drug is given at day 1 in the DME trials so that -- we hope to show that even if we're non-inferior and equivalent to Eylea, but we can provide the benefit earlier with fewer injections, then we will be able to have a great advantage to patients and therefore, a commercial success.

There are other secondary endpoints that we can look at that are not direct measurements of IL-6 or JAK inhibition. For example, leakage on fluorescein angiography. And you may recall that in the VERONA trial, we had a significant reduction in leakage as measured by an independent reading center, and it was dose-dependent, with the higher dose of 2.7 milligrams showing much greater leakage reduction compared to the lower dose and compared to the aflibercept control. And that is the kind of secondary endpoint that if we can show reduction in leakage greater than aflibercept, I think the evidence would lead to that is due to IL-6 inhibition.

Our next question comes from the line of Faisal Khurshid with Jefferies.

I just wanted to ask on the ongoing wet AMD studies, are you guys able to see blinded rescue rates? And are those tracking in line with your expectations?

Thanks for the question, Faisal. Again, I'll let Ramiro talk about the supplementations and what we're seeing and what we're not seeing.

Faisal, thanks for the question. We -- there's a very small team at EyePoint that reviews the supplementation injections essentially to make sure that the clinical sites are following the protocol. But we don't review aggregated supplemental injection rate, and that's something that we don't disclose publicly.

And if I may add, we -- again, as Ramiro indicated, have no insight into the number of supplements, supplementation rate, et cetera, at this point. It's all masked. But we do anticipate that the supplementation rates in the Phase III trials will be less than what we saw in the Phase II for several reasons, again, due to the tightening of the supplement criteria, getting rid of the physician discretion in supplements, the reinjection at month 6 and the inclusion of the majority of naive patients, all of those together should result in fewer supplements in Phase III.

Our next question comes from the line of Yatin Suneja with Guggenheim.

I'm sorry. This is Eddie on for Yatin. Thinking about the fixed-dose regimen that you guys are going after, are patients who are already dry with stable vision still receiving that third dose at week 56? And if so, is there any incremental safety signal from redosing well-controlled patients? And further, has the FDA weighed in on how this complicates the retreatment redosing schedule?

Thanks, Eddie. Very good question. And yes, this is a fixed dose regimen. It has nothing to do with whether the patient at the time of their repeat dose of DURAVYU is dry or wet or what the visual acuities are. So just like any drug, for example, take 2-milligram Eylea, when it was first studied every 2 months, that was fixed dose where they received that injection, whether they were active or not. So that's going to be true in our trial.

From the perspective of safety, we've done extensive preclinical safety in animals. And in rabbits, we never found a maximally tolerated dose of vorolanib, and we've injected scale dose of about 10x higher than anything we could achieve in humans. We've also not found the maximally tolerated number of inserts in rabbits. And so from a safety perspective, we were not concerned about reinjection. Again, we are reviewing the masked safety. And I will once again turn to Ramiro if he wants to comment on the upcoming DMC meeting that is going to be occurring shortly.

Yes. No, thanks, and thanks, Eddie, for the question. We -- as Jay mentioned, safety is something that is, of course, paramount for EyePoint, and we conduct ongoing safety review of the data. If you do the math, we have now have patients that reached that week 56 visit that you mentioned, which is the third dose of EYP-1901, and we haven't seen anything different than what we saw before. We do have an upcoming DMC meeting in the month of May, where the members will review our masked data, and we look forward to provide updates after that meeting.

Our next question comes from the line of Debanjana Chatterjee with Jones.

So what have you seen in the masked safety data set so far? And has anything shifted your expectations going into the DSMB review that is scheduled for late May?

Thanks for the question, Debanjana. And we're not commenting on any individual SAEs or AEs. But in total, I would say and repeat what Ramiro has said, what we've seen so far is consistent with what we have seen in the prior 4 trials. No new safety concerns and no incidents that we haven't seen or expected from before. Again, Ramiro, I don't know if you want to add any more color to what I said.

Yes. No, I think just again, to reiterate, safety at EyePoint is paramount. We -- internally, we review the data on an ongoing basis on a masked fashion. And as Jay mentioned, we have no safety signal. We haven't attacked anything that is new. The safety profile continues to be very similar to what we saw in our previous completed studies.

Just a very quick follow-up. Can we expect any formal public update following the DSMB meeting?

Yes. I think it's likely that we will give an update, yes.

Our next question comes from the line of Lisa Walter with RBC Capital Markets.

Congrats on the progress. We have seen a long-acting TKI competitor had a successful readout of their pivotal study earlier this year. And we've heard their plan is to file with the FDA and seek approval on this trial alone. In a scenario where essentially both, yours and the other long-acting TKI, are being launched within similar time frames, does perhaps having 2 products with the same mechanism of action actually help break into a market which already has an established therapeutic base with the anti-VEGF? How should we think about this?

Yes, Lisa, thanks for the question. It's a great question. And I think you've really hit on a very important point. This is not a zero-sum game. The TKIs are going into a multibillion-dollar market. And there is certainly room for 2 competitors to both be very successful in this very large market. There is evidence from -- as I think you're alluding to, from other launches with new mechanism of action into an established space that having more than one entry really helps both because doctors are hearing it and learning about it from multiple places. So we welcome another competitor. And part of that is we believe we've got a better drug and a better delivery system. And hopefully, if both are FDA approved, well we will have the opportunity from a commercial basis to really show that.

Our next question comes from the line of Nick for Colleen Kusy with Baird.

It's Nick on for Colleen. So just at ARVO and other recent scientific conferences, just wanted to ask what -- just what the takeaways were on DURAVYU, sentiment among physicians and if you got any learnings about how physicians intend on using DURAVYU upon a potential approval?

So one point I'd like to make, and thanks for the question, Nick. One point I'd like to make about ARVO is we had a poster there, which showed another preclinical model of leakage induced by VEGF and IL-6. And in that model, vorolanib, the active ingredient in EYP-1901 was able to suppress the inflammation induced by IL-6 and VEGF equal to an anti-VEGF and an anti-IL-6.

So again, one more model that suggests that vorolanib does have potent anti-IL-6 activity through the JAK1 receptor. There was a lot of interest in that poster. A lot of KOLs saw it, and there were quite a number of comments. Ramiro met with multiple KOLs at ARVO, and I will let him weigh in on what the sentiment seems to be around EYP-1901.

Yes. No, thanks, Nick, for the question. And we had a very productive ARVO this year with several posters being presented, including the one that Jay just mentioned. We also had a few advisory boards and some interactions with our Phase III wet AMD and DME investigators. I think first on the sentiment of the clinical trials, I think everybody, of course, is very excited for the upcoming data for LUGANO and LUCIA. Mentions are, this is going to be the highlight of the retina space for the year of 2026.

For DME, the investigators, again, reflect that this is a really well-studied plan, very patient-centric, and they were all excited about bringing the therapy for patients with DME. In terms of future use of DURAVYU, as Jay mentioned previously in the call, they expressed the important unmet need that we're trying to address with DURAVYU. And they see this if we can replicate the results that we saw in the Phase II study as something that is going to be very meaningful for patients, especially for those patients that require frequent treatment.

Our next question will be coming from the line of Yale Jen with Laidlaw.

And I just follow up a little bit on the commercial question earlier, which is that besides the TKIs, in terms of the long-acting biologics, VABYSMO and the high-dose Eylea, which one you think you [ scale really ], if approved, will be competing more or less? And any comment on that?

Thanks for the question, Yale. It's an important question because these are excellent medications that are multibillion-dollar drugs that are really helping many, many patients. I think the first point to be clear on is we're not another anti-VEGF biologic. We work at the receptor level. We have multi-MOA block VEGF, PDGF, and we do believe the inflammation related to IL-6 elevation, which is not something that they do.

In addition, it looks like from our Phase II data that at least 2/3 of the wet AMD population could be treated with our drug alone every 6 months should physicians choose to do that. That's not something that we're seeing in the real world with those new medications. While there are extended durations, what the real-world data is suggesting that most patients are getting about a week or 2 extension from either of those drugs compared to what they were on before.

Now that's great, but we still believe that it leaves a lot of room in the market for a 6-month or longer medication. I -- it's hard to predict which of those drugs will be -- I don't want to say the winner because I think both drugs are doing well when we launch potentially. But we -- again, our belief is that we can provide benefits greater than what either of those drugs can do for patients. And we believe in the long term, we will achieve better visual acuity.

Mike Campbell, our Chief Commercial Officer, I believe, is on the line. And I don't know if he's going to maybe have any other comments now. I think it's a little early to talk about commercial strategy. But maybe, Mike, you can talk a little bit about how you view the competition.

Yes. Thank you for the question. The one point I would add is that while we have these very good anti-VEGFs, longer-acting anti-VEGFs in the market, not only is the real-world data showing the extension that Jay mentioned around 8 days. We also look at what the retina specialists are saying in the community and where the needs are.

And so if you look at the American Society of Retina Specialists, ASRS, every year, they put out a PAT survey. And very consistently, the #1 need in wet AMD treatments that is reported from ASRS is still durability even with VABYSMO and Eylea HD in the market. So to Jay's point, there is a very clear opportunity should DURAVYU be successful and be approved, there's a very clear opportunity or room in this market for more durable agents.

Our next question comes from the line of Samuel Rollenhagen with TD Cowen.

This is Sam on for Tara. Can you hear me?

Yes.

Congrats on another great enrollment update. So I just wanted to ask on safety for the LUGANO data. And if you could help us set some expectations there for what you're hoping to see. I guess, besides avoiding some of the more serious back of the eye events, are there any other AEs where you think DURAVYU could be differentiated versus competitors? And then also, it'd just be great if you could clarify how you're anticipating to disclose those safety data in the top line release? Will you be reporting all events or just those above a specific threshold?

Thanks for the question, Sam. And so again, the -- one of the hallmarks of the current anti-VEGF approved drugs with perhaps one exception, is they're quite safe. And while patients and physicians will probably be willing to accept perhaps a few more AEs from a long-acting drug, there can't be a big difference. There's really a high bar that's out there for safety. And the good news is that all our safety from our 4 reported trials shows no real increase in any SAE or AE that would preclude our drug from being widely accepted, in our opinion.

So from a safety perspective, again, a lot of the safety issues that can occur are injection related. And if you're reducing the number of injections that a patient gets, then you're likely in the long term to have fewer adverse events. We hope to be able to show that in our pivotal trials. And from a reporting perspective, I don't know how granular the safety reporting will be initially, but we do expect to have complete AE tables when we present the data from LUGANO and LUCIA.

I'm showing no further questions in the queue at this time. Ladies and gentlemen, thank you for participating in today's conference. This does conclude your program, and you may now disconnect. Everyone, have a great day.

Morning. My name is Michelle, and I'll be your conference operator and recent corporate development conference call. There will be a question-and-answer session to flow at the completion of the prepared remarks. Please be advised that today's conference is being recorded at the company's request.

I would now like to turn the call over to Greg Elston, Executive Vice President and Chief Financial Officer of EyePoint. Sir. Please go ahead.

Thank you, and thank you all for joining us on today's conference call to discuss EyePoint's Fourth Quarter and Full Year 2025 financial results and recent corporate developments. With me today is Dr. Jay Duker, President and Chief Executive Officer of EyePoint. Jay will begin with a review of recent corporate updates and discuss our clinical programs for DuraView and wet AMD and DME. I will close with commentary on the fourth quarter and full year 2025 financial results. .

We will then open the call for your questions where we will be joined by Dr. Ramiro Robero, our Chief Medical Officer; and Mike Campbell, our new Chief Commercial Officer. Earlier this morning, we issued a press release detailing our financial results and recent corporate developments. A copy of the release can be found in the Investor Relations tab on the company website, www.eyepoint.bio.

Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. These include statements about our future expectations, clinical developments and regulatory matters and time lines, the potential success of our products and product candidates, financial projections and our plans and prospects.

Actual results made materially from those indicated by these forward-looking statements as a result of various important factors including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC and in other filings that we have made or may make with the SEC in the future. Any forward-looking statements represent our views as of today only.

While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change. Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. I'll now turn the call over to Dr. Jay Duker, President and Chief Executive Officer of EyePoint.

Thank you, George. Good morning, everyone, and thank you for joining us. 2025 was defined by significant progress and achievement for EyePoint as we made important advances that set the stage for success and potential value creation for the year ahead. As a result of our exceptional clinical execution, driven by our derisked and patient-centric programs, our lead asset, DURAVYU, is on track to deliver top line data in wet age-related macular degeneration, or wet AMD, beginning in mid-2026. We -- in parallel, we advanced DURAVYU as the only tyrosine kinase inhibitor or TKI program in diabetic macular edema, or DME.

We are pleased to report that as of last week, the first patients were dosed in both pivotal Phase III in trials with a strong cash position that is expected to fund operations into the fourth quarter of 2027 and multiple inflection points on the near-term horizon, we are entering a transformative period for EyePoint with significant momentum.

Our conviction in DURAVYU blockbuster potential is underpinned, first and foremost, by its compelling clinical profile, and our Phase II trials in the largest retinal disease markets. A single dose of DURAVYU demonstrated durable efficacy with improved vision and tight anatomical control. Importantly, DURAVYU has a favorable safety profile with no safety signals in over 190 patients across 4 completed clinical trials.

The safety trial so far remains consistent in the ongoing Phase III Lugano and Lucia trials for wet AMD based on continued masked internal safety review and two interim reviews conducted by the independent Data Safety Monitoring Committee. In addition to its robust clinical profile, we continue to believe that the potential for every 6-month dosing the standard in-office intravitreal injection, a best-in-class delivery technology and a novel multi MOA that inhibits VEGF, PDGF and IL-6 via the JAK1 receptor with no tie 2 inhibition are the key drivers of its differentiated profile.

This unique profile positions DURAVYU to address both VEGF-mediated vascular leakage and IL-6 mediated inflammation that contribute to disease pathogenesis in wet AMD and DME, thereby potentially enabling improved long-term outcomes for patients with fewer injections. Our confidence is also grounded in our established and clinically rigorous approach through outdoor reviews development. Our Phase III wet MD program was intentionally designed to inform real-world practice and generate meaningful data for the retinal community by comparing DURAVYU to on-label aflibercept as the control.

Additionally, we will be evaluating statistical or in treatment burden reduction and 6-month redosing to support a compelling and relevant label. Based on the success of our large Phase II DBO 2 trial and with our proven regulatory pathway and strong execution to date, we believe our wet AMD program is uniquely derisked and optimized to support success. We look forward to reporting top line data beginning in mid-2026.

The clinical and regulatory rigor that defines our approach also extends beyond Wet MD as we work to position DURAVYU for multiple indications. We are pleased that randomization is now underway for both COMO and CAPRI, our two pivotal Phase III trials in DME where we expect to drive rapid enrollment by leveraging our pre-existing clinical trial infrastructure and investigator network.

In line with our wet AMD program, our DME program follows an established non-inferiority design with an on-label standard of care control and redosing every 6 months. It was similarly informed by impressive Phase II data from the VERONA trial where eye treated with DURAVYU demonstrated meaningful visual and anatomic improvements as early as 4 weeks. We anticipate top line data in the second half of 2027 and look forward to building upon our strong track record of clinical execution as we advance DURAVYU through our Phase III DME program.

We believe that DURAVYU is well positioned to be the first to market among all current investigational sustained release programs in both wet AMD and DME, with a potential best-in-class profile, and we remain focused on building DURAVYU into a durable franchise, targeting the largest retinal disease markets. With the combined current global market of $10 billion and growing, wet AMD and DME make up the vast majority of the global branded retinal disease market.

DURAVYU's unique MOA, robust clinical data package, proven release technology and attractive storage and administration benefits offer a compelling value proposition that we believe will address the long-standing need for innovation and support strong commercial positioning. As part of our ongoing commercial readiness efforts, we are thrilled to welcome Michael Campbell as our new Chief Commercial Officer. Mike is a seasoned commercial leader with a proven track record of successful product launches and oversight of prominent ophthalmology franchises, including Lucentis and Xiidra. As we prepare to deliver on EyePoint's next milestones, including potential approval and transformation into a fully integrated commercial organization, Michael's deep commercial expertise will be instrumental as we position to review for a successful U.S. launch.

In addition to strengthening our commercial leadership we continue to expand operations at our 41,000 square foot CGMP manufacturing facility in Northbridge, Massachusetts. The facility has been online for over a year, supported by about 60 full-time employees and continues to not only support the CMC submission for a planned new drug application, or NDA, but also commercial supply.

As we near regulatory submission, we are preparing for preapproval inspection, underscoring our growing independent commercial readiness and commitment to ensuring that we are well equipped to deliver DURAVYU to patients if approved. Before passing it over to George to review our financials, I'd like to thank the entire EyePoint team for your continued dedication to improving vision and patient outcomes.

We are proud to advance our therapeutics for the benefit of the entire retina community and grateful to the patients, study coordinators and clinical investigators who make our research possible. As we look ahead, we are excited about the upcoming milestones and the opportunities in store for us to extend our leadership and sustained ocular drug delivery. I will now turn the call over to George.

Thank you, Jay. We ended 2025 with a strong balance sheet of $306 million in cash and investments, driven by continued stewardship of our resources and $173 million follow-on financing in October. As the financial results for the 3 months and full year ended December 31, 2025, were included in the press release this morning, my comments today will be focused on a high-level review of the quarter.

For the quarter ended December 31, 2025, total net revenue was $0.6 million compared to $11.6 million for the quarter ended December 31, 2024. The decrease was primarily driven by recognition of remaining deferred revenue related to the company's agreement for the license of YUTIQ product rights in the second quarter of 2023. Operating expenses for the quarter ended December 31, 2025, totaled $71 million compared to $57 million in the prior year period. This increase was primarily driven by the ongoing Phase III trials for DuRaVie and wet AMD and DME.

Net nonoperating income totaled $3 million and net loss of approximately $68 million or $0.81 per share compared to a net loss of $41 million or $0.64 per share for the prior year period. Turning to the full year ended December 31, 2025. Total net revenue was $31 million compared to $43 million for the year ended December 31, 2024. The decrease was primarily driven by the recognition of remaining deferred revenue related to the company's agreement for the license of YUTIQ product rights in the second quarter of 2023. We Operating expenses for the full year ended December 31, 2025, totaled $275 million versus $189 million in the prior year period. This increase was primarily driven by the ongoing Phase III trials for DRIVE and wet AMD and DME.

Net nonoperating income totaled $12 million and net loss was $232 million or $3.17 per share compared to a net loss of $131 million or $2.32 per share for the prior year period. Cash and investments on December 31, 2025, and totaled $306 million compared to $371 million as of December 31, 2024. We expect the cash and investments on December 31, 2025, and will enable us to fund operations into the fourth quarter of 2027, well beyond key milestones and NDA preparation for the Phase III wet AMD program in 2026 and fully funding the Phase III pivotal DME program. In conclusion, we are incredibly pleased with EyePoint's progress in 2025 and are well capitalized to continue advancing Du Review through both of our late-stage development programs. I will now turn the call back over to Jay for closing remarks.

Thank you, George. EyePoint's progress in 2025 reflects the strength of our programs and our consistent execution. As we prepare to drive value through transformative catalysts in 2026, we will continue to be guided by our derisked clinically rigorous and patient-centric approach. We are well positioned to deliver on our near-term priorities, including reporting top line data for the Phase III LUGANO trial anticipated in mid-2026, with LUCIA data to closely follow, Completing enrollment in our pivotal Phase III DME program in the second half of 2026 and preparing for regulatory filing in wet AMD, assuming positive Phase III data. Thank you all for your attention this morning. I'll now turn the call over to the operator for questions. .

[Operator Instructions] Our first question is going to come from the line of Talmer with JPMorgan.

Jay, George, can you clarify the rate of ocular AEs that you have seen across your cumulative safety database with DURAVYU, in particular, around the incidence of victorious floaters and cataracts -- and then relatedly, what specifically has the physician feedback been around your safety profile?

Sure, Jess. Happy to address that. As you probably recall, we've treated over 190 patients in completed trials, that's 1 Phase I and 3 Phase II trials. And the number of cataracts that were measured by the investigators in those 191 patients is 5.8%. In contrast, -- if you just look at the AVO 2 data, the cataracts in the DAVIO-2 study in the study arms was approximately 8% and -- in the EYLEA control arm, it was numerically higher. It was -- so this is an elderly population you do expect cataracts.

But of course, in the controlled AVIO II trial, there was no mismatch between the cataracts at all. With respect to try floaters, once again in the entire population, 5.2% of the Drive patients reported floaters which is, again, consistent with what you might see in any type of study that has injections into the eye. So I think to answer the second part of the question, which is how do the clinicians perceive it. I think 1 of the main reasons that we were able to enroll the Wet MD trial so rapidly is the doctors had a really good Phase II data to evaluate both the efficacy and the safety of our drug.

And I think that gave them a great confidence in enrolling patients. I think, again, I'd like to make one more note on safety and efficacy. We think of visual acuity as the primary efficacy endpoint, which it is for all of these studies, but visual acuity also is a safety outcome. And again, just to remind the listeners in the DAVIO 2 trial, are treated patients in wet AMD gained vision. And in fact, in the unsupplemented isen DAVIO 2 trial, the treatment arms gained 2.1 letters over the course of the trial, which is actually numerically greater than the EYLEA arm gained learn at that point was getting 3 injections over that time frame because it was on label EYLEA. So that to summarize, we're very comfortable with our safety. We've had no ocular or systemic SAEs attributed to our drug. And in those 4 prior trials, no safety signals.

Our next question comes from the line of Yatin Suneja with Guggenheim.

Just a quick one on the regulatory front. Just love to hear from you how are you thinking about recent sort of FDA chatter around single study driven regulatory approvals. Does that change your strategy just as curious what is possible? And then Jay, I appreciate your comment on the safety clearly has been pretty good across Phase II studies and also Phase III blinded review that you have provided. Anything on opacity that you can comment like how are those numbers relative to what we see with other TKIs in development? .

Thanks for the question, Yatin. So for the first question, the regulatory yes, I think in general, we would all welcome a more rapid and less expensive pathway to drug approvals. But as you heard this morning, and as most listeners know, we have 2 identical Phase III wet MD trials underway that are reading out this year. If in fact, the FDA would allow us to file with a single trial. Our second trial is only 2 months behind. And so overall, I don't know that, that would give us any particular advantage in a single trial.

In DME, we have 2 simultaneous trials that we expect to read out in the fourth quarter of 2027. And given that other regulatory agencies around the world are probably still not aligned with a single trial. We don't believe we have any reason to alter our approach for these 2 indications. Future indications, of course, we will discuss with the agency.

With respect to single trial in retina studies, I think that it's certainly something the agency may be considering in the future. Of course, the rules around single trial filing that the FDA updated in 2023. Those rules are already out there. And in order to do that, you not only need to have a large trial, but you need confirmatory evidence that your drug is active if it's single trial. Of course, in the case of rare diseases, there are exceptions that are made. But wet AMD, DME, unfortunately, are not rare diseases.

So with regard to the regulatory pathway, we think our pathway is derisked. We have taken the non-inferior approach, which is the approach essentially the 5 of the last approvals have taken, and we've got 2 trials in each of those large indications already in motion. With respect back to safety for a second. Opacity is a sign that the mass investigator can see when they look into an eye. They see if there's a blockage in their ability to look into the eye, either in the back of the eye in the vitreous or the front of the inter chamber. In our DAVIO 2 trial, we had about a 1% rate of vitreous capacity.

We had no rates of antechamber opacity. That has not been seen at all with DURAVYU in any of the treated eyes. And we wouldn't have expected it. DURAVYU is designed to hold the drug until the drug is fully eluted. So we have no free floating drug particles. We've had not seen any migration of the inserts, so far at least have not been reported in humans to break up into pieces. They just slowly buy or road and release their payload, which again, I'd like to mind everybody, our scientists have been able to upgrade the insert so that they're 94% payload, they're only 6% matrix. So we haven't seen any antigen capacity, and we wouldn't expect to in the vitreous capacity percentage is low.

Our next question comes from the line of Yigal Nochomovitz with Citigroup.

I'm just curious with regard to the conduct of the wet AMD trials before they read out this summer and into the early fall. Will there be additional looks at mass safety what will the cadence of those be? And will you be reporting that to us as you proceed.

Thanks, Yigal. We've got Romero on the line, our CMO. So Romero feel free to answer that question about continued safety looks in the WMD trials.

Good to hear from you. So we have, as a safety monitoring body for the studies, both internal mass review that we do as an ongoing basis as well as the independent data monitoring committee that reviews the unmasked data. The last DMC meeting was in November. At that point, they reviewed the data from patients. And I remind you that at that point, we had over 25% of patients getting the second dose. The safety profile of DURAVYU so far has been consistent with our previous experience in the Phase I, Phase II studies with nothing near to be aware. Our next DMC meeting is scheduled in May. So that's going to be the next opportunity for that group of physicians to review the MS data and provide updates to us. .

And just 1 question on biomark because I know you identified IL-6 recently. I'm just wondering what additional biomarker work may you be doing to further explore the the activity profile overall? .

Yigal, thanks for that question. Additional biomarker work around the JAK1 receptor and its ability to block downstream effects of IL-6. We will have additional data on that that we're presenting at ARVO in May, we have additional ongoing diet really try to assess the impact of that in humans. With respect to the rest of the potential receptors, we did a very extensive evaluation of the kinome last summer at the time that we discovered that vorolanib was a potent inhibitor of JAK1 with an IC50 of about 80nm and we didn't discover at the time any or significant receptors involved in retinal disease, either positively or negatively that Verolme was active against. .

Our next question will come from the line of Clara Dong with Jefferies.

So just in terms of the durable multi-genic profile beyond the VDFinhivision. So how prominently do you expect this mechanistic differentiation to really be featured in your regulatory discussions and maybe eventual commercial messaging as well? And is there any plan for you to report more preclinical evidence of the IL-6 inhibition In the future? .

Yes, Clara, great question. Thanks for it. And a bit complicated because the story, I think, is still unfolding. Ultimately, what we all want is better visual acuity. -- our patients certainly and the physicians who treat them. And so the great thing about what we do is eventually, it's all about the data. And what we hope to show -- and really, if we can show it, I think, primarily in our DME trials is that, that additional IL-6 blockage does give a more rapid onset of visual acuity improvement. That's what we showed in the Verona data. If you recall, as early as week 4, the treatment arms with Derive had already separated from EYLEA. .

We were already 4 to 5 letters better in about 40 microns drier than EYLEA. And we believe most likely that's the effect of the IL-6.

IL-6 has also been implicated in wet AMD. I think it may be perhaps a little more difficult to winnow out the effects of in the wet AMD population, but I certainly wouldn't rule out that we might end up with better visual acuity in the wet AMD population overall. Again, I mentioned earlier with respect to subgroup analyses, the subgroup in W-2 that was not rescued ended up with slightly better vision than on-label EYLEA. With respect to regulatory, I'm going to let Ramiro take a stab at that. And with respect to commercial, Mike Campbell's here, and maybe Mike can try to take a stab at how that might affect us commercially. Ramiro, why don't you go ahead first?

Yes, sure. Thanks, Clara, for that question. So the regulatory path that we're following with both the wet and the DME studies, is a noninferiority approach. So if we show that BCVA are similar to the control arm that, of course, might be sufficient for regulatory agencies. With that, for both DME study as part of our analysis plan and hire testing, we are going to be testing for CDA. And as Jay mentioned, there are a body of evidence suggesting that IL-6 has a role in both DME as well as warm. So we're going to be investigating that in our Phase III clinical studies.

And Mike, if we're able to show this additional benefit of IL-6, can you perhaps comment on the commercial aspects of that? .

Yes. Thank you, Jay. And the commercial approach, specifically with visual acuity and safety and as Jay mentioned, our unique MLA, gives us a real opportunity here with IL-6 as part of that. complete package. I mean the messaging around this and the opportunity to commercialize gives patients and providers a real opportunity potentially to have a best-in-class durable approach to treating wet AMD and DME. .

As mentioned, if there's an opportunity to be able to show the benefit of IL-6 in the DME population that has a real meaningful commercial opportunity to really separate yourself in the marketplace.

Our next question will come from the line of Greg Suvanovich with Mizuho.

Congrats on the first dosing in your DME Phase III studies. Maybe a question for Mike as the new Chief Commercial Officer, as you come into the company, how are you thinking about commercial prep for the potential launch of DURAVYU, what are the key steps that are needed at EyePoint over like the next 6, 12, 18 months to ensure an optimal U.S. commercial launch, especially when you might be going head-to-head in the competitive landscape versus another competitor.

Go ahead, Mike.

Yes. Thank you, Greg. There is a complete go-to-market strategy and approach for sure. And as we think about the opportunity here, and, to your point, potentially even having a competitor in the marketplace, there's a lot of precision that goes into a market approach, especially in the specialty retina marketplace. So it's areas, for example, around not only positioning and messaging the market search, the pricing research. All of that is priority along with patient access services.

I mean we can have a fantastic and we believe we will have a fantastic opportunity here. But if you can't really get good at allowing patient access through coverage and reimbursement then it can really hinder you. And so there's a lot of effort that we're putting behind making sure we have the right rigor to come to market and make it easy for doctors to be able to DURAVYU, but also easy for patients to access DURAVYU.

And just lastly, I would also add that there's a lot of really good work that is going on and will continue to go on around coverage with payers and good payer research that we've done.

And Jay, if I could just quickly follow up your Phase III trial designs in DME are just slightly tweaked or different from the Phase III trial designs in wet AMD. Just wondering if you could point us to reasons why they're slightly different in terms of kind of loading doses, maybe maintenance doses, just things like that.

Sure. Go ahead, Ramiro.

Yes, Greg. Thanks for the question. So when we look at our DME study in comparison to our WebMD program, there are 2 main differences. The first 1 is on the control arm. For nonfert studies, the FDA mandate that we use own label medication and the own-label regimen for fibercept in DME is 5 loading dose, followed by every 8 weeks. So that's how we're going to be dosing patients in the control arm. The other difference is that for the DME study, we are now dosing review at day 1. If you recall from the wet AMD study, we actually dosed to a view after the reloading dose at week 8.

The reason for doing what we're doing in the DME study, which is to dose at a 1 is to try to replicate the findings that we had in our Phase III study. If you recall from Phase III study, we dose patients on day 1 with a fibroses review compared to fibers alone. And then in that study, we show a greater improvement in the CBA in CSD early on in the study at week 4. So -- and we believe one of the reasons it could be because of the role of IL-6 JAK1 in the DME disease. So we believe that if we can replicate those findings in the Phase III study, providing patients an earlier improvement in the CB and CST is going to be something that is going to be advantageous for our patients.

Our next question comes from the line of Debanjana Chatterjee with Jones.

One more on safety. So we saw a handful of cases of uveitis and its in competitor trials. Could you just tell us tell me again about your broader clinical experience in terms of this kind of inflammatory signals even if miles are moderating on your view? And also, is there anything intrinsic to your design injector or the overall product profile that you believe mitigates these kind of events?

Sure, David, John, thank you very much for the question. With respect to intraocular inflammation, the studies usually divided into iritis, which is inflammation in the front of the eye and while somewhat troublesome or not typically site threatening, vitreous inflammation in the back of the eye, a little more serious in uveitis, which usually refers to inflammation in both those cavities. .

We do know historically, biologics can cause inflammation and there are various rates to the biologics. When they were first out their papers that were written that up to 10% or more of patients at certain times, we're getting at least mild inflammation. Obviously, inflammation is not ideal. And 1 of the real issues even in mild inflammation is the concern that it might actually be an infection, which can be much more serious.

So with respect to the 191 patients that we have treated in those 4 studies, we had 2 cases of its in both cases were mild, treated with topical drops and resolved quickly without any sequelae. We had no reported cases of uveitis, no reported cases of vitreitis. So the overall intraocular inflammation rate is just those 2 patients about 1%. We're optimistic and confident that drug shouldn't cause inflammation to a large degree because Varoli, of course, is a small molecule, it's not a biologic, we're not gene therapy. And the matrix that we're using, that 6% matrix in the inserts, that matrix has been used in our prior FTP products, and there was virtually no very low rates of inflammation recorded in those previous products.

So given that and given the safety profile, we've obviously seen in humans, which I just reported, the safety we've seen in animals, intraop inflammation is not something we're very concerned about.

Our next question comes from the line of Colleen Kusy with Baird.

Number of months still before the top line readouts of the wet AMD studies. But just a clarifying question on the reduction in treatment burden. The secondary endpoint. How do you plan on measuring that? Would that include the loading doses or is that measured after the loading doses. Just curious on the math there? And just what our expectations should be for reduction treatment burden. And then just an addendum to that, what would be clinically meaningful? .

Colleen, thanks for the question. First of all, the reduction in treatment burden is to be measured after load since all the patients in the WMB trials get loaded with 3 monthly injections. The treatment burden clock, so to speak, starts after that. So in the first year of the trial, the DURAVYU patients mandated should receive 2 DURAVYU injections. The EYLEA arm, the control arm has a mandated 5 injections. So if there's no supplementation in the entire study, we would expect a 60% reduction in treatment burden in the DURAVYU arm.

I can tell you that our expectations there will be some supplementation probably in both arms, just like there was in the DAVIO-2 trial, although we do believe it's likely that there will be less supplementation in the Phase III for various reasons. But if you apply the supplementation rates that we saw in Db2 to the Phase III we would have an approximate 40% reduction in treatment burden, which is excellent. So I think from the perspective of what the doctors want to see I think any kind of significant reduction in treatment burden will be welcome because a supplementation with a TKI in the real world is not a failure.

Doctors don't mind doing injections. They just want to do fewer number one. And obviously, the more important thing is they want to get better visual acuity for their patients in the long term. So the concept of sustained release is not about reduction in treatment burden. That's a positive side effect. But what we really want to see is better vision control in the long term, and we believe we can provide that.

I think some doctors may be excited about the possibility of using 2 MOAs having a ligand blocker biologic and having a receptor block at TKI at the same time. And that may prove to be better for long-term visual acuity results. So this whole idea of supplementation, it has a strict definition within the trials. But in the real world, I think the doctors will approach it a little bit differently. Now as part of the trial, I think, Ramiro, maybe can you comment on the superiority testing that we'll be doing about treatment burden?

Sure, Jay. So our our higher testing, none is going to be, as I mentioned before, the nonfronBCVA. The next 1 is going to be superiority on treatment burden. This study, of course, is well powered for the primary endpoint on CRTP CPA. For this key secondary endpoint in treatment burden, this study is also well powered and we should be able to detect the difference, even if the difference is 10% or 7%.

Our next question will come from the line of Lisa Walter with RBC.

Congrats on the progress. Maybe just 1 on safety. Wondering how we should think about the safety profile in Lugano Lucia as it relates to Davio-2. I believe in Dave to the 2-milligram arm performed better on things like iPay, cataract and floaters versus the 3-milligram arm. But my question is -- so how much of the safety or differences in DAVIO 2 are due to the 2 arms using a different number of inserts versus a different amount of drug? And how might this impact safety in Lugano, Lucia, where 2 inserts are being used like the 2-milligram arm in Daviot but the amount of drug is closer to the 3 milligrams that was used. Any color here would be helpful.

Sure, Lisa. First of all, with respect to dosage, we have animal data that shows no maximally tolerated dose of vorolanib so far. We dosed animals with approximately 10x higher dosing than we have ever done in a human. So we don't believe there will be any sign of vorolanib toxicity at the current doses that we're using even with reinjection. So no, I don't believe any of the AEs reported have been due to vorolanib. And I'd extend that to say so far, all the TKIs that have been used for wet AMD, as far as I know, there's no AEs that have been suggested to be due to the drug itself.

So these drugs at the doses we're using appear to be very safe in the back of the eye. With respect to insert number, the numbers are too low to really know, and that's not something we've really essentially considering. There was a higher incidence of floaters in VO2 with a 3-milligram 3 insert versus the 2-gram 2 insert. And maybe it had to do with a number of inserts but given that we're using 2 inserts in the Phase IIIs and ongoing, it's not much of a concern and especially because the rates were low, and we had nobody report decreased vision due to the inserts -- we had nobody leave the trials due to the inserts. Nobody has to have the inserts removed.

So from a clinical outcomes perspective we're really not concerned either about the number of inserts we're using or the doses of vorolanib that we're achieving. I think that the safety and the entire cohorts really speaks for itself.

And 1 moment for our next question. Our next question will come from the line of Yan with Laban.

And I recall in the press release, you have mentioned that there's a floater and the mechanism of actions of the drug could potentially reduce that. So could you elaborate a little bit more on that?

I'm sorry, you asked about the mechanism of action, reduce...

The drug, the drug that potentially could reduce floater or in of the .

No, I'm not sure I followed that. The mechanism of action of rolling it again includes its anti-VEGF effect. -- potentially the anti PDG effect to give a benefit to fibrosis and potentially the anti-IL-6 effect to give a better and quicker results in visual acuity. I don't think the MOA would have any effect on patients' perception of floater. And again, given that the rate of floaters for the whole 191 patients was 5.2%, and I just don't think it's a concern.

Okay. Yes, I just it says to prevent the free-floating drug particles...

That's the design of the inserts. And once again, the design of the insert, as we already stated, we designed these inserts so they control drug release until the drug is gone. That's the whole purpose of a sustained release insert is to control the drug release at therapeutic levels for an extended period of time. And so we would not expect for floating drug particles. We haven't seen free-floating drug particles in any of the animal studies -- and so far, there have been no reports of free-floating drug particles in the eye. So that is more of an effect of the delivery system, not the MOA of rolling it.

That's very helpful to clarify that. And then maybe a quick one. How many sites for the COO and the APRA study in total and the -- some of those are viewers U.S. versus in the U.S.

Ramiro, why don't you take that question, please? .

Yes. So we have -- both studies are global studies. So we have sites in the U.S. as well as outside of the U.S. We are planning to have approximately 140 sites across both studies. And we are leveraging a lot of the infrastructure that we use for our WebMD program. So a lot of the sites that are part of DME, most of them were also part of our wet AMD program, and which was very interesting and very encouraging for us is that all sites from the wet MD program that we invited to participate in the DME studies, they agreed to be part again of the DM program, which, again, I think highlights the confidence of the investigators in our clinical program.

Next question comes from the line of Daniil Gataulin with Chardan .

In your conversations with KOLs, what are you seeing in terms of which patients they would initially be willing to focus on when considering vorolanib, -- for example, the thinking more of stable patients versus newly diagnosed patients or patients with hybrid? And second part is, how do you expect the step through requirements to affect the adoption of vorolanib .

Thanks, Daniel. First of all, with respect to patient selection, I think we're all speculating a little here because we don't have the Phase III data in the label. But if 1 extrapolates from the Phase II data, I think that at the beginning, where most doctors will try it is there are patients who are being treated more frequently than they would like. every 4 weeks, every 6 weeks, every 8 weeks.

I think that will be the initial adoption of it. And as doctors get comfortable with its therapeutic profile and its safety, I think it will get expanded. Now I'll modify that a bit, which is if we can show in the clinical trials that we can deliver better vision than EYLEA on label or that we're antifibrotic or we have neuroprotection, other benefits that are potentially going to -- - that we might see, then I think the adoption will be much broader than that. I mean if we can show that we're antifibrotic, I think retinal physicians will acknowledge the fact that fibrosis in the long term is an important cause of visual loss, and if you can prevent it from happening, you will result in improved vision over the years.

So I think it will start off with the eyes that likely need a lot of treatment, but it may expand well beyond that. With respect to step therapy, we wouldn't anticipate it would be an issue. First of all, again, we don't know what our label will look like, of course, but our study in wet AMD is being done with a 3 injection load. So if the label contains use of review after 3 injections of an anti-VEGF, for example, then that automatically puts us beyond the initial injections into a branded drug.

I will say we are looking into the possibility of our different MOA and our 6-month efficacy, if it's there in the IL-6 blockage, if we can show a benefit there to be considered different than the ligand blockers, which may also be advantageous to us in the long term. But of course, that's all dependent on the data we show in the pivotal trials.

I'm showing no further questions in the queue at this time. Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may now disconnect. Everyone, have a great day.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is EyePoint. And presenting on behalf of the company, we have President and CEO, Jay Duker. Jay, over to you.

Well, thanks, Tess, and good morning, everybody. I hope you've had your jolt of coffee this morning, but I expect this presentation and subsequent discussion will really wake you up. So as Tess said, I am President and CEO of EyePoint. These are our legal disclaimers, which if you'd like to read more, feel free to go to our website.

EyePoint is the leader in sustained-release drug delivery for retinal disease. And the #1 reason for that is our lead product DURAVYU. DURAVYU is currently in Phase III trials for wet age-related macular degeneration. Both trials are fully enrolled, and we anticipate the top line data from both trials this year, starting midyear. In addition, DURAVYU is also in Phase III DME and the program is underway, and we are on target to dose the first patients in both trials this quarter. Durasert is our proprietary delivery system, and it has been in 4 FDA-approved products with a strong safety and efficacy record. We have a veteran leadership team, some of whom are next to me up here in the podium. And we have over 3 decades of experience, not just with clinical drug development, but equally importantly, with the successful commercialization and manufacture of drug.

Speaking of commercial manufacturing, we built our own commercial manufacturing facility in Northbridge, Massachusetts. If you're looking for it on a map, it's right next to Uxbridge, Massachusetts, about 45 minutes west of our headquarters in Watertown, but obviously, that is still in the United States. That facility has been up and running for over a year. We now have about 60 employees there, and we are gearing up for pre-approval inspection as well as commercial success with manufacturer. Our financial situation is terrific. As of the end of the year, we had approximately $300 million in cash, which gives us a runway well past data into the end of 2027.

This is our pipeline. Again, we are in the 2 largest markets for retinal disease, wet AMD and DME in Phase III in both. In addition, we have a pipeline drug that is moving forward, EYP-2301, which is a TIE-2 agonist, also sustained release. Following the history of anti-VEGFs in both wet AMD and DME, it's an interesting story of how relatively small gains in durability led to very successful multibillion-dollar products. And in fact, the most recent, of course, is Vabysmo, now almost a $4.5 billion product 3 years after the launch with, again, just relatively minor improvements in durability. So here we are in 2026. And if you ask the question, okay, what are the unmet needs in these VEGF-mediated disease. The first one still is longevity because in the long term, despite these excellent drugs we have, patients still lose vision. And the primary reason for that is they just can't keep up with the necessary visits and injections over years. The second unmet need is new mechanisms of action. And it's becoming increasingly clear that VEGF suppression is not the only story, but inflammation plays an important role in both these diseases, and we believe DURAVYU will be the solution for both of these problems. Vorolanib, which is the active ingredient in DURAVYU, is a small molecule tyrosine kinase inhibitor with multi-MOA. It addresses both the vascular leakage that is the result of elevated VEGF and PDGF levels. And it does it, of course, with a new MOA at the receptor level. In addition, vorolanib is able to block IL-6 signaling also at the receptor level. IL-6 is a potent pro-inflammatory protein. And by blocking it, we can reduce not only inflammation leakage, but also suppress VEGF.

Our delivery system is called Durasert E. It's the next generation in sustained-release intravitreal drug delivery, and we have 3 decades of experience developing sustained release in the retina drug for drug delivery. Our technology, again, spans 4 FDA-approved products, including Vitrasert, Retisert, ILUVIEN and YUTIQ. DURAVYU is different in that it is fully bioerodible. The first iteration of DURAVYU had a payload of approximately 1 milligram of vorolanib, and our scientists were able to improve the insert so that the inserts now contain 1.34 milligrams of vorolanib. This represents a drug payload of 94% of the weight and volume of the insert.

Most intraocular inserts are about 50% to 60% drug. So this is a really unique formulation to deliver vorolanib sustained release. There are multiple advantages of DURAVYU. I've already spoken briefly about the multi-MOA, which we uniquely provide. But Durasert allows for immediate and sustained therapeutic levels of drug. In animals, we can measure vorolanib within hours after injection, and we can sustain it in humans for at least 6 months, and we believe virtually everybody. The release is also controlled, and this is important. We designed these inserts so the matrix holds the drug until the drug is completely eluded. So we control drug release until the end. Therefore, no free floating drug particles in the eye.

One of the unique aspect of this, which I think will really help us in commercial success is the convenience. DURAVYU can be shipped and stored at room temperature. All the other approved drugs, and I believe all the others that are in investigation now are either refrigerated or frozen. From a safety perspective, our inserts contain no PEG and contain no PLGA. I think this slide summarizes very well why we are so confident that DURAVYU will be a market leader. You can see the important things that retina specialists are looking for in treating these VEGF-mediated diseases. Of course, you have to have VEGF inhibition. But DURAVYU also has IL-6 inhibition.

In addition, we block PDGF, which should be helpful as fibrosis is another reason that eyes lose vision in the long term. We have at least 6-month durability, and we can redose, and we are testing it as every 6-month redosing. Also, ours obviously can be administered in the office through a standard intravitreal procedure. And as you look at the single approved sustained release device, that's the port delivery system and all the other competitors in the space that are being developed, we are uniquely positioned here. We've performed 4 trials and completed them successfully, including a Phase I called the DAVIO trial, which was previously treated wet AMD patients. And we are almost at the 5-year anniversary of the first patient dosed in that Phase I trial. And I do like to point out what great execution we've had over those 5 years. So we've gone in 5 years performing 1 Phase I, 3 Phase IIs, and we're now in 4 Phase III trials. The other Phase II were the DAVIO 2 trial, again, a large trial enrolling previously treated wet AMD patients, the PAVIA trial, which enrolled NPDR and the VERONA trial, which is our Phase II DME trial. All of these trials showed efficacy and all showed safety.

With regard to safety, as I'm sure you know, this is a really important topic in the retinal space. And I'm delighted that these 4 trials, there have been no reported ocular systemic SAEs due to the review of vorolanib, and we've had no safety signals. In addition, in the ongoing Phase III LUGANO and LUCIA trials for wet AMD, we're monitoring the masked safety, and we have seen similar safety as we have seen in these previous trials. Nothing new, nothing unremarkable. And I would like to add in the timing of the trials that all the patients who have enrolled in these Phase III, approximately 450 likely have received our drug. All of them have received the first dose. And by now, about 50% of them have got their second dose and the safety persists. So let's talk a little bit about the wet AMD program. We believe we're in the position to be first to market among all these investigational sustained delivery, and we believe we will have the best-in-class profile.

The key elements of the Phase III design is, first of all, we did a large Phase II, and we learned a lot from the Phase II about our drug, about how it works, about who it works in and how to conduct large wet AMD trials successfully. The trial was developed in align with both FDA and EMA. And in fact, we had European sites enrolled patients in the LUCIA trial. The primary endpoint is noninferior change in visual acuity versus an on-label Eylea control. This is the same trial design that the last 5 anti-VEGFs that have been approved successfully used. And we believe and have evidence, of course, that we will be the first pivotal program that's evaluating redosing of sustained release in both trials throughout the entire trial.

Both of these trials are fully enrolled, and they enrolled in record time. Each trial enrolled over 400 patients in about 7 months. Typically, wet AMD trials take about a year to enroll. And I think this is a testament, first of all, to how accepted our drug profile is in both the retina community and for patients. I think this speaks very well for our potential commercial success. The top line dates are a week 52, week 56 combined. And again, the first trial, the Lugano trial, we expect the top line data sometime in the middle of the year with LUCIA data to follow.

This slide shows the schematic of the pivotal trial design. Again, noninferiority regulatory pathway, which is the tried and true. We are testing a single dose of our drug, 2.7 milligrams of DURAVYU against the aflibercept 2-milligram control. And again, the FDA insists that if you're doing a non-inferiority trial, you have to use on-label either Lucentis or 2-milligram EYLEA, and you have to randomize the patients on day 1, and we're doing that. All patients get loaded with 2 milligrams EYLEA over the first 3 visits. And on the third visit, they either get a sham 30 minutes after the EYLEA or they get their dose of drug. Patients are then followed monthly. A masked observer determines whether or not the patient meets what we refer to as supplement criteria. So if the patients had recurrent fluid from best on study of 75 microns or drop in vision of 5 letters from best on study, then the eye will receive a supplemental EYLEA injection. Notice that we're redosing every 6 months. Primary endpoint is 52, 56 weeks combined, which is derisking and also at the request of the FDA, this is a 2-year trial. The second year is for safety. We will be able to submit the NDA after 1 year. This slide summarizes the results from our DAVIO 2 trial. It was both doses, 2 milligram and 3 milligram that were tested in the DAVIO 2 trial were statistically non-inferior to the EYLEA control. And you can see the absolute change in vision was less than 1 letter. Now remember, when you're reading the eye chart of the doctors, that line is 5 letters. So there was less than half a letter difference. And so statistically identical to on-label EYLEA.

All the other secondary endpoints were met, including a significant reduction in treatment burden between 75% and 90%, depending how you measure it. About 2/3 of the patients were able to go up to 6 months without reinjection. And we only injected these patients once with DURAVYU in this trial. And the trial went out to 12 months. 50% of the eyes did not need supplement injection at the end of the year. So while we are going for an every 6-month label, we believe some of the patients can go longer with this injection. The only difference, and you can see it on this chart is that the higher dose of 3 milligrams had slightly better anatomic control on OCT. OCT is a measure of permeability. Normal thickness in the retina is about 300 microns. When you get above 325 microns thick, that usually means there's excess fluid. So when you're looking at differences of 5 or 10 microns, that's less than the standard deviation on the test. The other thing I want to point out, and this is important, is while these were previously treated patients, both groups had an improvement in vision in this trial. So our drug was able to improve the vision, albeit slightly.

We went back and did multiple subgroup analyses from the DAVIO 2 trial. But one of the subgroup analyses that we did is we wanted to look at the patients who were in DAVIO 2 who would have been eligible for the pivotal trials. So some of the eligibility criteria was changed. And therefore, we wanted to see how the Phase III eligibility criteria would have affected the results from the Phase II. And the answer is it didn't. The results were robust for the patients who would have met Phase III criteria. You can see the visual acuities were between approximately 1.5 letters and 2 letters, and there was no statistical difference. The bottom graph is the OCT, which is the anatomic results of these same patients and notice again at the end of the study, very good anatomic control in all 3 arms. This gives us increasing confidence for the Phase III result.

About 1/3 of the patients were supplemented in the Phase II at the primary endpoint. However, we have changed the supplement criteria for Phase III. Ramiro Ribeiro, our CMO, who's at my left, his group did some important work to look at the supplements and answer the question, which supplements made a difference? In other words, if you had a supplement criteria, the patient received a supplement, but the vision didn't improve in a sense, you wasted a supplement and you didn't help the patient. So we then went back to DAVIO 2 and said, let's apply the supplement criteria that we're now using in pivotal to the DAVIO 2 patients. And say, how many would have been supplemented. So the bars on the left were the numbers of supplements from DAVIO 2 and on the right were the ones who met criteria for Phase III.

You may remember, and if not, I'll remind you that about 20% of the supplements in DAVIO 2 were at the physician discretion and met none of the criteria for supplementation. So you can see across all 3 arms, there would have been a significant reduction in the supplement rate by anywhere between 1/3 and 50%. And you can see in the higher dose, the 3-milligram dose, only about 13% of the eyes met the criteria, again, giving us confidence in the Phase III result. These pictures show you our new commercial facility in Northbridge, Massachusetts, 41,000 square feet, built completely from the ground up to our specifications by our landlord, and our landlord gave us a terrific deal. We didn't start paying rent until it was fully occupied less than a year ago. And so this facility was built to FDA and EMA standards, and we are currently completing registration batches for stability for our NDA. And again, we are amidst in preparing for not only the pre-approval inspection, but also for commercial success and the ability to scale and makes hundreds of thousands of inserts a year at the facility.

So now I'd like to talk about DME, diabetic macular edema, and we are the only TKI development at this point for DME and Phase III program underway. We had a very positive Phase II VERONA trial for patients with previously treated DME who are active. Again, this is aligned with both FDA and EMA. And we're using the same clinical trial infrastructure that we used for wet AMD, giving us confidence that we can enroll both of these trials rapidly. We are doing 2 trials in DME for global approval, but we are able to leverage the safety data from the wet AMD trial. So each of these trials will only have to enroll approximately 240 patients. This is the schematic of the Phase III DME program. We call the trials COMO and CAPRI. They're identical. And just small difference from the wet AMD trial is we're dosing DURAVYU on day 1, not at week 8. But again, it's non-inferiority change in visual acuity against EYLEA on label. EYLEA on label has a load of 5 injections monthly before it goes to every other month. We're only doing 3 injection load in the DURAVYU arm.

Secondary endpoints, of course, similar safety, resolution of fluid, percent of the eyes that are supplement free at the 1-year endpoint. This graph is from the high dose in the control group in the VERONA trial. All of these patients had active DME, they have fluid and decreased vision. On day 1, they either got an EYLEA injection or they got EYLEA and 30 minutes later, they got 2.7 milligrams of DURAVYU. The red boxes show you what happened at week 4. Notice the DURAVYU eyes at week 4 were already 4 to 5 letters better, and they were 50, 60 microns thinner. That to us did not represent solely a VEGF response, an anti-VEGF response. EYLEA is a great anti-VEGF. This represented something additional, and this is what set us out to discover that vorolanib was also a potent JAK1 inhibitor. And therefore, through that, we block IL-6. At the end of the trial, we were identical to EYLEA in this trial. And if we, of course, do a non-inferiority trial in the Phase III, so if we end up identical to EYLEA, obviously, we're going to be non-inferior and likely approved. But if we can show the same effect at week 4, we show better vision in dry retinas versus EYLEA. I think that will lead to great commercial adoption and success of our drug because what patient wouldn't want to see better faster. Now one of the patients in this high dose missed some visits. And you can see between week 20 and week 24, there was a drop in the vision overall from 10 letters to 7 letters. If you actually remove that patient, the rest of the group had a 10-letter improvement.

So we have increasing data, both preclinically and clinically that IL-6 makes a difference. I'm going to show you a study that Genentech did called the BARDENAS trial, which was a trial of diabetic macular edema patients who received either Lucentis on label or Vamikibart, which is an IL-6 biologic monthly. This is the improvement in vision if you give them Lucentis alone. When they received Vamikibart on top of the Lucentis, notice at week 4, there is a substantial improvement in vision over anti-VEGF alone, which was sustained.

On top of that, I've now shown you what happened with our 2.7 milligram eyes that were not supplemented, that they received an EYLEA on day 1, they received 2.7 milligrams DURAVYU on day 1, and they received nothing else for 6 months. And you can see it overlaps the IL-6 plus anti-VEGF blockage. What's the difference? We accomplished this in 2 injections. They required 12 injections to get that result. Some additional evidence from Verona. This is a measurement of vascular leakage, and that's a biomarker for vascular integrity. And you can see in a dose response, our drug reduced vascular leakage significantly more than EYLEA. And finally, a case, as you're probably aware, Vabysmo is really the treatment of choice for most doctors now in DME. This is a patient on the top right, you can see before the trial was getting Vabysmo monthly, suggesting that the retina specialists didn't feel that the response was enough to allow Vabysmo to be extended.

And in the top left OCT, you can see there's fluid. And by the time the patient got enrolled in the trial, the fluid had actually increased. They received 2.7 milligrams with one shot of EYLEA and received nothing else through week 24. And notice at week 24, this eye was 8 letters better than they were with Vabysmo and [ dryer ]. Now you can imagine if we can do this with a significant group of Vabysmo patients, how commercially successful we will be.

So in summary, only DURAVYU in the sustained release field shows a novel multi-MOA with 6-month durability. We have robust data from both Phase I and Phase II efficacy, both wet AMD and DME, favorable safety so far, including the mass safety data from our ongoing Phase III trials and the top line data is coming in approximately 7 months. The DME program will have first patient in shortly. Thank you very much.

Thanks so much, Jay. So I thought I would start our conversation here just taking a little bit of a step back and before we get into some of the details of DURAVYU and the emerging product profile, can you talk a little bit more about what you are seeing in terms of what physicians are reaching for in the market to try and extend the treatment interval for wet AMD?

Yes. So I think, again, with the data around the acceptance of Vabysmo shows it's now over a $4 billion product. High-dose EYLEA is approved as well, and I believe just recently got a label for every month dosing, and that's important to retina specialists. About 20% of eyes, no matter what you give them, have to be treated monthly. And if you look at the Vabysmo study, about 50% of the eyes could not be extended beyond 8 weeks. So despite these 2 innovative drugs, we still have a great need for more durable therapies. I suspect, and again, as a very, very part-time practicing retina specialists that these 2 will compete until a better sustained release option comes out.

And how has the feedback from the physicians and institutions evolved over time about DURAVYU? What is the level of awareness that you think is around the emerging TKI class in DURAVYU specifically?

Yes. So it's interesting because our commercial team talks about an A to B shift, meaning, A, is the way you do things now and B is the way we hope you do things in the future. And physicians are used to this paradigm of the next anti-VEGF saying, don't use the old one, use us because we are better, we last longer. We're not another anti-VEGF. We do things that they can't. We last 6 months and should be in virtually all patients. We block PDGF, we block IL-6. So we have other things to offer their patients. And in addition, it's not an either/or. I notice in our patient -- in our studies, all the patients are getting loaded with EYLEA and some get supplemented with EYLEA. So the idea of using 2 mechanism of action, I mean, what chronic disease nowadays isn't treated with more than one mechanism of action, including glaucoma. Our ophthalmologists are used to that. And I think that will be likely a paradigm that's going to be used.

Okay. And just a couple of housekeeping questions before we get into some scenarios around the data. Should we expect 2 top line announcements from EyePoint or do you think they're going to be together?

So the plan right now is they're likely to be separate. One never knows, but our plan is to when we have locked the data on the first trial and are confident in the result, we will release it.

Okay. And if I did my math right, maybe I didn't, but it seems like there will be one more DSMC meeting before the top lines.

Ramiro, do you want to comment on that?

Yes.

And maybe what you've seen to date might be helpful, too.

That's right. So we, as a company, we provide oversight of the safety of the studies on an ongoing basis. So we review that data on a masked fashion, of course, on an ongoing basis. And then we have an independent DMC that reviews the masked data every 6 months. So we had so far 2 meetings, the last one in November. We're going to have another one in May. So this is before the top line results. They're going to be reviewing the data. So far, both the mask assessment tell us that the safety profile overall is very similar to what we have seen before in our Phase I, Phase II studies. So everything as we expected. And very importantly, the DMC reviewed the mask data and told us that there is no need to change the protocol or the conduct of the study.

Okay. And what -- can we talk a little bit more about what you think represents positive data here for each of these studies? And what relevant detail do you plan to provide at the time of your top line?

Sure. So I think...

Sorry. And Jay, just in that context, just I know we talked a little bit about your primary endpoint, but what are you specifically looking for around your secondary endpoints of reduction in treatment burden and percentage of eyes free of supplemental EYLEA injections?

So I do believe it's going to be pretty straightforward. We need to be statistically noninferior to 2 milligram EYLEA. The actual numerical difference will probably not matter unless we're superior. And frankly, while that's not our expectation of superiority, we have some data to suggest that we could be numerically superior, including the DME data without that outlier, we were 3 letters better.

And the wet AMD data, if you looked at our DAVIO 2 trial and you just looked at the unsupplemented eyes, the DURAVYU arms did slightly better visually than the EYLEA did. But we need to be obviously to hit the primary endpoint. And I do like to remind everybody that retina specialists, if we're a letter or so worse, probably doesn't matter. High-dose EYLEA was 1.4 letters worse than 2-milligram EYLEA, but it hasn't stopped my colleagues from using the drug. Obviously, safety that goes hand-in-hand with efficacy here. And you just heard from Ramiro that we now have given our drug to approximately 650 patients and really aren't seeing anything at this point, which would suggest an issue. Obviously, the study is not done yet there.

And the third thing we need to do is in the secondary endpoint is be statistically superior to 2-milligram EYLEA in reduction in treatment burden. And I have to say when you actually do the stats on that, that should be an easy bar to hit. The percentage of eyes that are rescue-free, I think, will help us from a commercial perspective, but not sure it's actually as relevant to the FDA. Just like the OCT data, important to retina specialists, but probably not as relevant to regulatory. So again, there's 3 things we need to hit. I like to hit them in both trials. Both trials are essentially identical. And so we have quite a bit of confidence based on the data that I've talked about already today that we will be able to achieve that.

Okay. So in that context, what keeps you guys up at night?

Did the time change? No. I have to say, I've been in this role about 2.5 years, and I've learned a lot in a very short period of time. And one of the things I've learned is we have a really, really good team of people. And for those of you who do drug development, you know every day is a new challenge. But when you see how your team fights through the challenges, some easy and some hard, you get very confident in their ability to tackle anything. And I do want to point out, again, Ramiro's clinical team, we did faster and I hope better recruitment to those Phase III trials than all of the big companies, Roche Genentech, Regeneron, we did better.

So what keeps you awake at night is we have a daunting task. I think we have a great drug that has a lot of advantages over the ligand blockers, but we're going to have two 10,000 pound gorillas out there, Roche Genentech and Regeneron that we'll be going up against. But we have enough differentiation that if approved, I think we will carve out a very, very good market share.

Okay. And assuming positive data here, how quickly do you think you can file in the U.S. and Europe?

Ramiro, do you want to take that one?

Yes. So I think the same efficient work that we have done with the enrollment, we're going to be looking to do that for the database lock as well as the submission. The beauty of our program is that the 2 studies are identical, and we're going to get Lugano first. So we're going to get that data. We're going to start to write the CSR, the modules. And then we get the LUCIA data which, again, because this says are very similar, the write-up of those documents should be quite quick. If you look at industry standard, submission is about 6 months after a database lock. We believe we can do better than that for the U.S. and then after that for EMA.

Okay. Great. And how are you thinking -- I think there were some comments in your presentation here, but just to maybe elaborate a little bit more. How are you thinking about the TAM for wet AMD? And what is the reasonable penetration of the market for an extended-release TKI like DURAVYU? And what -- are there any potential challenges that you envision from an adoption standpoint?

So let me take the last one first. From an adoption perspective, again, doctors are used to doing things in a certain way. And so one nice thing about being in retina is we're at heart surgeons. And so we don't always follow labels or directions all that well. And we're not afraid to try new things. So I think that's going to help with our adoption. And when you talk to some of the younger retina specialists, they are just overwhelmed with injections, and they really want the ability to take at least some of their patients out longer so that they can actually not be working until 8 o'clock at night seeing 100 patients in the day. I'm sorry, I took the last one first. So could you -- what were the other 2 you asked?

I don't know. Is it only Tuesday? No. Just talking through any challenges and just how you think about TAM, but you kind of covered it, I think.

Yes. The challenges, again, are really educational is to educate the physicians on quite simply who to use the drug in and how to integrate it into your practice. And the whole concept of it's not an either/or. You don't have to give up your favorite anti-VEGF. And if you want to use 2 MOAs, feel free. We can dose products that are approved once every 28 days. And so alternating a ligand blocker with a sustained-release TKI can make sense.

And I just wanted to ask kind of a quick question here. Just we know there's a competitor out there that has a study reading out shortly, the Phase III [ SOL-1 ] study. Can you maybe talk through, Jay, really what I'm interested in is what the read-throughs are for your program from those data from your perspective?

So sure. So at a high level, I think we already know this. TKIs work. There's been, to my knowledge now, 8 TKI trials with various delivery systems, intravitreal, orally suprachoroidal and wet AMD, and they've all been positive. And so I do expect the study to show a positive benefit of TKIs. Beyond that, however, the study design, again, is very, very different than what we're doing. And given that retinal physicians don't typically watch patients lose 15 letters, it's hard to know how applicable that result will be in the real world. But again, I go back to our trial design. We're going up against 2-milligram EYLEA on label. I believe physicians, if we're positive and approved, they will know exactly how to use us because they know what other products do against 2-milligram EYLEA because that's been the standard.

So maybe a couple of quick hits to round us out here. Just turning now to DME. How derisked do you think your Phase III trials are here? Like any nuances to be thinking about from like an opportunities and challenges point of view?

So I think we're very derisked in DME. Again, we had a very good result in the Phase II, and we block IL-6. And if you look at some of the data on that, for example, there's a study that was done where they were doing vitrectomy on eyes in the eyes that had diabetic macular edema had significantly higher IL-6 levels than normals or diabetics without diabetic macular edema. We know that high IL-6 levels result in poor response to anti-VEGF. And again, we showed you some of the combo data for anti-VEGF and anti-IL-6. So we believe that's going to be a significant advantage not only in the trial, but in the real world. Once again, who wouldn't like to see better faster with less injections. So I think the DME results, I'm very confident in them given the positioning and given the study design, I -- we are quite confident in the results.

Last question for me to round out the conversation here is maybe you could just remind us of your cash on hand and what milestones that allows you to complete to bring you in, George?

Go ahead, George.

Yes. So as part of the presentation, we ended 2025 with just over $300 million of cash, puts us our cash guidance remains unchanged into Q4 '27 that funds all of the ongoing Phase IIIs, including the 2 DME trials, which we expect to read out sometime in Q4 of '27. And so when we read out the wet AMD trials later this year, we'll have well over a year of cash. So we're feeling great about our balance sheet, no debt.

Okay. And any considerations just around commercial supply build-out?

Yes. So that's included in our projections as well. As Jay pointed out, our Northbridge facility is up and running. We've had remarkable activity there, and we're gearing up to meet that CMC section and registration batches, and that will also continue to support some of the initial commercial build.

Great. Thank you so much to the entire EyePoint team for being here, and appreciate all the listeners for joining as well. Thank you.

Good morning. My name is Antoine, and I will be your conference operator today. At this time, I would like to welcome everyone to the EyePoint Third Quarter 2025 Financial Results and Recent Corporate Developments Conference Call.

Please be advised that this call is being recorded at the company's request. I would now like to turn the call over to George Elston, Executive Vice President and Chief Financial Officer of EyePoint. Please go ahead.

Thank you, and thank you all for joining us on today's conference call to discuss EyePoint's third quarter 2025 financial results and recent corporate developments. With me today is Dr. Jay Duker, President and Chief Executive Officer of EyePoint.

Jay will begin with a review of recent corporate updates and discuss our clinical programs for DURAVYU in wet AMD and DME. I will close with commentary on the third quarter 2025 financial results. We will then open the call for your questions where we will be joined by Dr. Ramiro Ribeiro, our Chief Medical Officer.

Earlier this morning, we issued a press release detailing our financial results and recent corporate developments. A copy of this release can be found in the Investor Relations tab on the company website, www.eyepointpharma.com. Before we begin our formal comments, I'll remind you that various remarks we will make today constitute forward-looking statements for the purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995.

These include statements about our future expectations, clinical developments and regulatory matters and time lines, the potential success of our products and product candidates, financial projections and our plans and prospects. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factors section of our most recent annual report on Form 10-K, which is on file with the SEC and in other filings that we have made or may make with the SEC in the future. Any forward-looking statements represent our views as of today only. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change.

Therefore, you should not rely on these forward-looking statements as representing our views as of any date subsequent to today. I'll now turn the call over to Dr. Jay Duker, President and Chief Executive Officer of EyePoint.

Thank you, George. Good morning, everyone, and thank you for joining us. I am pleased to discuss with you today the tremendous progress we've made during the past quarter, continuing our strong track record of execution. As you will hear, our momentum underscores our confidence in the differentiated clinical profile of DURAVYU, our lead program and its potential to transform the treatment paradigm in the 2 largest retinal disease markets, wet Age-related Macular Degeneration or wet AMD and Diabetic Macular Edema, or DME.

I'd like to start with a brief overview of our recent highlights. DURAVYU is on track to be the first to file and first to market among all current investigational sustained delivery wet AMD and DME programs, positioning DURAVYU at the forefront of the treatment landscape with potential first-mover advantage. We completed enrollment of the LUCIA trial, the second Phase III trial for DURAVYU in wet AMD in July. Both trials, LUGANO and LUCIA were enrolled in 7 months and together recruited over 900 patients, making them among the fastest enrolling wet AMD pivotal programs to date.

Top line data for DURAVYU and wet AMD is expected in mid-2026. Following the positive end of Phase II meeting in July for DME, we were pleased to align with the FDA on a non-inferiority trial design that we believe is clinically rigorous, efficient and derisked. As a reminder, DURAVYU is the only tyrosine kinase inhibitor or TKI in development for DME. We are rapidly moving forward with a pivotal Phase III DME program with first patient dosing expected in Q1 2026.

The Phase III DME trials, COMO and CAPRI will leverage our existing wet AMD clinical trial infrastructure and our enthusiastic network of investigators.

We announced new preclinical data showing that vorolanib, the active drug in DURAVYU, is unique among TKIs being tested in retinal diseases as it inhibits both [ VEGF ]-mediated vascular permeability and interleukin-6 or IL-6 mediated inflammation. This multi-mechanism of action has the potential to be particularly effective in the treatment of multifactorial diseases such as wet AMD and DME. These new data underscore the impressive Phase II results of the VERONA trial in DME and strengthened our confidence in our clinical programs.

Finally, our path to potential success in Phase III is supported by our strong balance sheet. We ended September 2025 with over $200 million in cash and equivalents and closed a $172 million follow-on offering in October. Our cash is now expected to fund operations into Q4 2027, well beyond Phase III wet AMD data anticipated in 2026. With this continued exceptional track record, EyePoint will enter an eventful 2026 from a position of strength.

Now I'd like to take a closer look at the current market landscape for wet AMD and DME. With a combined current global market of $10 billion and growing, these indications make up the vast majority of the global branded retinal disease market. Despite the size and scale of these diseases, they are dominated by a single treatment modality, monotherapy anti-VEGF biologics. Due to the high burden of frequent injections, many patients remain undertreated, even with the addition of recently approved extended duration options.

Additionally, these current standard of care anti-VEGFs demonstrate subpar real-world efficacy in DME with growing literature supporting the role of not only VEGF activation, but also IL-6 signaling and inflammation driving disease severity. We believe our lead product candidate, DURAVYU, is well positioned to deliver much needed innovation in both wet AMD and DME. As a differentiated sustained-release TKI, DURAVYU is designed to improve the current standard of care by providing durable disease control while reducing the treatment burden.

Further, DURAVYU's potential multi-MOA blocking VEGF, PDGF and IL-6 signaling may be uniquely suited to effectively address multifactorial retinal diseases such as DME and wet AMD. Beyond its unique MOA, DURAVYU offers a compelling product profile that supports strong competitive positioning in both wet AMD and DME. Unlike other sustained release options in development, DURAVYU is formulated in our Durasert E technology. a biodegradable sustained release insert specifically designed to prevent free floating drug particles.

Additionally, DURAVYU is shipped and stored at ambient temperature and administered via a standard intravitreal injection. DURAVYU features the most robust clinical data package among all investigational sustained release programs. This includes Phase II wet AMD and DME data, demonstrating meaningful visual and anatomic improvements from a single DURAVYU dose and a consistent and favorable safety and tolerability profile with no safety signals observed in over 190 patients across 4 completed clinical trials.

Given its advantageous clinical profile, multi-target MOA and unique storage and administration conveniences, we are confident that DURAVYU offers a differentiated value proposition that is meaningful to physicians and patients. And if approved, would present a compelling option within the current and future landscape for retinal disease treatment. Let me now walk through recent updates for our Phase III programs, beginning with wet AMD.

Our fully enrolled Phase III pivotal program remains on track to deliver top line data starting in mid-2026. As a reminder, in July, we completed enrollment of the Phase III program with over 900 patients randomized across the 2 trials. To ensure we are positioned for commercialization, we are highly focused on our manufacturing capability and CMC submission for an [ NBA ]. We have already produced DURAVYU registration batches at our state-of-the-art GMP-compliant manufacturing facility in Northbridge, Massachusetts. The 41,000 square foot facility was built to both U.S. FDA and EMA standards and will have capacity to support the commercial launch.

Moving on to the recently initiated Phase III program in DME. Our program consists of 2 non-inferiority trials, COMO and CAPRI, evaluating DURAVYU 2.7 milligrams versus on-label aflibercept control. Each trial will enroll approximately 240 patients. Additionally, given the established non-inferiority pathway as well as our ability to leverage our existing Phase III clinical trial infrastructure, we believe the program is significantly derisked. We look forward to dosing our first patient in Q1 2026.

As I mentioned earlier, there is growing clinical evidence supporting the multifactorial nature of retinal vascular diseases with both VEGF-mediated vascular leakage and inflammation contributing to disease pathogenesis. IL-6, a pro-inflammatory cytokine is a key driver of this inflammation and is found at significantly higher levels in DME and wet AMD patients versus healthy individuals. Recent preclinical findings, which we presented at the American Academy of Ophthalmology meeting in October, demonstrate that vorolanib, the active ingredient in DURAVYU, inhibits IL-6 signaling through [ JAK1 ] receptor blockage in addition to its known inhibition of PDGF and all VEGF receptors.

In vitro data shows a meaningful reduction in IL-6 activity of more than 50% with vorolanib, suggesting a multi-MOA capability. This data may explain the rapid fluid reduction and vision improvements observed as early as week 4 in the DURAVYU arms in the Phase II VERONA trial.

In summary, we are well positioned to extend our clinical leadership in sustained release therapy for the 2 largest retinal disease markets. We remain focused on reporting top line Phase III data for both LUGANO and LUCIA starting mid next year, positioning DURAVYU to be the first to file and potentially first to market among all investigational sustained release programs in wet AMD.

Our Phase III DME program is now underway, and we expect first patient dosed during the first quarter of 2026. We are moving swiftly and confidently to bring DURAVYU to patients in need while continuing to ensure our progress follows a derisked, clinically rigorous and patient-centric approach. Before passing it over to George to review our financials, I want to thank the entire EyePoint team for your dedication to improving patients' lives through better vision as well as the patients, study coordinators and clinical investigators outside of our organization who enable our clinical research. We are grateful for your confidence, and we are proud to advance our therapeutics for the benefit of the entire retina community. We look forward to continued progress towards our upcoming milestones as we further our leadership in sustained ocular drug delivery. I will now turn the call over to George. George?

Thank you, Jay. To begin, we continue disciplined financial management and good stewardship of our resources, ending the third quarter with $204 million in cash and investments. As Jay mentioned, in October, we completed a $150 million follow-on financing plus the exercise of the underwriter's greenshoe option on October 29 for a total of approximately $172 million in gross proceeds, adding to our cash position and enabling the execution of the Phase III DME program.

We expect that cash and investments as of September 30, along with net proceeds of the financing will support our operations into the fourth quarter of 2027, well beyond key data readouts from the Phase III LUGANO and LUCIA pivotal trials anticipated in mid-2026. As the results for the 3 months ended September 30, 2025, were included in the press release issued this morning, my comments today will be focused on a high-level review for the quarter.

For the quarter ended September 30, 2025, total net revenue was $1 million compared to $10.5 million for the quarter ended September 30, 2024. This decrease was primarily driven by the recognition of deferred revenue related to the company's 2023 agreement for the license of YUTIQ product rights in the prior year period. Operating expenses for the quarter ended September 30, 2025, totaled $63 million compared to $43.3 million in the prior year period. This increase was primarily driven by clinical trial costs related to the ongoing Phase III LUGANO and LUCIA clinical trials of DURAVYU for wet AMD.

Net nonoperating income totaled $2.3 million and net loss was $59.7 million or $0.85 per share compared to a total net loss of $29.4 million or $0.54 per share in the prior year period. As I noted earlier, cash and investments on September 30, 2025, totaled $204 million compared to $371 million as of December 31, 2024, which, along with net proceeds from the October financing, we expect will enable operations into Q4 2027.

In conclusion, we are very pleased with our progress and continued execution in 2025 and are well capitalized to deliver DURAVYU Phase III wet AMD data in 2026, while advancing our Phase III DME program with the COMO and CAPRI clinical trials. I will now turn the call back over to Jay for closing remarks.

Thank you, George. As you've heard this morning, EyePoint is on the cusp of a milestone year in 2026. Our decades of drug development experience, clinical track record, next-generation technology and blockbuster potential of our DURAVYU franchise underscore our exciting growth story. With our strong balance sheet and disciplined cash management, along with our thoughtful derisked development strategy, we are prepared to execute through our key upcoming milestones, including top line data for the Phase III LUGANO trial anticipated in mid-2026 with LUCIA data to closely follow, positioning us for a potential MDA submission for DURAVYU in wet AMD and the first patient dosing in our pivotal Phase III DME program anticipated in Q1 2026, with full enrollment expected in the second half of 2026. Thank you all for your attention this morning. I will now turn the call over to the operator for your questions.

[Operator Instructions] Our first question comes from Tess Romero from JPMorgan.

I wanted to ask a market sizing question today. Can you just refresh us for the wet AMD population overall here in the U.S.? What percent of patients are treated every 4 weeks, every 6 weeks, every 8 weeks or longer? And what is your latest view on how the doctors will use DURAVYU, if available in that context?

Thanks for the question. It is insightful. And as you may surmise, the data is not strong to give exact numbers for each of those intervals. What we do know is approximately 20% of wet AMD patients have to be treated monthly regardless of the drug that they're using. If you look at the clinical trial data, even with the newer extended duration agents, 50% of the eyes can't go longer than every 8 weeks. Depending on a doctor's toleration for fluid, some patients can certainly go 3 and 4 months in between injections. But again, it's individualized to the patient and oftentimes individualized to the doctor's tolerance of fluid and adherence to the label.

So I don't, off the top of my head, have exact numbers to give you for those other percentages. And I'll pause and see if Ramiro has any other insight.

Yes. No, thanks, [ Tessa ], for the question. I think when we think about DURAVYU, in our Phase II data, we showed that after dosing DURAVYU, about 65% of patients did not require any supplemental injection with anti-VEGF. And even when we look at 0 or 1 injection over that 6-month period, then the number is about 90%. So we believe that DURAVYU is really well positioned if we see the results in the Phase III study being replicated to bring the market for wet AMD patients.

And to answer the second part of your question, Tess, I don't think you can look at it as an either/or, meaning if DURAVYU is approved, doctors will be limited to just using one agent. We're a different MOA. And clearly, the more recent data with IL-6 inhibition suggests that we may offer an MOA that the [ ligand ] blockers cannot. That would open up market tremendously to us. And as Ramiro just explained, physicians, I'm sure, would be willing to take advantage of 2 MOAs. We do that in chronic diseases all the time. And therefore, the market share for DURAVYU, when you speak to some of the KOLs on the podium even recently have said up to 80% of their patients would be eligible. So we're really optimistic that the acceptance of a multi-MOA TKI with sustained release in both wet AMD and DME is going to be high.

Our next question comes from Yigal Nochomovitz from Citi.

This is [ Jen Kim ] on for Yigal. Regarding DME, can you provide any additional color on how you're structuring your enrollment criteria to provide the broadest reach in the DME marketplace relative to competitors in the long-acting TKI space?

Sure. I'll let Ramiro answer that question. Thank you very much for it. And again, I can quickly answer the second part of the question. We're the only TKI sustained release that has a DME program. So that part is easy. But Ramiro, why don't you talk a little bit about how we've designed the trial?

Yes. So first, to give an overview on our Phase III DME program, CAPRI. So we are going to be enrolling patients with active DME, both treatment naive and previously treated. as a control arm, we're going to use aflibercept on label and then DURAVYU is going to be being dosed every 6 months. We are very fortunate to have a strong infrastructure here at EyePoint as we conducted our wet AMD study. We have also a very strong relationship with investigators. So for our DME program, we're going to be able to leverage those strengths into a hopefully rapid enrollment for the DME program. I think it's our understanding that we might be the only Phase III program enrolling patients next year for this indication. So again, I think we expect to see a rapid enrollment, similar strength that we did for the [ wet AMD ] program.

And regarding enrollment, just for clarification, I believe I heard you say second half ' 26. Is that for both COMO and CAPRI?

So I think what we're guiding now is that both studies are going to be starting Q1 of next year, 2026.

Our next question comes from Tyler Van Buren from TD Cowen.

This is Sam on for Tyler. I wanted to ask about the use of the blended endpoint, which you guys have remained consistent on with the pivotal wet AMD and DME trials. We have seen the FDA greenlight a single endpoint more recently. So curious if you thought about using a single endpoint at all for the DME studies and why you believe the blended endpoint is the best approach?

Thanks, Sam. I appreciate the question. And I'll let Ramiro go into the details. But to answer quite simply, did you think about a single endpoint, quick answer is no. Ramiro, why don't you talk a little bit about our interactions with the FDA over endpoint and why the blended endpoint is actually derisking?

Yes. Thanks, Sam, for the question. So for both our wet AMD program and our DME program, we are using blended endpoint, meaning that for the primary endpoint, we're counting 2 visits. The benefit of that is that we prevent missing data. So in this type of study, it is not uncommon to see patients missing the visit because they have medical appointments or they're in the hospital for some [ systemic ] disease. So by having 2 visits, we reduce the amount of missing data. And also very important, if a patient has, for any reason, a loss in vision in one of the visits, they have the ability to capture the recovery of that vision in the next visit.

The use of blended endpoint has been common in clinical trials for retinal disease for the past few years with the main goal of decreasing the variability and increasing the power of the study. And that's why we feel confident on using the blended endpoint for both wet AMD and DME. And of course, we have the green light from the FDA to do so.

Our next question comes from Claire Dong from Jefferies.

This is Jenna on for Clara. Could you talk about the differentiation in IL-6 inhibition? And could you help us kind of elaborate on how that could translate into clinical benefit in DME versus an anti-VEGF only approach?

Thanks for the question, Jenna. And this is really timely because you may be aware, there's some recent data from Genentech who used an IL-6 blocker in a DME trial combined with an anti-VEGF. Both were delivered monthly and the arm with the IL-6 blocker along with the anti-VEGF had better vision as early as week 4 and sustained through the trial. We were able to show a very similar vision improvement and course of improvement in our VERONA trial using just 2 injections over 6 months as opposed to 12 injections over 6 months. And when we looked into it more closely, we discovered that, in fact, vorolanib is a potent inhibitor of IL-6 pathway by blocking the JAK1 receptor.

There is substantial evidence in both wet AMD and DME that IL-6 plays a pathogenic role, especially in eyes that are not responding. And therefore, the ability to block both VEGF pathway and inflammatory IL-6 pathway could be a significant improvement over what we have now, especially coupled with sustained release. so that you're not having to give 2 biologics on a monthly basis.

Our next question comes from Yatin Suneja from Guggenheim.

Maybe 2 questions from me. One is on the mechanism regarding the IL-6. Jay, if you can comment on the relevance of it in one disease versus the other? Do you think there is more relevance in DME versus AMD? So that's one. And then the second question is now more around the expectation now that the studies -- wet AMD expectations, right. Now the studies are enrolled, I think our investors are sort of beginning to think about what we should be expecting from the data. And I think there is focus on 3 things. One is the BCV and noninferiority, what sort of injection burden you can produce? And how should we think about rescue rate? So if you can comment on that, that would be very helpful.

Thanks, Yatin. Two great questions. Let me start with the IL-6 question. IL-6 has been implicated in inflammatory macular edema for well over a decade. And additional data suggests that IL-6 levels in the vitreous are much higher in DME patients than in diabetics with no diabetic retinopathy. In addition, there's data that suggests high IL-6 levels in aqueous humor portend a worse outcome in both DME and wet AMD.

So overall, the evidence for a role of IL-6 as an inflammatory pathway in DME is very strong. And while it's there in wet AMD as well, it appears to be a prognostic factor in the percentage of eyes that aren't doing well with VEGF blockage alone. We believe that if the preclinical data we have shown and the rapid and early and sustained response in our VERONA DME trial can be shown in Phase III. This would be an exceptional result, which would put us at the forefront of both wet AMD and DME therapies.

As for the clinical trial results, which we expect, again, the first trial, LUGANO mid next year, second trial LUCIA soon to follow. Based on our strong Phase II data, we would expect non-inferiority to the on-label Eylea control with continued safety. And again, safety is of paramount importance here, as I'm sure you all know. But based on the ongoing mask safety that we've seen in these 2 Phase III trials as well as the extensive safety database we have for both DURAVYU and vorolanib.

we're confident that the safety will be quite good. As for reduction in treatment burden, again, that's important. There's no specific cutoff that says it has to be above or below a certain level. And based on our discussions with KOLs and the design of the trials, we think a 50% reduction in treatment burden will, again, put us into the forefront of therapies for wet AMD.

Our next question comes from Debanjana Chatterjee from Jones.

Congrats on all the progress. So assuming LUGANO and LUCIA meets its, the non-inferiority endpoint, does your statistical analysis plan allow for testing superiority? And if so, how do you expect clinicians to interpret those data related to on-label Eylea compared to potential competitors pursuing superiority claims based on like less frequent dosing?

So Ramiro, why don't you answer that? Thanks, Debanjana. I appreciate the question.

Yes. Thanks for the great question. So our -- as you mentioned, our analysis plan does allow for testing superiority again, aflibercept if our noninferiority is met. So it's a hierarchical testing. So we have the ability to test for that. Of course, if we see that DURAVYU produce superior visual outcomes compared to on-label aflibercept, then, of course, I think it will be an outstanding results for the retina community and wet AMD patients and would allow us to position DURAVYU as a premium medication. Of course, having a superiority claim against on-label aflibercept, I think from a retina specialty perspective is much more relevant than having a superiority versus a single dose of aflibercept.

So we are -- we continue to be optimistic with our LUGANO and LUCIA study. We were very fortunate to have the [ DABE2 ], our Phase II study to support the design of the Phase III programs, a lot of the learnings coming from there, and we're looking forward to see the results mid next year.

This concludes the question-and-answer session. I will now turn it over to Jay Duker for closing remarks.

Thanks very much. Before we close, I do want to mention a tremendous honor that EyePoint received this week. We were voted a 2026 Best Places to Work by BioSpace. In fact, we were in the top 5 best biotech companies nationally. This is a testament to the incredible team and culture we built here at EyePoint. Exceptional execution does not come in a vacuum.

I want to thank all of our amazing team for this honor, but especially our human resources group led by our Chief People Officer, Jen Leonard. Thank you all for your time and attention this morning.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.