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

Ladies and gentlemen, thank you for standing by. Welcome to DAVIO 2 Topline Data Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to EyePoint Pharmaceuticals' President and Chief Executive Officer; Dr. Jay Duker, please go ahead.

Thank you very much, and good morning, everybody. With me this morning is George Elston, our Executive Vice President and CFO. We really appreciate you joining us for this really exciting data release of our DAVIO 2 Phase II clinical trial top line results. As we may be making forward-looking statements, we need to remind you of that. And if you would like more details around the forward-looking statements, you can visit our website. EyePoint Pharmaceuticals is a company that's dedicated to improving the lives of patients by sustained delivery of medications to the back of the eye. Our lead asset, which you're going to hear about this morning is called EYP-1901. It consists of the small molecule tyrosine kinase inhibitor called vorolanib, which is in our patented delivery technology called Durasert E. Durasert E is completely bioerodible. We are going to review these positive top line Phase II data and wet age-related macular degeneration this morning. But I'd also like to remind you that we currently have an ongoing study, Phase II in nonproliferative diabetic retinopathy that's fully enrolled. That's called the PAVIA trial and we are on target to release the top line data of the PAVIA trial in Q2 of 2024. We will be initiating a Phase II trial in diabetic macular edema called the VERONA trial, and we're on target to dose the first patient in the first quarter of 2024. Our pipeline includes a new addition called EYP-2301, that is razuprotafib, a patented TIE-2 agonist and we were able to formulate it into our Durasert E technology to deliver sustained release intravitreally in the back of the eye. Our Durasert, as you may be aware, is in 4 FDA-approved products safely administered to tens of thousands of patients across those 4 indications. EyePoint has a strong balance sheet with $136 million in cash and investments as of September 30, 2023, which gives us a cash runway into 2025. So we're using EYP-1901 initially in wet macular degeneration for sustained delivery of 6 months or longer. There is a need for more durable therapies in wet age-related macular degeneration, the therapies we have right now are safe and effective, but they typically do not last more than a month or 2. We know in the real world, many patients with wet age-related macular degeneration are undertreated and when retina specialists are pulled, over 80% will say, it's due to patient noncompliance or scheduling issues. To treat and extend protocols that most of us use to treat patients still put a significant burden on patients, on physicians, on their families and on the health care system. We also learned, unfortunately, during COVID that a delay in care or missed visits even briefly can result in vision loss that is not recoverable. And there are aging population means more patients at risk for loss of vision due to this noncompliance. Why did we choose vorolanib? well vorolanib, first of all, features a new mechanism of action in the treatment of VEGF-mediated disease. We block all isoforms of VEGF at the receptor level. In addition, we blocked PDGF, which theoretically should result in less fibrosis. We have composition of matter patents out to 2037 on vorolanib with additional patents we hope will take us into 2040. Our molecule vorolanib has demonstrated neuroprotection and a validated retinal detachment model, and it does not feature off-target binding or inhibition of TIE-2 at clinically relevant doses. Our delivery system, Durasert, as I mentioned, has been used in 4 FDA-approved products that's delivered in the office with an intravitreal injection, similar to all other intravitreal injections that are currently in use. Durasert features zero-order kinetics. which means after insertion, we do see a burst of drug for the first few weeks, but following that for months, the drug levels are constant. This allows theoretically for what has been referred to as micro dosing where you can get therapeutic levels at relatively low doses because of the zero-order kinetics. Durasert E differs from the previous versions of Durasert, the non-erodible polyimide shell has been removed making this fully bioerodible. The inserts were designed to deplete the drug fully before the matrix goes away. EYP-1901 is a cylindrical insert injected through a 22 gauge needle in the physician's office with standard intravitreal technique. Zero-order kinetics that should deliver therapeutic levels of the drug for approximately 9 months in humans. We've previously shown you positive safety and efficacy data from the wet AMD Phase I DAVIO trial, and we have continued positive safety data from our 2 ongoing Phase II trials. One important differentiator for EYP-1901 is we are prepackaged in a sterile container, and we are shipped and stored at ambient temperature. The DAVIO 2 clinical trial is a noninferiority trial endpoint using 2 doses of EYP-1901, approximately 2 milligrams and approximately 3 milligrams against aflibercept on-label control. This trial was designed to support the pivotal trials, which we anticipate in the near future. It was based around a Type C meeting with the FDA and further interactions with the FDA last year, and we designed this trial to look as similar to the pivotal trials as we could. Multicenter randomized double-mass trial, previously treated wet AMD patients only. The anti-VEGF supplement criteria for the trial was similar to what has been used in other trials with 1 particular addition, 5-letter loss from [indiscernible] study with 75 microns of new fluid in any eye triggered a supplement. The primary outcome is the difference in change in visual acuity from day 1 to a blend between week 28 and week 32. That blended endpoint is something that the FDA mandates in the pivotal trials, and that's why we used it in DAVIO 2. Important secondary endpoints are safety, reduction in treatment burden the percentage of eyes that could go supplement free and the anatomic results. This is the structure of the trial. Everybody in the trial got reloaded with EYLEA on day 1, week 4 and week 8, they received aflibercept injections. At week 8, the eyes that have been randomized to receive EYP-1901 30 minutes after the aflibercept received it through an intravitreal injection and the aflibercept arm got a sham. The eyes were then launched monthly and at each monthly visit they were evaluated for disease activity. At week 16, week 24 and week 32, the eyes that were randomized to EYP-1901 got a sham in the eyes that were randomized to aflibercept got a real injection of aflibercept 2 milligrams. Theoretically, it is possible and as you'll see, this actually occurred that the aflibercept eyes could also get rescued, but only at week 12, week 20 and week 28. By definition, a supplemental rescue injection can't be given on a day in which an eye has a mandated injection. This is the baseline characteristics for the 3 groups in the study, and we believe that they are well balanced. The one thing I'd like to point out is the mean number of injections normalized for the 12 months prior to enrollment. These numbers are higher than what we saw in our Phase I trial. The explanation is almost 30% of the patients that we enrolled in DAVIO 2 had the disease for 6 months or less. So what that means is those patients were still being treated either monthly or had just started their treatment extend. So when their number of injections was extrapolated out to 12 months, many of those extrapolated to 10 injections, 11 injections, 12 injections, et cetera. But as a group, this was a heavily pretreated group of patients. Topline clinical results, here's the summary. EYP-1901 in both arms was statistically noninferior to the EYLEA control with change in best corrected visual acuity. The actual numerical difference between the visual acuity outcomes in the point -- I'm sorry, the 2-milligram arm was only 0.3 letters. In the 3-milligram arm, it was only minus 0.4 letters. We have a continued favorable safety profile. There are no EYP-1901 related ocular or systemic SAEs, the ocular AEs are -- majority are mild in severity in the type of AE that would be expected with the mode of administration, which is intravitreal. We also met all of our secondary endpoints with approximately 80% reduction in treatment burden at 6 months, nearly 2/3 of the eyes in both arms could go supplement free up to 6 months and strong anatomic control. Here is the visual acuity results in a tabular form across the top, you notice that all 3 arms gained about a letter of vision. This is primarily due to the reloading, suggesting that some of the eyes may have entered the study a little bit undertreated, but there was not a big rise in the vision across the board. The difference you can see again, minus 0.3 letters for the 2-milligram dose, minus 0.4 letters for the 3-milligram dose. And when we ran the statistics, these were statistically noninferior to a 95% confidence interval despite the end of the study being only 160. This graph shows the mean change in best corrected visual acuity at each visit. You can see it hovers around 0 with slight improvement at some time points. The scale of this graph is 5 letters. There's 5 letters in a line. And so this type of graph is something you would see with eyes that have very stable vision. I already talked about the systemic and ocular safety with EYP-1901 and to repeat there were no reported EYP-1901 related ocular SAEs, no reported systemic SAEs, the AEs that were reported were generally mild and expected. We saw no cases of insert migration into the anterior chamber and no cases of retinal occlusive vasculitis. There was also a very low patient discontinuation rate of 4%, and none of the discontinuations were related to EYP-1901 treatment. This is the slide on reduction in treatment burden, and this is the historical reduction. In other words, the number of injections that the patients received for the year going into the study normalized against the number of injections they received after EYP-1901 went in. So you can see the number of injections between week 8 and week 32 for those 6 months in the 2-milligram dose was 0.55 and in the 3-milligram dose was only 0.71. And our Phase I trial across all doses, that number was 1.2. The mean number of injections over the 6 months normalized leading into the trial for these 2 arms was approximately 5, giving an 89% reduction in treatment burden in the 2-milligram dose and an 85% reduction in treatment burden in the 3-milligram dose. So this is a retrospective or historical way of looking at reduction in treatment burden. But in this study, we were also able to look at it prospectively, ongoing against the aflibercept control. Once again, the number of injections mean number for the 2-milligram for those 6 months after insertion was 0.55, for the 3-milligram 0.71. And all the aflibercept eyes were to receive 3 mandated injections. But as you can see, they got more than that. They got 3.32 injections because 3 of the aflibercept eyes got rescued and these were rescues that met criteria. 2 of the eyes got 2 rescues,1 of the eyes got 1 rescue. In addition, we were able to look at how many of the eyes met rescue criteria at any point in the study. And this is something that was masked by the study sites, the doctor that determined if an eye met rescue criteria did not know which group the patients were in. 20% of the aflibercept eyes met rescue criteria at some point over those 6 months. The inference is that this was a group of patients who really needed quite a bit of treatment. This is the rate of supplement free up to the 6-month visit, 65% for the 2 milligrams and 64% for the 3 milligrams. And this next slide shows this graphically. Two points to be made here. The first point is that there has been some talk that TKIs as a class are slow to act in the eye. We don't believe this is true for vorolanib or for EYP-1901. We have preclinical data that shows within hours our drug is in the animal core in a therapeutic level within hours. But if our drug were slow to work, one would expect to have seen extra supplements at month 3 and month 4, and you can see that wasn't the case. These numbers also show a smooth decline, not arise at month 7, suggesting that the drug was still working in patients who were good candidates and sensitive to it. This is the anatomic data. The anatomy remember is measured on OCT, optical coherence tomography. The center of the macula is called the central subfield. So we talk about CST. Normal CST is up to about 280 microns. You can see that the 3 arms were well balanced for CST, and there was a slight increase in CST at the end of the study in all 3 arms. But the actual change between the 2 1901 arms and the aflibercept control was minimal. The standard deviation for OCT test is about 10 microns. This is the graphics of the OCT data. And again, you can see there was a little bit of a response in the first few months to the load and then there was a slight rise at around month 4. And then in the 2 1901 arms, it was very stable. We see the typical sawtooth pattern that one would see from every other month EYLEA, and we have known that since the VIEW 1 VIEW 2 trials. Two points to be made here. One of the criticisms of all these trials that include supplemental criteria is they can be criticized as to being not real world. And granted that is probably true, it's a clinical trial. However, one of the worries that the clinicians expressed would be that given the supplement criteria we had, maybe some of these eyes were gaining fluid and the supplementation rate was really good, but in the real world, these eyes would have been supplemented. I think you can see that, that wasn't the case. There's no rise between month 3, month 4 in the end of the study in the EYP-1901 arms. In fact, they're very flat. The second thing I think you may be able to infer from this is even those supplements were given, there didn't seem to be any deleterious effect on the eventual anatomy despite the need for supplements. So this is the summary slide again. Statistically noninferior change in best corrected visual acuity with very, very small differences in the letters. One comment about the statistics here, the standard deviation, as expected, the standard deviation for the change in vision was low, less than 7. As trials that are noninferiority, the most important part of this is that the lower limit of the confidence interval not cross minus 4.5 letters. Our lower limit of noninferiority did not cross 3 letters. That's how good and tight the statistical result was. And in fact, the confidence interval for the top did cross EYLEA, which means on a statistical basis it's still theoretically possible that in a larger trial, our result could be statistically superior. That was not shown in this trial, however. My understanding is that non-inferiority trials don't typically consist of p values, just confidence intervals to 95%, which we've shown and talked about. However, we did run statistical tests between the groups to look at p-value of the change. And I can tell you all the p values that were run, they were 0.000 followed by a number. So that tells you that statistically, these 3 groups were essentially identical for visual acuity. As I mentioned, continued favorable safety profile. Again, this is not a surprise to us. We've seen really excellent safety throughout the Phase I and Phase II as well as the preclinical data. No matter how you calculate reduction in treatment burden, you get a number of about 80%, whether it's retrospective or prospective. And nearly 2/3 of the eyes were supplement free up to 6 months with strong anatomic data to back this up. So needless to say, we are delighted with these results. Now some of you may remember that prior to the results, we talked about some baseline results that we'd like to say is these were the floor results that we'd like to do better. You can see that on the right, these lower limit baseline from our November IR deck. We wanted to do better than minus 3 letters, we did much better than that, essentially no different than EYLEA. Favorable safety profile continues, we wanted to be 50% or better on reduction in treatment burden, we were close to 90% in 1 calculation. We wanted to be better than 50% in supplement free rate, we were 65% and 64%. And we set a limit on the OCT of no more than 30 microns greater, and we were considerably better than that. If we were a baseball team, I think I could say we hit a Grand Slam. So before I open this up to questions, I want to say a few words. And first, thank you all for listening in today. I do think it's obvious that as a company, we're just really thrilled with these results that we shared. None of this is accidental and it all starts at the top. We have an excellent Board of Directors, they're highly experienced with drug development and with expertise across all levels. But I especially want to mention the Chair of our Board, Göran Ando; and Nancy Lurker, who is our Executive Vice Chair. I need to really thank all the EyePoint team from the executive committee all the way down to the second shift. They've just done a fantastic job to get this study completed so rapidly, but also to collect and analyze the top line data in such a very short time frame to allow us to share it this morning. This team has executed flawlessly. We dosed our first wet AMD patient with EYP-1901 in January 2021. And we're now in December of 2023 reporting excellent topline data from a robust Phase II trial. And before we start the Q&A, I do need to remind you that we just saw this data a few short days ago, and we've literally been working straight to get this data to you this morning. I know you'll have questions and questions about the data and where we go from here. But we really haven't been able to do any kind of subgroup analysis yet or drill down in any degree beyond the top line that you've just seen. So I apologize, if at least temporarily, I can't answer some of the questions, but we will be presenting this data in multiple venues at both biotech conferences and ophthalmology and retina meeting starting in 2024. I can assure you that as we dig deeper into the data, we will share the findings and answer your questions as it becomes available. So thank you very much, and I'm happy to open it up to questions at this point.

[Operator Instructions] The first question comes from Tyler Van Buren with TD Cowen.

Congratulations on the tremendous results. The curves look great and there's not much controversy. So I have a couple for you. And the first one on the data is somewhat minor. But on the CST curves, I know you mentioned 10 microns is within the normal range of variability, but I was hoping you could just elaborate mechanistically on why you might be seeing the increase in CST with the 2 EYP-1901 arms versus EYLEA after month 3 or a month after the insert? And then the second one after that is just can you elaborate on the potential for a meaningfully lower-sized and lower-cost pivotal Phase III as described in the press release?

Well, thanks, Tyler. Thanks for the questions. The first question around CST, I think the first thing that everybody should realize is numbers like 5 and 10 microns are barely noticeable to a clinician. When you're evaluating an OCT cross-section, these changes are slight. The machine software can pick them up, but they're slight. I really can't answer the question why we saw that slight increase because we haven't drilled down into the data yet, whether it was driven by 1 or 2 or 3 of the patients, I can't say. So there will be more elaboration on that when we really know what drove it. But I'm not worried about it. I don't think any of my colleagues will be worried about it because the visual acuity is so stable. Remember with EYLEA every other month, there's a sawtooth pattern. And there -- in VIEW 1, VIEW 2, there was a change of about 12 microns between the months. But that didn't stop any of us from treatment extending EYLEA out to 2 months or longer. So those slight fluctuations in OCT are not something that bother clinicians. But what I'm really encouraged by is the stability that the eye showed with our drug because I think that's one thing that doctors do want to see. They don't want to see wide variations of 50 or 100 microns swings in the CST. So the second question about sizing of the study. Yes. So we hit statistical significance in -- to a very good outcome with 160 patients. I think if you plug these kind of numbers into your statistics packages, you'll see potential numbers for pivotal trials of 60, 70 or so in an arm. It's not to say that's what we're going to do. But we could have a very good statistical result with a relatively small trial. We have been talking about cost of between $90 million to $150 million per trial. I think that the costs right now are going to be closer to $150 million for both trials. George, do you want to make any comments around that?

Yes. I think -- and we're still obviously working through the size and modeling, et cetera. But I think what we had talked historically that Phase IIIs would be in that 400 to 600 patient range. I think based on what we're seeing today, we're going to be able to come in below that at a very reasonable cost. And there'll be more to follow on that. So we're thrilled with this very tight statistics. It's going to help us meaningfully forward.

The next question comes from Yatin Suneja with Guggenheim.

Jay, indeed, Grand Slam, so congrats for delivering such good results. So a couple of questions for me. First one is on the doses or the dose response. So it seems like the 2-milligram and 3-milligram both look pretty similar. So I'm curious in terms of your expectation as you think about Phase III, how are you going to decide which dose you're going to take forward? So that's one. And then again, I think the data are better than what we or most of the investors or KOLs that we have talked to were hoping. So I'm just curious if you can put these data in context in terms of the market potential, who is the right patient population? Are there any subset of patients that should not be eligible or would be prioritized for 1901? That would be great.

Yes. Thanks, Yatin. Two great questions. Let me start with dose response and where that leaves us. So prior to the data, we did have a lot of discussion internally and externally about dose response. And I can tell you there were 2 very smart people in this organization, including our Chief Technology Officer, Said Saim, who said, you're not going to see a dose response. And the rationale was the 2-milligram dose was several fold higher than the IC50 and it's zero-order kinetics. And so once the receptor is blocked, it's blocked. Extra drug, especially in the zero-order kinetic situation, doesn't really help you. We also, again, before I get to the answer to where we go from here to talk a little bit more about dose response and the receptor activity at the Retina Society, Sophie Bakri, presented a study that we did where we looked at a model of angiogenesis called the CAM model. And we dosed the CAM model with all 3 TKIs that have been used in the back of the eye, axitinib, sunitinib and vorolanib. And it was against -- the control was Avastin. Sorry, I'm blanking. So the control is Avastin. And at IC50, all 3 of the TKIs block the CAM model better than Avastin. So then you say, well, that's great, but what if you increase the dose, so we did, so we increased the dose 200x IC50 and got the exact same result. So that preclinical model suggests to us that once it's blocked, it's blocked and these TKIs as a class do pretty well. So where does that leave us? Well, I think if you look at the data at the top level here, it does not look like we got a dose response. And before I absolutely state that with certainty, we really need to drill down and look at the data a little more. But where does that leave us for the pivotal? I think I can stick to a 99.9% certainty that we will not be using 3 inserts in the pivotal trials and the go-to-market. I remember the 3-milligram dose was 3 inserts, the 2-milligram dose was 2 inserts. We do have quite a bit of flexibility around payload in each of the inserts, but I am confident that the pivotal trial will feature 1 insert of a payload to be determined against 2 inserts of that -- the same payload. So that actually, for us, is good news because while there has never been an issue that we've seen in patients around the 3 inserts, I think some people had some theoretical concerns around it, but it's also from a COGS perspective, that's favorable. So now putting the data in context, so I think many of my colleagues and myself as well, we're trying to answer that question, which is how much vision are you willing to leave on the table in order for more longevity. And I think if you talk to KOLs, many of them were saying, hey, 3 letters, 4 letters, doesn't bother me. If I can reduce the number of injections safely, I'll lose that type of vision. Now I have to remind everybody, we just saw high-dose EYLEA results, 8-milligram EYLEA versus 2-milligram EYLEA. And 8-milligram EYLEA did show more longevity, but at a cost of minus 1.4 letters. We were less than that. So I don't think the clinicians are going to need to worry about the trade-off here between vision and longevity, because we were able to show really good stability. Who are the best candidates? I think I'd like to tell you, everybody is going to be a good candidate for EYP-1901. And some of our KOLs have said that publicly. But we'll see. I certainly think patients or doctors who want the flexibility to dose patients less frequently are going to want to try the drug. The other thing about it is once you start to take elderly patients out to visits every 4 months or 5 months, they're going to miss visits because they're older. And if you have a ligand blocker that you're using and you're out 4 months, there's no drug in the eye anymore. With EYP-1901, there's still drug in the eye. So if they miss a visit, it's a bit of an insurance policy against loss of vision. And I do think that some clinicians will want to take advantage of the difference of the 2 mechanisms of action, that blocking at the receptor and blocking at the ligand maybe in the long-term favorable. And finally, if we can show newer protection and we can show antifibrosis either in this study or an ongoing study, I think there'll be a strong argument to use it in virtually every patient. One of the other ways to look at this data, though, which I didn't mention in this slide deck, but remember, 2/3 approximately the EYP-1901 eyes did not need a rescue. So if you just say, look, strictly, I'm only going to use it in eyes that I can just use it exclusively. Well, that's 2/3 of the population right there. But if you look at it a little differently and say, wait a second, how many of the rescued eyes only got 1 rescue? Well, in the 2-milligram dose, 88% of the eyes got either 0 or 1 rescues, which technically means if this data holds in the pivotal and in the real world, you could take almost 90% of your wet AMD population and treat them with 4 injections a year or less if you choose to. So I think this type of data, it will take a while for the retina world to absorb it. But I think what we're doing is giving doctors and patients flexibility to dose longer and considerably much longer if they choose.

One more question, if I may. So you talked about a robust, maybe is a more robust Phase III program because these data are robust or could be shorter. So my question is around the safety. What is the safety database requirement from the FDA? And if you can talk maybe about the time lines for the Phase [indiscernible], that would be great.

So in the guidelines we've gotten from the FDA and in the draft guidelines, the FDA wants to see safety on 400 patients approximately in your go-to-market dose. So for most wet AMD programs that were treating naive patients with a higher standard deviation and the change in visual acuity, those studies were powered based on the statistics and because they were large studies, you hit the 400 patients sometimes with even 1 study you hit it. Our study probably will not have to go nearly that high for the statistics, which means it's one of the things we've been thinking about would be a 2:1:1 or a 3:1:1 type of randomization, where we put more patients into the higher dose to get that safety data and fewer patients in the lower dose and in the aflibercept control. Now of course, this is all a point that will be negotiated at the end of Phase II meeting with the FDA, and we believe the really strong safety data that we've shown to date may also have some influence on that final number.

The next question comes from Jennifer Kim with Cantor Fitzgerald.

Congrats again on great data. I have a few questions here. The first, just following up on, Jay, your comments on trials, pivotal trials potentially costing $150 million for both. I just want to ask, is that -- does that -- within that $150 million assume you go with the 2-milligram and 1-milligram dose and something like a 2:1:1 or 3:1:1 arm? And then related to that, in your end of Phase II discussions with the FDA, would you expect any type of deeper discussion around the selection of those doses or arm sizing? Or would it be fairly reasonable to assume that the FDA would -- like there would be no reason for them to have any questions around that?

So the answer to your first question about the sizing of the pivotals and the ability to do both for around $150 million. The quick answer is yes, is that we would go with the 2-milligram and 1-milligram dose approximately. And I say approximately because we do have leeway in the payload. I don't see any data right now that suggests we need to go as high as 3 milligrams. And that would probably to get to that $150 million do entail a randomization that's not 1:1:1, but that's to be determined. Again, the FDA, I'm not sure I expect a robust discussion around the dosing. The dosing, I think, again, if the data holds up and there's no dose response, I don't think the FDA will ask us to do 3 milligrams. Quite the contrary, in the past, at least, the FDA has talked about finding the lowest effective dose. But in our discussions with the FDA prior, the use of the lower dose was to help masking. It was not to find a lower effective dose. So that there has been some discussion in the retina community recently about the use of saline injections instead of sham injections. And that is not an issue for us. The FDA discussed it fully with us in the Type C meeting and in subsequent communications that we've heard from the FDA, the FDA doesn't want to see a sham control group, but if you have 2 doses of your drug, that allows sufficient masking that a sham for the double dummy is acceptable. We're not going to use a sham control group, we're using an EYLEA control group. So I hope that answers the question.

Yes, it does. And maybe one more question. I think you mentioned taking a single insert in your payload at a dose to be determined, is that -- would that be feasible at the 2-milligram dose and would that be ready in time for the pivotal?

That's a great question. So anything is feasible. But the problem again is to get 2 milligrams into a single insert. You're talking about a larger bore needle or a longer insert, which I don't think that we will choose to go in that direction. We've not seen a problem with multiple inserts, not in animals, not in humans. And so the 2 inserts, we believe, should be safe, tolerable and effective. It's -- again, I think while it's possible to put it into 1 insert, I don't think it's practical to do that.

The next question comes from Colleen Kusy with Baird.

Great. Jay, Grand Slam sounds like an accurate description here, so congrats to the whole team. A couple from us. When can you expect to have an end of Phase II meeting with the FDA to discuss the Phase III trial design? And then in light of these data, any updated thoughts on a potential partnership to move this program forward?

Colleen, thank you for that. So we are -- need to get all this data together and get the briefing book together for this FDA and we're looking at an end of Phase II meeting at the end of Q1 2024. It may slip into the very beginning of Q2 2024, we'll see. But we're pointing towards, we hope, by March, to get it done. From partnership, wow, I mean this is -- I think these results are really great, and I think that there will be quite a bit of strategic interest. There was prior to the data as you may know. With this type of data in this type of visual acuity results in safety, it certainly should spur interest. And as we've said publicly, having a strategic partner to not only support the Phase III trials from a financial perspective, but also to give us a better glide path to commercial success internationally is something that we would look forward to provided the deal is good.

Great. And you've guided -- a quick follow-up. You've guided on starting the first pivotal study in the second half of next year. Any thoughts on when the second pivotal study might be in?

So our internal time line is several months later. So that's -- its best I think I can say right now.

The next question comes from Graig Suvannavejh with Mizuho Securities.

Congrats on the data. Jay, you've always been great with me in terms of providing your sense of the overall landscape in wet AMD and other diseases. And I'm wondering if you could opine just on how you think this data for 1901, which again was just beautiful data, how that's going to change kind of the view of whether it's I think you referred to high-dose EYLEA previously, just maybe other TKI-based programs. Just love to hear your thoughts on how you think this kind of shifts the conversation for treatment of wet AMD?

Thanks, Graig, and thanks for the question. So in reality, when you really take a hard look at where we've been in the past 15 years with respect to anti-VEGFs, as soon as we had Avastin off-label, and we, retina specialists, got experience with it, we knew that it worked, and we knew that it was basically safe, if compounded correctly. Ever since then, we've been looking for more durability. And that's it. Every other drug has shown noninferiority to Lucentis or to EYLEA. None have shown superiority. And the big push for the next drug was we can let your patients go another week or 2 or so in longevity. So this discussion about longevity is old, it's not new. What we've been able to do is shift, it is a quantum shift in longevity because we're zero-order kinetics from another week or 2 to several months. And again, I think doctors, retina specialists, we figure it out. We can -- we have the tools in our office, we have the patient right in front of them with -- or in front of us with a dilated pupil to figure out how they're doing. And we'll figure it out. But what we're going to be able to do is give them the flexibility to tailor individually the type of treatment that they believe is best for the patient and the patient believes is doable, without, we believe, now sacrificing hopefully, any vision to get there. So the second thing about kind of where we're going is the ability to monitor at home is coming with home OCT. And I think that this type of sustained release is a perfect setup for home OCT because it will enable the doctors to have some comfort if they start to treat and extend out further. And finally, beyond wet AMD and the whole anti-VEGF landscape, I'll remind everybody that every drug that's worked in one indication has worked in all the indications. So this gives us increased optimism that we will have a benefit in nonproliferative diabetic retinopathy, DME in any other anti-VEGF disease that we choose to tackle.

Sure, Jay. Maybe just a follow-up, just if I could get you to provide maybe updated thoughts on kind of your view for your peers that are also working on TKI-based therapies and how this either helps them or doesn't have any impact at all?

Graig, at this point, it's hard for me to answer that question. I think that we have a very well thought out strategic and operational success here with this Phase II. We've had a clear plan to do this for years with guidance from our Board. And again, I want to give a shout out to our former CEO, Nancy Lurker, who spelled all this out. And so our program has been steady but effective for the last few years. And as a result, I am optimistic about this team's ability to execute. For other programs, I think, again, there's probably a lot of opinion out there around it, and I'll just let that opinion kind of -- can throw the question back to you and say, will there be read through for other TKIs? Yes, there probably will. There may not be. It's just, at this point, hard for me to say, does it really, I think, help the discussion today, I really want to focus on what a great job the EyePoint team did.

The next question comes from Daniil Gataulin with Chardan.

Congrats on the data. Just a quick one for me. For those who started getting rescues, I wanted to ask how are those rescues spread out both in the 2-milligram and the 3-milligram dose?

Thanks for the question. And from a spread out perspective, we haven't had a chance to actually look at that at a patient-by-patient basis. So that's one of the great questions that I won't be able to answer today. I can tell you, again, in both the 2-milligram arm and the 3-milligram arm, the big majority of the patients who got rescued only got 1 rescue. And in fact, in the 2-milligram arm, I believe the number was 19 patients were rescued and 15 got 1 and 4 got 2. That's my memory, but maybe off by patients. But my point is the majority of eyes over 6 months who did get either breakthrough fluid or a change in the vision, they only got 1 rescue.

The next question comes from Annabel Samimy with Stifel.

Congratulations on some great data. I wanted to ask just a bigger picture, obviously, it looks like TKIs could be really paradigm changing for wet AMD and obviously, you could have a pretty big impact on the anti-VEGF market. When you think about how and who physicians will use this in, if you think about these compounds potentially having an impact on neuroprotection and fibrosis and neuroprotection is kind of like the Holy Grail of drug. Is there anything that you're going to be doing to measure this? And are you going to be able to do it ahead of potentially commercializing the product and how can this be measured? So just thinking about bigger picture for these patients, how you might be able to further differentiate the TKIs?

Yes. Those are really excellent questions, and those are things internally that we have been thinking about how we do that. And so first of all, neuroprotection, one of the ways one could measure it from a point of view of the anatomy, of course, is OCT. And there are ways to quantify photoreceptor loss or slowing down a photoreceptor loss. And that would be, I think, indirect evidence of neuroprotection. We will look at that as a subgroup analysis in DAVIO 2, but with only 50 some patients in each arm, it might be hard to show that. We'll see. And it's only again an 8-month endpoint. So maybe hard to show. We obviously will look at other things, geographic atrophy, for example, would it be possible that our neuroprotection extends to that? Sure, it's possible. We're going to be looking at that as well. But ultimately, what the doctors and the patients care about is the visual acuity. And that if we're neuroprotective, what we hope to show in the long term, not necessarily over 8 months, but perhaps over 2 years, is that we slow down the visual loss that occurs with wet AMD. The problem, again, is in the real world, patients continue to lose vision. And in the short term, what we've shown in this group of patients is they're not losing vision, they're stable, but we need to show that in the long term. And so that's ultimately what we need to try to do and we hope to be able to do that in the pivotal trials. The second thing about the antifibrosis I'd say the same thing. There's structure and then there's function. You can measure fibrosis on a color picture on an OCT and on a fluorescein, and we'll be doing that as an analysis in the DAVIO 2 trial. But ultimately, even if you show reduction in fibrosis, you want to show that it helps the vision, and that's much more long term. We do know some of the visual loss in wet AMD long term is from the formation of fibrous tissue. So if we can block that, I think physicians would accept that in the long term, even if over an 8-month or even a 2-year trial, you couldn't show a better visual acuity outcomes statistically, you're likely to show it in the longer term under patient treatment.

The next question comes from Yale Jen with Laidlaw & Company.

And congrats on the great outcome for all your efforts. And maybe I have 3 short ones here. The first one is based on the patient demographic compared to DAVIO 1 and 2, what do you see the major impact on that other than the 2 trials to have a size difference in terms of the patient?

So the major impact there, Yale, was that I think we generally were able to not enroll eyes that were failing standard of care. Remember, in the Phase I, we had 3 eyes that required supplement at month 1 after the drug went in for 17%. If you noticed in the Phase II trial, only 2 patients were rescued a month after the drug went in out of 160. So we haven't analyzed these patient by patient. But I would say that we had very, very few failures. And in fact, I don't even know if one of those rescues was in the EYLEA arm. So we does look like we were able to eliminate those really bad patients who are failing standard of care. And that's also indicative of the data I just gave about the 2-milligram dose in the rescues. Nobody got more than 2 rescues. In the Phase I in the first 6 months, we had eyes that got 5 rescues. So we were able to eliminate them. And again, the difference in the rescue rate of 1.2 in the Phase I and 0.55 in the Phase II might be totally explainable by getting rid of those really bad patients who dragged down the vision results and dragged down the supplement free results. So I think that's the major difference. But I also think, again, by allowing some fluid, 350 microns allows fluid, we're going to be able to treat the majority of wet AMD patients out there. Those really bad actors who are failing standard of care with increasing fluid despite monthly aflibercept, there's not a lot of them out there in the real world.

Okay, great. That is very helpful. And my next question is that -- I may miss that. Have you talked -- have you guys talked about standard deviation on the visual acuity? And does that range change across the time over the 6-month period or 8-month period?

So I mentioned standard deviation of the change in visual acuity being less than 7. We're not talking about any details beyond that yet. And that was expected. If you recall, the only other large trial that looked at previously treated patients in a prospective manner was the port delivery trial, and they had a inferred standard deviation of 7.1%. And so ours was a bit less than that. I don't -- I haven't seen this, but I have no reason to believe it was very much different from month to month.

Okay. Great. And maybe the last question here, which is that I understand you talked the previous question asked about the partnership. But given the trial costs, presumably could be reduced almost potentially half, as you previously estimated. Will that be something that you guys will be even more willing to carry that forward by yourself and ultimately partner the drug actually at the commercial -- filing of commercial stage because that potentially gives you guys even greater value in that regard?

Yes. So that's an excellent question. And I think strategically, the team needs to work through that based on the results that we're seeing because I think the value -- potential value has changed. In saying that, as a company, I have complete confidence that we could execute successful Phase III trials on our own. And I would relish the opportunity to lead those. But putting my ego aside, we're going to do what's best for the company, best for the patients I've said all along. The goal here is to get this drug FDA approved as quickly as possible, as safely as possible with the broadest label that we can. And that is going to be kind of the guiding principles over how we go forward with partnerships or any other type of situation for funding. Thank you all for the questions. It's been a really enjoyable hour. It's been a very, very long but productive weekend. And I think as a company, we're going to just take a quick victory lap.

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