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

Good day, and thank you for standing by. Welcome to the VERONA 6 months top line data conference call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Jay Duker, President and CEO. Please go ahead.

Thank you very much. Good morning, everybody. We really appreciate you listening this morning. We are really excited to present the 6-month VERONA data. We think the data is outstanding, and we are really excited to be moving forward with a program in diabetic macular edema. These are the legal disclaimers and of course, you can visit our website if you'd like more detail. EyePoint is the leader in sustained release drug delivery for retinal diseases. DURAVYU, which is our lead product, contains patent-protected vorolanib, which has a new mechanism of action delivered via the best-in-class intravitreal delivery technology, which we call Durasert E. EyePoint has the most robust data set in wet AMD and DME among all the sustained delivery programs that are in development. And we have 2 ongoing global Phase III non-inferiority pivotal trials in wet AMD that are enrolling rapidly. We are the only sustained-release TKI program in DME, and it's bolstered by the highly positive Phase II clinical data, which we are about to share. We have a strong balance sheet with $370 million in cash and cash equivalents at the end of last year with a runway into 2027. This is our pipeline. As I mentioned, we have DURAVYU in 2 wet AMD pivotal trials that are currently enrolling, enrollment is going very well, and we anticipate completion of enrollment in both trials in the second half of this year. We're about to share this positive 6-month data in diabetic macular edema. And the next step for that will be meeting with the FDA, we hope in the second quarter of this year, to start the program also in 2025. And our pipeline is EYP-2301, which I'll mention briefly, that's razuprotafib, a TIE-2 agonist that is able to be delivered sustained release. Durasert E is a sustained release drug delivery system is delivered in the office by a standard intravitreal injection. Durasert features continuous dosing with 0 order kinetics release for at least 6 months in humans. The inserts are solid. They are heavier than water. After injected, they sink to the bottom of the vitreous cavity, which they generally remain stable there. The drug is formulated in a bioerodible matrix and it's designed to release the full drug load before the matrix completely goes away. And we've now shown the favorable safety profiles across multiple indications. You can see on the left of this slide, an illustration of the size of Durasert E to approximately 1/5,000s of the vitreous cavity. VERONA is this best-in-class tyrosine kinase inhibitor selectively inhibits all forms of the VEGF receptor, which means we block all isoforms of VEGF, including VEGF CNV. In addition, VEGF is blocked, which could potentially mean an improvement via anti-fibrosis. We have excellent patent protection with composition of matter on vorolanib into 2037. And once again, this provides a new mechanism of action for VEGF-mediated disease by acting intracellularly. In an animal model, we demonstrated neuroprotection and at the doses used in humans, we do not inhibit TIE-2. The review is vorolanib in bioerodible Durasert E, it provides immediate bioavailability reaching therapeutic levels within hours. The constant dosing, which is called zero-order kinetics provides a steady-state release for up to 6 months in humans, which allows for relatively small doses to be very effective. We are able to control the drug release via this bioerodible matrix to allow for no free-floating drug. And these inserts contain no pay or no PLGA. Our inserts come in a preloaded sterile syringe injectors, making it very easy for doctors to deliver this in their office. And one other advantage we have is we can be shipped and stored at ambient temperatures. These newer version of the inserts, which we used in the VERONA trial have a payload of 1.34 milligrams of drug and these inserts are 94% drug. We've performed 4 clinical trials, which are listed on the left. 2 in wet AMD, 1 in NPDR and 1 in diabetic macular edema. So over 190 patients to date have been dosed with DURAVYU with no ocular or systemic SAEs reported. The key efficacy outcomes are on the right for these 4 trials. And of course, today, we're going to talk about the VERONA trial. So the VERONA trial is a Phase II clinical trial in diabetic macular edema with a 6-month outcome. What you'll see from the data is our drug provides immediate bioavailability and provide sustained delivery for up to 6 months. But why is this important? Well, there is a large unmet need in diabetic macular edema for more durable treatments, probably even more so than in wet age-related macular degeneration. It's currently estimated that in the United States in 5 years, there'll be over 50 million diabetics and about 1 in 4 will get diabetic macular edema within 10 years. In 5 years, it's estimated that the global market for DME will approach $4 billion. But the problem is delaying in this visits, about half of patients do not get the visits, the injections, the treatment that their doctors recommend and this can result in severe permanent visual loss. But the problem goes beyond individual diabetics. This is a global health problem and in the United States, it's huge socioeconomic problem. It's estimated by 2050 that the vision loss, not just the therapy, but the vision loss due to diabetic eye disease will approach $0.5 billion. The Phase II VERONA trial is a randomized open-label aflibercept controlled trial for DME. All the patients entered the trial with active DME. They had to have a CST as measured on OCT of a minimum or maximum -- I'm sorry, a minimum of 325 microns and you'll see most of the patients were a lot thicker than that. The primary endpoint of this trial was time to first supplementation. The key secondary endpoints, of course -- endpoints were safety, change in next corrected visual acuity versus the control and anatomic control as measured an OCT. On day 1, all of the patients received a single injection of 2-milligram aflibercept. And 30 minutes later, they either received a 1.3 milligram dose of DURAVYU, that was 10 patients randomized to that arm or they received 2.7 milligrams of DURAVYU at 11 patients in that arm or they received a sham after the aflibercept. That was the aflibercept controlled arm. The patients were then watched monthly, and there were no other mandated injections of either DURAVYU or aflibercept. However, there was supplement criteria, which allow any of the patients to be supplemented if they met that criteria. And here is the supplement criteria. Starting at week 4, the first visit, eyes could be supplemented if they had a reduction in 10 letters due to DME, a reduction of 5 to 9 letters with increasing fluid due to DME, an increase of 100 microns of new fluid over baseline or investigator discretion. And these are essentially the same supplement criteria that we use in DAVIO 2, our wet AMD Phase II trial. However, VERONA, we added a fifth supplement criteria. And this is a unique supplemental criteria that had not been used to our knowledge in any other trial. And we don't plan on using the pivotal trial. This was due to the PRN design of the trial. So starting at week 12, if that eye had not improved, at least 10% in CST, we wanted the eye to be supplemented. The rationale here was these eyes all had active diabetic macular edema with decreased vision, and it wouldn't be right to continue to watch them if they didn't improve without treatment. And as it turns out, this unique supplemental criteria was responsible for the majority of supplements in the trial. Here is the summary of the results for the 2.7 milligram dose, which is the dose we're currently testing in Phase III wet AMD and if approved, would be our go-to-market dose. The data supports to review as a potential treatment because it showed improvement in both vision and anatomy with a secure dosing interval. The 2.7 milligrams are met the primary endpoint extended time to first supplement versus aflibercept control. There was a best corrected visual acuity improvement of 7.1 letters and a significant CST improvement of 76 microns. Compared to the aflibercept control, there was a 73% of eyes who are supplement-free up to the 6-month visit, 50% of the control eyes were. And the 2.7 milligram arm of DURAVYU showed a 2/3 reduction in treatment burden. DURAVYU Safety continues to be very good. No ocular or systemic DURAVYU-related SAEs. And in this trial, there were no cases of impaired vision, endophthalmitis, retinal vasculitis, intraocular inflammation or insert migration. This is the visual acuity graph for the 2.7 milligram arm. Note that there was significant improvement as early as week 4, and that improvement was sustained throughout the length of the study. This is the graph for the control arm, the green, notice there was a similar improvement in the control arm of about 7 letters at week 24. This gives us great confidence that DURAVYU in a non-inferiority trial would be noninferior to an Eylea control. The red box highlights the difference at week 4. Notice that there is a significant difference with the DURAVYU arm having a much more immediate improvement in visual acuity. One of the things to note here and as you'll see when we review the supplements is there was no supplementation given before week 12. So the visual acuity results that you're seeing at week 4, week 8 and week 12 are all driven by those medications that were delivered on day 1. The effect of the supplements would not start until week 16. And you can see that in the DURAVYU arm, there really wasn't much improvement with the supplementation as opposed to the control arm, which did continue to improve with supplementation. And one way to interpret this, of course, is that the visual acuity improvements in the DURAVYU arm had already reached their maximum. There was a drop off between week 20 and week 24 in the DURAVYU arm, and that was driven by a single outlier. That outlier had actually missed visits and therefore, their 24-week visit would have been a 20-week visit. They did get supplemented and that decrease in vision that was documented at week 24 have reversed 4 weeks later when they returned for a week 28 visit. If we did this analysis without that outlier, the DURAVYU arm would have improved 10.1 letters. The magenta line shows you the low-dose DURAVYU 1.3 milligrams, and it showed a similar improvement to the high dose right away with a subsequent slow reduction in visual acuity until week 16 when the supplements did cause the vision in the lower dose arm to improve to almost exactly the same as the other arms. Next is the anatomic data. And the first I'm showing is the 2.7 milligram and noticed the immediate drawing effect vision visible at week 4 with a relatively stable dry retina through week 24 of minus approximately 76 microns. This is a control arm, which will also show the drawing effect of about minus 32 microns, did not achieve the same drawing effect as either the high dose DURAVYU or even the low dose DURAVYU. We think this is especially important since visual acuity doesn't always follow anatomy in diabetic macular edema right away, but drawing the retina in diabetic macular edema will eventually lead to improved visual acuity. This graph shows the supplement-free percentage up to each visit. The 2.7 milligram dose ended up 73% supplementary up to week 24 and is featured approximately 2/3 reduction in treatment burden. The green graph is the control group with a 50% reduction in the treatment burden up to 6 months. And the magenta line is the low dose to review, which was in between suggesting a possible dose-response. I will now show a couple of cases. This first case is from the 2.7 milligram arm. This patient did not receive any supplement throughout the study. And you can see on day 1, there was a significant thickening of the retina with the best corrective visual acuity of 46 letters. At week 4, there was an immediate drawing effect with essentially normal contour and improvement in the vision significantly. The improvement in the vision continued up to week 24 with the continued drawing of the retina, although on the triple side of the retina, at week 24, you can see a mild recurrence of some fluid design didn't meet supplement criteria. But remember, in the pivotal trial, this would be the time at week 24 that another DURAVYU would have been injected. This patient was also in the 2.7 milligram arm and also did not receive any supplements. Interestingly, in the 7 months prior to enrollment in the trial, this patient has received 1 Avastin and 5 VABYSMO. On day 1, they had significant fluid with decreased vision. At week 4, 1 month after 2-milligram Eylea and 2.7 milligrams DURAVYU, there was a reduction in the fluid, but no change in the vision. But watch what happens throughout the study. Week 16, there was further reduction in the fluid and starting to be improvement in the vision of 7 letters over baseline. And you can see at the end of the trial, the retina was essentially dry with the normal full-view contour and continued improvement. And this is really explainable by DURAVYU alone. From a safety perspective, I mentioned this already, really no safety issues came up in this trial or really in any of the 190-or-so patients that we treated. There has been no significant safety issues related to DURAVYU. In this particular trial, no cases of endophthalmitis, retinal vasculitis, insert migration or intraocular inflammation, and there were no discontinuations in any new arms, all the patients finished the trial. So let me highlight the findings. The primary endpoint of time to first supplement was met actually in both of the DURAVYU doses. Both doses demonstrated clinical immediate bioavailability with improvements in visual acuity and anatomy seen as early as week 4 that was sustained throughout the trial in the high dose. These results were clinically meaningful and they were achieved without a full load of aflibercept. The significant vision improvement was also paired with a meaningful reduction in treatment burden and even more importantly, with a concomitant improvement in anatomy. The significantly better anatomy was achieved with fewer supplemental injections. And again, we've shown a continued favorable safety and tolerability profile for DURAVYU. So where do we go from here? We continue with development of the Phase III clinical protocol, and we're planning a noninferiority design. We're planning on discussing the proposed Phase III clinical protocol with the regulatory agencies in the next quarter, and we will show them the Phase II results. And based on recent information, we are optimistic that the agency will allow us to perform this with just 1 Phase III trial. We expect to initiate the pivotal program by the end of 2025, and we're going to leverage the experience that we have from LUGANO and LUCIA to not only speed enrollment, but make the trial more efficient, and these results will be presented at future medical conferences. One thing to note is that at the Angiogenesis Conference this Friday, Carl Regillo will be presenting our 16-week interim data of VERONA, but during the discussion, he may be able to discuss some of these findings as well. I'd like to touch on an update for the Phase III pivotal trials now. They're called LUGANO and LUCIA, and they are both noninferiority trials versus aflibercept control. The goal of the trial is to show that when DURAVYU is administered every 6 months, it can achieve similar visual outcomes as on-label aflibercept with a reduced treatment burden. We expect to enroll approximately 400 patients in each trial with 2 arms, 2.7 milligram DURAVYU and aflibercept arm label. The DURAVYU will be dosed every 6 months. We have a 1-year efficacy and safety endpoint for NDA submission, but the trials will be carried out 2 years for safety. Again, the primary endpoint is a blended 50 to the 56-week endpoint and the secondary endpoints of importance are safety, reduction in treatment burden, percentage of bio supplement free and anatomic stability. On this slide shows the outline of the trial. The patients are randomized on day 1. They received a single aflibercept injection on day 1, week 4 and week 8. And at week 8, they received either a 2.7 milligram injection of DURAVYU 30 minutes after Eylea or they receive a sham. They're then watched monthly, every other month of aflibercept, eyes receive another aflibercept to review eyes receive a sham for masking. And at 6 months after the initial DURAVYU, the DURAVYU eyes will receive a second, third and fourth injection of DURAVYU during the 2-year study. Enrollment is going very well in these trials, better than expected. We announced last month that the LUGANO trial was 1/3 enrolled with LUCIA trial also exceeding expectations. We fully expect both trials to be enrolled completely sometime in the second half of 2025 with top line data a little over a year later in 2026. One of the things I'd like to mention that we're especially proud of is our commercial manufacturing facility that opened in October 2024 in Northbridge, Massachusetts. It's a 41,000 square foot manufacturing facility for DURAVYU, it's built to our specifications by the landlord and it's built to conform to both U.S. FDA and EU EMA standards. We expect to manufacture DURAVYU for the DME Phase III trial in this facility. And when this facility is up and running, we should be able to supply all the commercial supply of DURAVYU globally out of this facility. And lastly, just to mention, again, EYP-2301, we continue to progress it through preclinical trials in order to get an IND. This targets VE-PTP, which activates TIE-2 by activating TIE-2, razuprotafib down regulates Ang2 and maintain vascular stability of the retina. We have been able to make razuprotafib in a way that we can put this into Durasert E for at least every 6 months delivery. This slide shows the execution of EyePoint, which has been excellent, and we are well funded through these DURAVYU milestones. We again anticipate the FDA meeting next quarter and anticipate initiating the Phase III pivotal program by the end of 2025. Thank you very much for your attention, and we can entertain some questions from the analysts. And once again, to reiterate, we are the leader in sustained-release drug delivery with DURAVYU leading the way in both wet AMD and DME.

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

So with the 6-week results, there was a separation between your DURAVYU high-dose arm and the aflibercept arm, which seems to have come in with the 24-week results here. To clarify on your earlier comments, it seems like this was driven by a single outlier. How do you interpret this overall? And then as a follow-up, as we look forward, how do you expect these Phase II results in a smaller trial population will translate into a larger Phase III program? And are there any changes that you're thinking about to the trial design?

Yes. Thanks, Tessa. So first of all, we think the results are excellent. The fact that our 2.7 milligram dose was the same as the Eylea dose with fewer supplements speaks very well for the likelihood that we can achieve noninferiority in a pivotal trial. Remember in the noninferiority trial, we don't have to be better than the control. We just need to tie them. And in fact, based on the statistics in the noninferiority trial, the -- one can be even a little worse than the control arm. I'd like to remind everyone that in the wet AMD, the high-dose Eylea trial, high-dose Eylea ended up 1.4 letters worse than 2-milligram Eylea, but it was not inferior and is in wide use. So again, the fact that the control arm and DURAVYU arm ended up with the same vision is a great result for us. We're very happy with that. In saying that, I think that outlier -- in the timing of the outlier visits, which was off-kilter for the study, did bring down by at least 2.5 letters the result. And that's okay. Again, do you expect in a larger trial, such an outlier won't have that result. But without that outlier, I think I mentioned the DURAVYU arms -- the DURAVYU 2.7-milligram arm would have been 10 letters better than baseline or 3 letters better than aflibercept. The other thing you could look at would be to -- we didn't have a blended endpoint in this trial, but we just had a fixed endpoint at 24 weeks. Had we blended at week 20 and week 24, which we're certainly going to do in the pivotal trial of blended endpoint, then there would have been a 2.5-letter separation between DURAVYU and the control. So this is, again, things like this can happen in the small trial that I think will wash out in a much larger trial. But we remain very optimistic that we will be noninferior. In fact, as I look at this data and I compare the data to our Phase II wet AMD trial, I think this data is even more impressive, because this was a wet population, these are all active eyes, and we dried them faster and better than Eylea did. So a larger trial, I think, I've said it already, very optimistic in the results in a larger trial. I think that we are still working through how that trial might be structured, but it will very likely be noninferiority, as I mentioned. And given the results, we remain optimistic. I mentioned this and I talked about the supplement criteria. I'm quite certain that the supplement criteria, the pivotal trial will look quite different, and we will not have that 10% supplementation rule that we had in this trial. But for the more details, I think, again, we're working through that. Ramiro, if you're on the line, if you can comment, Ramiro Ribeiro, our excellent Chief Medical Officer, believe me, just to be able to put a little more color into how we're looking at the pivotal program.

Yes. No, thanks, Jay, and thanks for the question. I think first to remind ourselves that we have the largest wet AMD the data in TKI to date, which also similar to DME is an executive disease. So combined, the results from VERONA, first what we saw in DAVIO 2 give us confidence in actually 50 diseases to move forward to a Phase III study. In terms of the design of the Phase III program, of course, we are considering different aspects. I think one option similar to what we're doing now for wet AMD is to ensure both previously treated as well as naive patients so that we have the experience coming from those 2 patient populations. We ensure we have a broad label and so on. So that might be something that we take into consideration for the Phase III program in the end.

Thanks, Ramiro. And Tessa, you didn't ask this, but I think I'll mention it. We have no plans right now to do the financing for -- to support this trial. We believe, in fact, that we may be able to get there if there's one trial with the current cash that we have. So once again, we're happy with the cash that we have at this point. Our cash guidance has not changed. And we are full speed ahead in the DME program.

Our next question is going to come from the line of Yigal Nochomovitz with Citigroup.

So I just want to come back to this concept around this supplement to fix supplementation role with 10% cut off that you mentioned. So you indicated that you wanted to offer that in the current study since it wouldn't be right not to do it, but then, of course, you're not offering it in the Phase III. So can you just expand a little bit on the logic on why you decided to include it in this trial when it's not going to be part of the larger Phase III program and may impact a little bit in terms of the read-through?

Sure. I think the impact of the read-through of course, will be more positive. But in saying that, again, you look at the 2.7 milligram arm and you look at the time after starting at week 16, where some supplements were given, not a lot, but some were, there's really no change in the visual acuity. And so you could argue that the supplements really didn't affect the primary outcome in this study anyway. But it's likely that we're going to have more of a load in the Phase III that we had here. We only had a single injection. And we hadn't treated patients with DME yet. We didn't really know a priority how these patients would respond. And so this was essentially a safety supplement criteria that our advisers suggest that we put in and we listen to them. We don't need it anymore. We know that our drug works really well in this disease. Look at the immediate drying effect that we have, look at the improvement in vision. So there's no need to attach that anymore because we are very confident in how our drug will work in DME.

Okay. That's super helpful. And then more of like a macro question on the wet AMD landscape. As you know, there's another large Phase III trial with a VEGF CD blocker that's going to read out assuming that works, how are you thinking about your drug in the context of a potential second injection coming to market in the wet AMD space?

So first of all, from the perspective of a read-through, we've locked CNV also by locking all the VEGF receptors. And, therefore, if that trial shows improvement in the visual acuity, I think that bodes well for not only our Phase III results, but our commercial acceptability, that's first of all. Secondly, this idea of doctors and patients accepting more injections for better vision, I think, again, it's all about risk benefit and all the rest of it. And so that -- and if the doctors and patients perceive that improvement is worth it, they may opt for additional injections. On the other hand, we may be able to provide the same benefit every 6 months. So, yes, I think that ultimately, what we're able to do with the 6-month dosing with zero-order kinetics with our safety profile that's nonsurgical and doesn't change people's DNA. I think that we are in a very good position should we be safe, effective, tolerable and FDA approved I really think that we will be widely accepted in the marketplace whether the CNV story plays out or not.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

I have a couple for you. Can you just remind us of the explanation for the potential more immediate benefit with DURAVYU versus Eylea 2 mg. And could it potentially be due to lack of Eylea loading doses? And then the second question is, if I recall correctly, the supplement free data were more similar with the arms in the study than what we've seen with wet AMD. So is this potentially again due to the added risk rescue criteria? And since I'm getting some questions from clients, did that added criteria benefit the Eylea 2 mg arm more than the DURAVYU arm?

Yes. So let me answer the second one. I think the evidence is a bit because -- look at the visual acuity curves at the end of the trial, despite few -- some supplements in the DURAVYU arm 2.7, there really wasn't any real change in the vision. Again, it is suggesting that the visual acuity those eyes, either their eyes were resistant to more Eylea, they needed more Eylea when they just had a ceiling effect. But one could argue, and I think it's obvious that the control group did benefit from more supplements. But back to the explanation of the immediate effect, in animals, we have been able to show that there is a bit of a burst effect with DURAVYU. That in animal eyes, the first week or 2, there's about a 10x greater level of vorolanib before it settles down into these order kinetics. So I think that is a potential explanation as to why both doses showed improvement at week 4, diverse. You could then go on to argue and again, this is hypothetical, that the 2.7 dose was enough to control these patients basically on its own. The 1.3 not so much. You needed a few supplements at the end there and get back to the visual acuity that was achieved with the other arms. So I think that's one explanation. The other explanation is, well, maybe blocking CNV is good in this disease, it gives an immediate effect. And of course, you can't rule out that it was a combination of Eylea and DURAVYU. Any way you look at it, if we can show this in a pivotal trial, this immediate effect, I think this will lead to a very great acceptance in the market. Why wouldn't the patient want to improve faster with fewer injections? So there -- I'm sorry, Tyler, your middle question, can you repeat it?

No, no. I think you covered it. I appreciate it.

Our next question comes from the line of Kambiz Yazdi with Jefferies.

Maybe on the Phase III trial design, kind of what gives me potential confidence that or optimism that the agency may allow you to perform just 1 trial? And then on the wet AMD pivotal program, is there any possibility that you'll be getting more granular patient enrollment data as we kind of proceed towards full enrollment?

So I think some of you may be aware that for AMD just announced about a month ago their DME plans and they had confirmation from the agency that along with their 2 wet AMD trials, they would be able to do a single DME trial. I think if you also look back at the Kodiak original trials, my understanding is that they were only running 2 trials in a single indication in a single trial and the others, at least at the beginning. So I think that there is some indication that the agency would consider just a single trial in DME after the 2 trials in wet AMD. As for enrollment, yes, we do plan on further updates in enrollment as it continues. Again, the enrollment, we set a pretty high bar for enrollment. And so far, we are blown through it. So it's going very, very well.

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

2 for me. So first on the pivotal study design. Would you be required to do a full load, which is 5 injections. If not, what are some alternative hypothesis or strategies you might have? And then second is just on the data and the interpretation itself because we're getting a lot of inbound from investor, I mean, the way we look at it is that you are noninferior to Eylea on visual or BCVA, you are readily bioerodible fast-acting, less supplements. So what is the disconnect? Is there anything particular that we need to sort of think about as we look at this data?

Well, I think looking at the data, I'd add also, I think the visual acuity is important, but I really would emphasize the anatomic results. There is a clear separation in the anatomy here that occurred at week 4. And that there is a correlation in the long term in this disease between function and anatomy that you may not see in the short term. And of course, some of it may have to do with the relatively small ends of the trial. I don't know what the disconnect is. We are really happy with this data. This is a really, really remarkable data for us. So back to the Phase III design, I think it's likely that at least in the control arm, if we go for a typical noninferiority trial that we would be on label for Eylea. This data does free up the possibility that we might have excellent results without a full load in the DURAVYU arm. We haven't obviously fully explored that yet. It's something we're going to consider. And once again, I'm going to ask Ramiro, if he has any further comments around the Phase III design.

Yes, Jay. I think we can -- and we're going to assess how many loads we're going to need for the active arm for DURAVYU arm. One option similar to what we're doing for wet AMD right is to use the same load as we have in the aflibercept label. DME, that will be, of course, platforming dose. But I think the data from DME shows that DURAVYU being used on day 1 is immediately available, provide a rapid increase in BCVA also reduction in CST. So one option is to consider to give DURAVYU early on either after the third loading dose or even maybe the first loading dose. So those are things that we're taking consideration. We're going to discuss the Phase III design with the FDA and then, of course, get their feedback for that program.

Our next question is going to come from the line of Jennifer Kim with Cantor Fitzgerald.

One, I appreciate you talking about the 1 patient who may have driven the DURAVYU week 24 BCVA change. But I'm wondering, can you give any color on whether or not you saw something similar in the aflibercept arm? Or is it really a ceiling effect across the 6 patients in the control arm? And then the second question is I know you've talked about this before, but since we have the full VERONA data. Can you talk about, I guess, the opportunity that you see in DME for the TKIs along -- and maybe compare that to the wet AMD market?

Let me take the second question first. So current estimates in the U.S. is DME market is about 35% of the wet AMD market, but recall that a lot of patients miss visits and don't get the required or recommended injections. And as a result, the visual acuity results aren't as good as what they want and what we want. So the idea of having essentially what we can refer to as force compliance in these patients with a 6-month or longer insert makes a lot of sense. And I think that if the data holds and we're safe, approved every 6 months tolerable, I think you'll see penetration even higher in DME than you will in wet AMD because of those facts that these are a group of patients that are often quite undertreated. And there's really been difficult for retina specialists to get around that. So back to the outlier patients. Again, I'm going to ask Ramiro to talk a little bit more about that patient and the timing of the visits in the role of the small end. I don't think perhaps we didn't run the study out every no longer than 6 months. If you ask about a ceiling effect, in the control arm might have the control arm got even better with more supplements in mind, but we know that, it was a 6-month trial. And so again, going back to my statements already, we think the fact that we improved the 7 letters is really terrific. Ramiro, do you want to comment on the trial in those -- in that single outlier?

Yes, sure. So I think, as Jay stated, we had that one patient that missed the 20 visit -- week 20 visit, and then when they came back to week 24, they saw a drop in vision that pull the mean down a little bit. And then removing that patient, we get a mean of about 10 letters at week 24. To answer your question in terms of the aflibercept control arm, we did have 1 patient increasing a little bit more vision towards the end of the study, and that's actually what's driving the gain towards the end. It's those additional sunitinib injections those patients got towards the end of the study.

The next question comes from the line of Graig Suvannavejh with Mizuho Securities.

First question I have is irrespective of the findings of the Phase II study and the use of the primary endpoint and changes you're going to make in the Phase III program. The data do come from a relatively small number of patients. And so maybe just for context, how large, even if it's just 1 study that you may be able to do in Phase III based on the data that you have right now, any ballpark and how large that study might be and even though you're going to start by the end of the year, just kind of timing around when you might be able to share data around that. I know it's still early days. And then secondly, if you could just remind us of the baseline characteristics of these patients? And what I'm trying to get a better understanding around was this patient population any more typical DME patient population or was there anything particularly unique about this patient population that you may seek to make subtle changes about as you think about Phase III?

Sure. Ramiro, do you want to talk about the initial thoughts around the end of the Phase III and potentially yes, trial design exactly?

Yes. So when we talk about size, as you know, it's size of the clinical program, it's all about the variability on the BCVA and the effect that we have on the treatment. So DME in a way, in terms of aflibercept BCVA, it's somehow similar to wet AMD. So I think one option is to run a study that has the same size as we're doing now for LUCIA. It's going to be, again, the variability on BCVA is similar between wet AMD and DME and if it's going to be a non-inferiority study. The sample size should be -- can be similar to go to about 400 patients. And then talking about your other question about the baseline characteristics. So first, we have to remind that this was a study enrolling patients that were previously treated. Not naive patients, right? Generally with the Phase III programs are mainly with naive patients. So the CST was about 400, 420 microns. So a little bit lower than the other Phase III programs with naive patients again and the vision was about 65, 66 letters. So -- and that ties with, I think what Jay was mentioning about the ceiling effect, right? So those patients, somehow, they were previously treated before. They still have edema, but they were previously treated before.

Thanks, Ramiro. Graig, does that answer the question?

Yes. It does.

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

Have you looked at the data on BCVA for just those eyes that did not need rescue? And then can you clarify the bar for noninferior for pivotal trial, that would be versus labeled Eylea that will be dose every 8 weeks, right, versus this control arm only had 1 dose of Eylea at baseline? So could you just help us translate your confidence to being noninferior versus labeled Eylea?

Sure. Again, Ramiro, do you want to take a stab at those questions?

Yes. Thanks for the question. So we have not done the analysis yet on BCVA outcome for patients that not get supplemental. And we're going to do that and present at future meetings. In terms of your question for the loading dose and how confident we are with on CRG, I think, again, summarizing what we discussed before, taking consideration of the results we got from the Phase II -- Phase II study in wet AMD, which is also activated disease as well as the result from VERONA DME data give us confidence that even running against the aflibercept arm with 5 loading dose, and I guess to review, we should be not here.

And to expound on that a little. I mean, if we do choose to do a full load in both arms, remember, at that point, most of the visual acuity means will have occurred already, in which case we just need to maintain them. Again, as Ramiro said, similar to what we did in wet AMD. But if you do go back to the Eylea Phase III trials, the improvement after the load was approximately, I think, between 7 and 8 letters and the subsequent injections every other month for the next 9 months or so got another letter improvement. Well, we're right there, depending again on the analysis, the combined endpoint, we're around 8.5 letters if we combine the endpoints. So there is any way to look at it from our perspective, we think we have really derisked the pivotal trial.

That's helpful. And then one quick follow-up for the pivotal, would you expect this would be a repeat dosing? Would you look for every 6-month dosing with a 48-week endpoint?

Yes, that's the current plan.

Our next question comes from the line of Yale Jen with Laidlaw & Co.

I just have one here, which is the supplement free of 73% versus 50% of proceed or comparators, I'd just like to know, what do you think this data is sort of reflected in the Phase III study, what sort of potential commercial impact or other impacts you think you might have for the drug?

So first of all, obviously, this is a small trial, so it's hard to extrapolate, but we were to use similar criteria in the DME Phase III that we're using in the wet AMD Phase III, I would expect there to be fewer supplements in the 2.7 arm. And one could hypothesize that the visual acuity results wouldn't be any different. Once again, when you start at week 16 and asked the question, did the supplements really change anything to week 24? Doesn't really look like they changed the visual acuity much, did they? So that's what ultimately we care about. Now from a commercial perspective, one of the things about the TKIs that you really want to emphasize is we're a different mechanism of action and that there are very few chronic diseases right now that are only treated with a single MOA. And even in ophthalmology, look at glaucoma, ophthalmologists will layer on multiple different MOA drops to try to achieve the endpoint. So while we are not setting this up as a combination therapy, we don't think in the real-world that doctors would be adverse to necessarily using DURAVYU on its own in patients who can go every 6 months and be stable or supplementing if you want to call it supplementing, let's call it in real world or probably addition but another type of MOA and try to get a better result. We do that now in diabetic macular edema. It's not unusual for a doctor who is treating a patient monthly with any of the anti-VEGFs to layer on a corticosteroid to try to get the patient out longer. Once again, corticosteroids have the known complications of cataract formation and elevated intraocular pressure. And so one could imagine if you had a sustained release that accomplished the same thing or even more, better anatomy and better visual acuity without those side effects, I think it would be widely accepted in the retina community.

Our next question comes from the line of Yi Chen with H.C. Wainwright.

Could you comment on potential payer perspective regarding the data of supplement-free patients, 73% versus 50% for aflibercept week 24, especially considering that the biosimilar are already on the market?

So I think the payer's perspective is why will to be driven more about the pivotal data and the reduction in treatment burden against Eylea control. I think, again, we are offering a unique mechanism of action and unique durability, and we expect that the payers will take that into consideration. There have been some preliminary discussions with them. And we believe that, that will be the case with the payers. So the biosimilars and the other ligand blockers really can't last 6 months in this population. And so we believe that if we are approved with the every 6-month label, that unique label will allow us to be separated, let's say, from the biosimilars.

I would now like to hand the conference back over to Jay Duker for any further remarks.

Thank you again, and thank you all for your attention this morning and your excellent questions. Once again, to summarize, we are really excited about this data, exceeded all of our expectations. I especially want to note the ability of DURAVYU to give an immediate trying effect that persisted with a significant difference between DURAVYU and the control, equal visual acuity in the end with fewer supplements, giving us high confidence in a noninferiority type trial for FDA approval. We think this is another potential $1 billion product for us and lapping this in with our DURAVYU wet AMD program, we think we're in an excellent position to be very successful in the sense of allowing people to maintain their vision with fewer injections and hopefully, better vision in the long term because of the sustained release aspects. Thanks again, everybody, for listening, and have a good day.

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