Ocular Therapeutix Inc Aktie

Maybe we'll get started. My name is Biren Amin. I'm one of the biotech analysts here at Piper Sandler. I'd like to welcome -- we're going to do a fireside chat this morning with Ocular Therapeutix and their Executive Chairman, President and CEO, Dr. Pravin Dugel. Welcome, Pravin.

There's been a lot that's been going on in the retina space over the last 24, 48 hours. But maybe before we get to talk about some of your competitors' datasets, if you could maybe just provide, I guess, an update from a company standpoint in terms of where Ocular is regarding the regulatory process for AXPAXLI. Any additional color you can provide on your FDA interactions? I know you gave us a substantial update at your R&D Day a few months ago, but anything you could provide in addition to that?

Biren, first of all, thank you for having me here. It's always a pleasure and honor to talk to you, and we really appreciate the opportunity to tell our story any time at all. So very grateful for the opportunity and the time.

The bottom line is, look, our job is to execute and execute and execute, and that's what we do all the time, and we've been doing that since this team came in. I know that we're going to talk about some recent news, but what I'll tell you is nothing has changed in terms of our execution with that news. We have continued to do what we said we would do, which is that we would have a pre-NDA meeting in the third quarter of this year, and we would submit the NDA filing at the fourth quarter of this year. Everything is absolutely on track. I couldn't be happier with the results.

One of the things that we don't talk about and I'm happy to talk about this is what we're doing in terms of CMC and commercialization. And there's a huge amount of effort there. We are ready to launch this product. We're ready to go. We are absolutely prepared, and I couldn't be happier with the progress that we've made.

And I guess with the planned NDA submission, what items remain for completion in order to get the filing in the fourth quarter?

Well, a lot of it is largely logistics, operational, right? I mean, I think I've said it earlier on that a pre-NDA meeting sounds ominous. I mean I've been involved in quite a few of these. It's actually not. It's purely operational. There are things such as what size [ spot ] one wants, where you want the graphs, et cetera, et cetera. Probably the most important thing, quite honestly, is the hyperlinks. You want to make sure the hyperlinks are where they should be, so it doesn't slow you down in terms of getting references and things like that.

So it's operational logistics, things like that. And obviously, what we also are going to do, as we've said, is we're going to use some patients from SOL-R to satisfy the FDA's requirement of having 300 patients who are exposed to the drug for safety purposes. We're going out of our way to make sure that the integrity of SOL-R is completely protected. In other words, we will never see that safety data at all. It's only safety data that is going to go through a third party to the FDA so that the integrity of SOL-R is absolutely and completely protected.

Although SOL-R may not be -- will not be necessary in our opinion and in our belief and in terms of all our interactions with the FDA, for the U.S. FDA, we believe that SOL-R will still be very important for OUS regulatory agencies. And it's vitally important that we protect the integrity of SOL-R. So we're going out of our way to make sure that we protect SOL-R from any kind of loss of masking.

And I guess with NDA submission around the corner, I'm sure there's a significant amount of prep going on in the commercial side of things. Can you just talk about how you're thinking about commercial launch in the U.S. and the enthusiasm in the retina community? And any read-throughs you can make, I guess, from the open-label expansion of SOL-1 that would support that enthusiasm in the retina community?

Yes. So let me just talk about the preparation internally first and then maybe the retina community thereafter. Internally, look, it wasn't long ago, and I remember this very well, when we came in and we had absolutely no money and the company was struggling where it was very tempting to go ahead and spin off DEXTENZA. And the people wondered why we didn't do that. And people said, "Look, you rebranded yourself and had the identity of this company as a company for retina, by retina and DEXTENZA is not a retina product." And they're right.

And the reason for that, and I've kept on saying this, was not just the product, but really having a commercial team. The importance of having a commercial team is incredibly underestimated, and I learned that in my last company. You can't just create a commercial team overnight. And now that decision to keep the commercial team, to keep DEXTENZA is paying off. The fact of it is that we are ready to launch because we've got such a great commercial team. And we're very fortunate to have David Robinson, who has, as you know, launched EYLEA, the most successful launch in the history of retina, leading this launch. So in that respect, we are very well prepared commercially.

From a CMC point of view, as you know, following our last raise, we said we're going to be investing heavily in CMC in terms of not only the hardware, but also in terms of automation, et cetera. We have done so. We're more than prepared for wet macular degeneration. Our inventory is stocked completely for quite a long time after launch, and that's been well prepared for quite a long time. We are scaling up now for diabetic retinopathy, which is 3.5x the size, as you know, of wet macular degeneration.

As far as the retina community is concerned, look, I couldn't be happier with the way that our message is going out there. We are emphasizing the important clinical parts of SOL-1, which is safety, disease control as well as durability, I think, is resonating extraordinarily well. Remember how quickly we recruited SOL-1. The people that recruited for us are the same people that will be the customers for this drug. So I think the retina community is more than well prepared for this.

The -- I will tell you that there are some questions that are not necessarily answered by us. And this is -- if you would ask what is the source of discussion in the retina community, the source of discussion is actually things that are quite appropriate and quite legitimate, which is, look, is this drug a first-line agent? Or is it a maintenance drug? And I think that's a very legitimate conversation. We haven't proven either, right? I mean I would argue that this would be a first-line drug based on the studies that we have in Australia, albeit with a few patients where we showed that the results in treatment-naive patients with monotherapy was what you would expect from commercial grade Lucentis or EYLEA, but that's a small study. And those kind of studies will be done in the community.

I'm thrilled that those discussions are ongoing because that means that there's no doubt in the retina physicians' mind that this drug will be in their hands, that this drug will be approved. So I don't think the discussion any longer is, will this drug be available to us. I think the discussion is how will we use this drug, which is great. That's exactly what we want.

And do you feel that the retina community would want to see data from SOL-R before they start to adopt in the first-line setting?

I laugh when people ask me that. Of course, they want to see data from SOL-R. They want to see data from everything. It's sort of like asking me, do I want more hair and do I want to be taller? Of course, I do. Who would say no to data? That's really not the question to ask. I think the question to ask is, look, if you believe in the SOL-1 data, as I really believe that everybody does, especially now, will you not use AXPAXLI until you get SOL-R? And the answer is no. I've not met a single retina physician who says, "Look, I really love the SOL-1 data, but I'm not using it until I get the SOL-R data." Nobody is going to say that. So the question has to be asked properly.

Everybody wants more data. Of course, everybody wants more data, but is SOL-R a gating item? Absolutely not. There's more than enough information in SOL-1 for its use today. And again, what retina physicians want to see are three things. One, they want to see safety. We've shown patient-level safety in SOL-1. Physicians want to see disease control, specifically OCT changes. That's our barometer of disease control. And what we've shown is that with a single injection, there's a stability in the OCT in this difficult patient population within 30 microns after 9 months, which is remarkable.

They also want to see durability. And what we've shown is that with a single injection in this most difficult patient population, 2/3 of patients are rescue-free. I think we've answered all the questions they need to go ahead and use this as soon as they get this in their hands.

On SOL-1, the company is enrolling patients now in the year 2. When do we start to see data updates from that year 2 portion in SOL-1?

Yes, it's a great question. Look, we haven't guided you as to the milestones as yet. But what we've said so far is to say what I just told you, which is when our pre-NDA meeting is going to be, when we're going to have the NDA filings. We will guide you to other milestones as appropriate. I've also said very clearly that we're not getting any credit for diabetic retinopathy. That's also something that is something that I'll be working on, that the company will be working on in order to fold into our valuation.

I did also want to pivot and talk a little bit about EyePoint, they had data yesterday from the LUGANO Phase III trial in wet AMD. They reported top line data. A lot of times, when I talk about AXPAXLI, investors kind of lump AXPAXLI with DURAVYU. So I guess my question is, what would you say to an investor that believes AXPAXLI is more like DURAVYU than the two programs are different. Maybe if you could kind of elaborate on that, and then we'll go into kind of the data that they presented yesterday.

Yes. Look, the data that they presented yesterday could not have been better for us, right? It's exactly what we predicted. I mean, again, it's exactly what we predicted. We've always said that TKIs work. We've always said that their drug has a signal. And that's exactly what it showed. What it showed was that there was a signal, which is what we predicted. It also showed that the drug didn't meet the primary endpoint, which is also what we predicted because we believe the drug is not nearly as potent. We have -- there's plenty of evidence to show that their drug is 100x less potent and 200x less specific. We also believe that their format for the drug is suboptimal.

And their previous data supports that, and I'm not really sure why people overlook that. But if you look at the only time the drug was ever used by itself where you could really see the drug, it was in the same patient population as our HELIOS patient population, exactly the same. And whereas with our HELIOS study, the results were so good that we launched into a Phase III program based on that. In their study, they completely failed. And why they failed has never been answered. And the reason is very simple is what we said from the very beginning. Their drug simply doesn't last.

So again, the results couldn't have been more aligned with what we predicted and couldn't have been better for us, which is that there clearly is a signal. However, their drug is simply not strong enough to last long enough to meet the primary endpoint, and that's exactly what it showed, and that's why they failed.

And do you think it's the potency of the TKI? Or do you think it's their implant versus your hydrogel and the release mechanisms around -- or is it a combination of both?

Well, it's a combination of both. It really starts with the TKI selection itself, right? I mean, again, we've said for -- since this team has been here that the drug is not nearly as potent and not nearly as selective, and that's been borne out in several studies now. And we've also said that the format simply is not sustainable from a commercial point of view. And that's also been borne out.

Remember there are four filaments in the eye. The needle gauge is 22 gauge, which is not self-sealing. That causes all kinds of issues potentially. And I think probably has. If you look at the infection rate and -- in DAVIO and hopefully, they'll come out with further information to see. But regardless, look, it's a failed study. But clearly, TKIs show a biological signal. And as I said, the results couldn't have been better for us, and it's exactly what we predicted.

And I'd love to get your thoughts. EyePoint provided an analysis yesterday during their investor call, where they excluded 9 patients that had greater than a 15-letter vision loss that was deemed unrelated to wet AMD. This -- all 9 patients were in the DURAVYU arm. They had 0 patients that experienced a 15-letter or greater loss in the aflibercept arm unrelated -- for those that were unrelated to wet AMD. So when they excluded that analysis or those patients, I mean, they report that they hit the primary endpoint in terms of meeting non-inferiority.

So I guess question is, is the patient population that they're excluding, those that have disease unrelated wet AMD like GA or glaucoma, I think about 1/3 of patients at baseline in the trial had that. Is that something that, that patient population would be considered irrelevant where a drug sponsor should exclude those patients from efficacy analysis?

Yes. Look, I don't want to make light of that, but you know as well as I do, Biren, that excluding patients from a clinical trial is sort of a ludicrous argument, right? I mean, again, I'm not making light of this, but at the end of the day, I mean, that's going down a crazy hole that nobody should go down.

But let me just kind of pause and backtrack a little bit. We're in a very difficult business. There are very few businesses where companies spend hundreds of millions of dollars knowing that 9 out of 10 times they're going to fail. And the first thing we've got to look at with this is I take no joy in people's failures here. There are humans that are involved, and we have to sort of pause and look at the human aspect of this. I know a lot of people in that company. I've done this for over 30 years. The vast majority of what I've been involved with have failed. And there are people that I've known, as I know people there, where their lives changed, their families changed, their children's schools change. I mean it takes a big toll. So we can never forget that. And I feel very bad for them. And I don't want to make light of this, but it is a human side that we can't ignore.

The second part of this is the scientific part. There's a great contribution that's made from failure as well as from success. We can only build success in our community from learning from failures. So I think one of the obligations that we have in this community is to be as transparent, as honest and as open as possible. None of us should be spinning data. None of us should be hiding data. None of us should be making something that's not there. It's just not right and it's not good for patients at the end of the day, right?

So I was actually very grateful to EyePoint that they went ahead and said, "Look, we did not hit our primary endpoint, and we failed." They said that very directly. They said that very clearly, and I'm very grateful that they said that. That's exactly what they should have said. But they should have stopped there. Whatever said -- they said after that, I don't understand, and I don't even understand why they went there. And maybe people that are a lot smarter than me can explain that to me. But from what I understand, they said that there were asymmetric patients. I have no idea what asymmetric patients mean. I've never heard that term. It's not a term that we're familiar with.

And from what I can gather, asymmetric patients mean patients that are bad patients. I don't know how you figure out who are bad patients in a study, right? What's the criteria? Why are there 9 and not 12 and not 20 or not 6 or 7? I have no idea how you take those patients out. That's never been done before. And that's totally foreign to any clinical trial.

And then what I understand they said was that they got really unlucky because out of 240-some-odd patients, these 9 patients that were really bad patients, however they got these 9 patients, all happen to be in their arm. I mean, what are the chances of that? I mean it just makes this so incredible that it's disappointing, right? I mean, if I were to ask you to reach into your pockets and get a coin and keep flipping it and keep flipping it, how long would it take you to get 9 tails in a row? A long, long time. And they're asking us to believe that just by chance, all of these really bad patients, however they were bad, all ended up in their arm. I mean statistically, that's just simply not possible.

And on top of that, what they're saying is that these patients lost on average, more than 20 letters of vision, but it was not due to wet macular degeneration. Well, even if that's true, it doesn't mean that it wasn't due to the implant. And the possibility of it not being due to the implant is totally improbable based on what I just told you. I mean what are the chances you're going to flip 9 tails in a row for it not to be due to the implant. It's practically impossible.

And then even following that, they said that the reason for the loss of vision was glaucoma and geographic atrophy. If you look at our textbooks, these are the two classic diseases that are described as being slow progressive diseases. And to have 9 out of 9 patients in less than a year lose more than 20 letters of vision each due to this slow progressive disease that all happen to be in their arm just seems statistically impossible.

Again, look, I am grateful that they admitted that they failed. I think they should have stopped there. And I'm also happy that they have a very, very good Scientific Advisory Board. They have people that are also -- that we also have in common. These are great doctors that are great advisers. Speakers come from their group. And I have every confidence in the world that when these speakers speak and when this information gets disseminated, it will be done in a way that will be credible, that will be transparent and that will be scientific and that will help us all learn what happened and why they failed. But until then, I suspect it is aligned with what we've always said, which is that this drug simply is not one that is strong enough to last for this period of time. It has a signal, but it simply is not strong enough to go ahead and meet the primary endpoint.

So your point on patients with glaucoma and GA is a good one in terms of they have slow progressing disease. By chance, have you -- or Ocular, have you looked at in SOL-1 patients that have had -- that came into the trial with a baseline of glaucoma or GA and how those patients fared compared to the overall population?

Yes. So Biren, I'll answer your question, but you see this is the danger of spinning stories, and this is the danger of throwing mud and hoping something sticks. It does not do any benefit to the scientific community, to science and to patients. Again, I'm not trying to make light of this but it's about as legitimate as saying, have you stratified for patients that are 6 foot or taller? Have you stratified for patients that have long hair. There is no association whatsoever between TKIs and glaucoma or GA. There never has been, there never will be. TKIs have been here for a long, long time. Glaucoma and GA have been here for a long time. There's never been such an association. And to simply spin that is just irresponsible.

But the answer to your question is, yes, I guess we're forced to look because people would ask, and there's absolutely no association in SOL-1 whatsoever. Let me just repeat, there's absolutely no association whatsoever.

Great. I mean, so that's -- yes, your point is well taken there. And I also wanted to ask your impression on BCVA, they clearly missed on non-inferiority in the overall population. What are your impressions of how DURAVYU behaved in the LUGANO trial compared to the aflibercept arm? And any key takeaways that you or Ocular have regarding how aflibercept is behaving in LUGANO and read-throughs to SOL-R?

Yes. So look, here's -- it's a great question, and I can answer it in several levels. I don't -- let's just be scientifically pure and let's just be data-driven, right? What we know is that in a hierarchical analysis, if you miss the primary endpoint, all the other sub-analyses really are meaningless, they're nominal. So let's just take that -- take everything that comes after this with a grain of salt.

What it shows, I hope, in general, and I'll step back a little bit, is how good the results were in SOL-1. It's really difficult to beat EYLEA. It really is difficult to even be non-inferior to EYLEA. EYLEA is a fantastic drug. We know that. And the fact that in SOL-1 AXPAXLI beat that with a p-value of 0.0006 and in every single analysis ended up being better is remarkable. I don't think we've gotten nearly the amount of credit for that. And I hope that -- again, I don't mean to ride on somebody's failure, but I hope that this puts the spotlight again on how good those results were.

And now pivoting to SOL-R. Let me just say, it's important to understand that SOL-R in our opinion and in everything we've heard from the FDA is not going to be necessary for approval in the U.S. at all for the U.S. FDA. So that's removed off the table. If you look at the timing, the timing of the card turn of SOL-R is going to be about 6.5 months after AXPAXLI is approved. However, SOL-R is going to be very important in our opinion for OUS.

We're not pushing aside SOL-R at all, but I want to make sure I make it very clear that this is not for the U.S., this is for OUS purposes. What I hope the EyePoint results do is highlight the importance of patient selection. We have been extraordinarily careful in both studies in selecting the proper patients, in derisking our patient population. People laughed at us when we said, look, we've got a 6-month ramp with 2 opportunities to simply observe patients to see if they fluctuate. Now people aren't laughing anymore.

We are hoping that with this kind of thoroughness that our standard deviation will be narrow. We are hoping and we're expecting that our patient population is going to be much more predictable, much more reliable and much more derisked to go ahead and achieve the primary endpoint, which we are more confident than ever that we will achieve.

So based on LUGANO, it feels like you feel that you've designed the right study with SOL-R in terms of excluding patients with early persistent fluid, for example, that would minimize standard deviation, standard variability. Is that a fair assessment? Or are there learnings that you might take from LUGANO that you would incorporate into SOL-R?

Look, we knew this way before LUGANO, right? And again, I'm not riding on anybody's failure. We knew this way before LUGANO and that we've done exactly what we have done way before LUGANO at all. And I think what these results show is that what we have done has been absolutely correct. And what we are doing is derisking patient populations in a proper way, in a bespoke manner for each trial.

And I'm hoping that with this failure that EyePoint has unfortunately had that the focus can be on us. Look, it's a failed study. They had a failed study. Let's move on. I don't want to get into a situation of trying to hypothesize why they failed, why we should exclude a group of patients. I mean those kind of discussions are insane. I mean nobody excludes patients in a clinical trial. That doesn't happen, right? So let's not legitimize things that are non-sensible. Let's just talk about data. Let's talk about science. And I'm hoping that rather than talk about somebody's failure, now we can shift the conversation to talk about our success.

That's fair. Maybe one last question on treatment reduction. EyePoint reported about a 42% reduction when you exclude loading doses. We've had this debate, I think, and I've asked you many questions around this in terms of whether one should include or exclude loading doses in their analysis. Typically, if you're running a week 52 or week 56 trial, you should be including loading doses. But can you talk about -- like they reported a 42% reduction, excluding it. But when you include loading doses, it's about a 27% reduction. What's the right method for drug sponsors and for industry?

So let's just be clear. Again, I always say this, let's stick to science, let's stick to data and let's stick to what we need to get these drugs to do, which is to be approved, right? Let's go ahead, and first before I answer that question, recognize, and I know you do, Biren, that the FDA has nothing to do with treatment burden reduction. It's not in any label. It's not approvable. The FDA doesn't even use that term. It is completely alien and completely invented. And let's just be clear on that. It's just a fact. It's just a made-up term.

And when a -- again, I go back to saying this, when a trial misses the primary endpoint, everything else in a hierarchical analysis is nominal and descriptive. It's really meaningless, and they missed the primary endpoint. But having said that, you probably saw the Endpoints article that Peter Kaiser, Jeff Heier and Nadia Waheed as well as Steve Pakola and Victor Chong, which I thought was fabulous, they described it very, very well in terms of what treatment burden means and more importantly, what it doesn't mean and why it's not approvable.

But the answer to your question is if you're going to go ahead and make up this parameter, which is not approvable, you might as well be honest about it and include all the injections that were actually given. I don't know how you exclude loading doses and claim that that's not part of treatment burden. And again, if you include loading doses, which you should, clearly, AXPAXLI looks very, very good. I think the numbers were that with loading doses being included, it was something like 56%. Without it, it was something like 72%.

But again, I'm not beating my chest based on those numbers because it is at the end of the day, a made-up parameter. And I don't know why we're talking about a parameter that somebody made up that the FDA does not recognize. Let's stick to science. Let's stick to the fact that on SOL-1, we hit a superiority primary endpoint that nobody has with a p-value that was extraordinarily impressive of 0.0006. That's the story.

That's fair. And then I guess on SOL-R, this is an ongoing trial comparing at least for year 1 to aflibercept 2 milligrams every 8 weeks. What's the non-inferiority margin that you're hoping to achieve?

And I know we talked a little bit about excluding patients with persistent fluid. What was, I guess, the drivers for that? Because I think at R&D Day, you did have some data from a paper in 2016 that showed that it's a much tighter BCVA change when you're excluding patients with persistent fluid. Do you feel that, that data set resonates today where if you exclude those patients, you're going to see a much tighter standard deviation as well as narrower margin on BCVA?

Absolutely. And look, again, the goal of a company that is derisking a clinical trial is to make sure that you select the proper patient population for that trial. That's the most important and thoughtful thing that a company can do. And that's exactly what we've done. As you've seen, we've selected a derisked patient population in a bespoke manner for SOL-1, and we've done that clearly for SOL-R as well. And everything you said is exactly correct, which is that we are hoping that the standard deviation will be reduced because we have a derisked, much more predictable homogeneous patient population that is as stable as possible prior to randomization.

And SOL-R, I think, also has a rescue criteria of 5 letters and 75 microns. That's similar to LUGANO. How do you think that will affect the SOL-R trial?

So let's just go back and say why we did that. Remember, we had a modification for that. And the reason we did that is because when we talk to the OUS regulatory agencies, and this has actually become more important now because, as I said earlier on, SOL-R really is for OUS regulatory agencies. And as I keep stressing, this is not needed for the approval package for the U.S. FDA. For OUS regulatory agencies, we wanted rescue criteria that they were familiar with. And that's exactly what we did.

So the rescue criteria that we modified to, which is what you see today, is our rescue criteria that the OUS regulatory agencies have understood, have approved drugs based on, and we're completely aligned with them. And this now becomes more important than ever. The other reason also is because, frankly, we wanted to be compared to other drugs. We invite the comparison. We want transparent data so that our drug can be compared to others. That's not going to be an issue anymore because the other drug has failed, but that was the original idea as well.

And how should we think about the use of rescue in SOL-R relative to SOL-1? Because I think in SOL-1, once the patient was rescued on the first injection, then it was at investigator's discretion. Whereas SOL-R is, I think, a different criteria. Can you just walk us through that?

Yes. So look, the rescue criteria are quite different, right? One is a superiority study. The other is a non-inferiority study. So you remember that in SOL-1, what was required for the SPA was a loss of 15 letters of vision and the patients are rescued and that rescue -- that first rescue was counted. And thereafter, patients could be treated as per the PI's discretion. Here, in SOL-R, you know the rescue criteria, which is 5 letters and 75 microns. Patients are rescued if they meet both those criteria, both have to be met. And that's part of the recording of the final calculation.

Now having said all of those things, what I also take issue with yesterday is that somehow the number of rescues and the cadence of rescues doesn't matter. I mean how could that possibly be true? I heard that yesterday in the conference call. I mean, just think about this. If the cadence and the number of rescues didn't matter, then you could have water approved, right? I mean, how can that be logically feasible? Of course, it matters. What the FDA has said very clearly is that the first rescue is allowed and every rescue thereafter is under review. And what they've also said very clearly is that any rescue that affects the primary endpoint, in other words, within 3 months of the primary endpoint, will not be counted because it will be taken as affecting the primary endpoint, which is also logical.

So what we need to know from studies that are non-inferiority studies is we need to know the number of rescues. We need to know the cadence of rescues. In other words, when those rescues occurred. And we also need to know the number of patients that had multiple rescues. All those -- all that information is very relevant, not only for the clinician, but also for the FDA.

So for SOL-R, do you have an external committee that investigators have to go to in terms of like rescue, use of rescue, especially around -- you talked about cadence of rescue. So to minimize risk within 90 days of the primary analysis. Is that something that you have an external group of investigators or committee members to kind of monitor your investigators in SOL-R?

Look, I don't think that that's really necessary. There's always -- we always have physicians that are available as we did in SOL-1 for any kind of questions and advice. But the rescue criteria are about as clear as they can possibly be. It's up to the PI. And obviously, this is why we trust PIs and why we pick sites very carefully to go ahead and follow the protocol. And the protocol clearly states when you rescue, as simple as that.

Got it. The other thing with LUGANO is you talked about they're not using a self-sealing needle. So I guess that is potential for infections. But they also saw higher rates of conjunctival hemorrhage compared to what we saw in SOL-1. Is there anything that would -- that you would attribute to those rates?

Yes. Look, again, I don't want to pour salt in the wound. I mean they have a failed study, and I don't want to beat a dead horse here. But let me just be fair and say subconjunctival hemorrhages really don't have any kind of adverse effect at all. They're largely cosmetic and they go away. They don't cause any kind of major problem.

Having said that, the size of the needle is important. We know from studies done with surgery that the threshold for a needle size being self-sealing is 23 gauge, right? So anything bigger than a 23-gauge needle will not reliably self-seal. And if you don't self-seal and you take a needle out, you at least have the potential of having vitreous that will be imbricated in the wound which will then have a conduit from the outside to the inside. This is something that we call the Vitreous Wick Syndrome, which will allow potentially for infections to occur in a later time. And that's always a danger and that's a known condition called a Vitreous Wick Syndrome. And any time that you have a needle gauge that does not self-seal, there's always a potential danger of that.

Now again, I want to stop there and tell you what I'm telling you is hypothetical. I'm not piling on, on a failed study. I have no idea if that happened there or not. What I do know is that the rates were quite high in their previous studies. Whether that was the reason or not, I don't know. But at this point, look, it doesn't matter. I'm not trying to pile on, on a failed study. And I appreciate all the questions that you're asking me about LUGANO, but again, it's a failed study. It's done and it's time to move on, and it's time to focus on our success and not talk about a failed study.

Okay. Fair enough. I guess a couple of -- we've got 3 minutes, a couple of last questions. On SOL-R, for the EYLEA HD arm, the company is clearly taking a superiority look at the end of year 2 comparing to EYLEA HD. What's the margin that you need to achieve to hit on superiority with AXPAXLI?

Yes, it's a great question, Biren. I don't think we've guided you to that as yet. But what I will tell you is, again, the superiority part of SOL-R was an opportunity that we could not resist, right? We've already shown superiority to regular EYLEA, the possibility of showing superiority to high-dose EYLEA is remarkable. And you don't get that kind of opportunity often. We couldn't do that with our 56-week primary endpoint because that would be very close to the last injection within 2 months. But with 96 weeks, as you know, that's 6 months after. So there's the possibility of showing superiority.

The question then becomes how do you show superiority? Well, it doesn't necessarily just have to be visual acuity. It can be visual acuity and/or other things as well, such as OCT, such as fibrosis, such as atrophy, such as number of injections. So there's a number of ways that we can show superiority. And remember, what we show as being superior, whatever parameter or parameters are shown to be superior at this point really is not for approval in the U.S., it's really for commercial advantage because, again, keep on reminding people that the card turn for SOL-R is going to be about 6.5 months after a potential approval for AXPAXLI.

And then on safety, once you submit the day 120 amendment to FDA, is that something that you'll update investors with that dataset on?

Yes. The answer is a definitive no, and I'll tell you why is what I start out saying, which is that it's very important for us to keep the integrity of SOL-R. We will never see that data. Again, SOL-R is very important outside the U.S., and it's essential that we maintain its integrity. What will happen is that only the safety data will be unmasked. It will go to a third party and then it will then go to the FDA. We will never have any possession of it. We will never see it. It is only the safety data, that's all it is. And we will protect the integrity of the study. We will take a very small alpha hit, again, to protect the integrity of the study, but we will never see that data.

What about year 2 safety data from SOL-1? Will we see that prior to approval?

Yes. Again, we haven't guided you as to that. But again, when the time is appropriate, we'll guide you to that. But what I will tell you about safety, and again, these are really important questions, and thank you for asking that, is remember that when this team came in, we had absolutely no data on re-dosing with AXPAXLI, right? And what the Data Safety Monitoring Committee told us very specifically is to say, look, we have no data on re-dosing. We're going to watch re-dosing very closely. And as you know, we have a Data Safety Monitoring Committee, and they have been watching the re-dosing patients very, very closely, and there have been no issues thus far.

So having said that, we are very proud of the safety profile that we have in SOL-1. In fact, we're so proud that we presented at the patient level. And I would challenge any company doing any study in retina to present data for safety at the patient level. We need to know the number of patients who have endophthalmitis. We need to know the number of patients who have vasculitis, ischemic or non-ischemic. Presenting something at a greater than 2% or greater than 3% or greater than 5% level is a disservice. We really need to know the data at a patient level, which is what we've done from the get-go when we had the card turn for SOL-1.

Great. Actually, I do have one more question. I don't know if you have a little bit of time, but...

Sure, absolutely.

An investor just e-mailed me a question. Didn't SOL-1 see the same difference in conjunctival hemorrhage difference versus placebo as the LUGANO trial? And how could this be due to the needle if you have different needles? Though I don't think you're attributing needle to conjunctival hemorrhage. Is that correct?

Yes, that is correct. Again, look, in all fairness, subconjunctival hemorrhage is not something we worry about. We worry about a lot of things, but subconjunctival hemorrhage is not one of them. It looks dramatic. It's little blood vessels in the white part of the eye that burst. They can happen when you give -- when you put a topical anesthetic in there, it may have absolutely nothing to do with the needle whatsoever. It can happen for a number of things, including patients straining, that kind of thing. So look, there is no direct relationship with needle size or any kind of AE whatsoever. It's not -- again, we worry about a lot of things. Subconjunctival hemorrhage is not one of the things we're worried about.

Great. Pravin, we're out of time. I really want to thank you for spending time this morning and going over, I think, the latest updates within retina. And I'm sure we're going to have more to talk about in the months ahead.

Biren, thank you again. It's always a pleasure to be with you and always fun and informative, and thank you for the opportunity. I'm very grateful.

Great. Thanks, everyone.

All right. Good afternoon, everyone. We're going to go ahead and get started here. Welcome to the Ocular Therapeutix 2026 Investor Day. So during today's presentation, certain statements we will be making constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially as a result of a variety of factors, including risks and uncertainties identified in the Risk Factors section of our annual report on Form 10-K and our other SEC filings. With that in mind, it is my pleasure to introduce Dr. Pravin Dugel, Ocular's Executive Chairman, President, and CEO.

Good afternoon, and thanks for being here. This is a terrific day for us, and I really appreciate you spending the afternoon with us. You'll hear a lot of data today. You'll hear a lot about our strategy today, and you'll hear also why we're so incredibly excited to have you here.

The last time we were here in this very place was in September. And at that time, for those of you who are here, which I think is most of you, I said that I would like to have this company defined by 3 characteristics. And those are that this company is courageous, it is bold and it is opportunistic.

And today, you'll hear the confirmation of that. That is absolutely true with everything we're going to say today, you'll hear that, that stands and even more so than ever. And when you are courageous and bold and opportunistic, you do things that people say you can't do.

And when you say you're going to do it, there are going to be naysayers. And I realize that we have naysayers. So what do you do to combat naysayers? It's really easy. You establish credibility. And how do you establish credibility? The way you establish credibility is by executing and executing and executing absolutely flawlessly and consistently without failure, and that's what we've done.

And let me just review some of the things that we've done. So when we first got this team together in 2024, we were told that SOL-1 would be an impossible trial to recruit. You remember that. In fact, the enrollment has not only been outstanding, but has been well ahead of schedule. We've executed that flawlessly.

Later on that year, we were told that SOL-1 would have poor retention and many off-protocol rescues. And in fact, the retention and the on-protocol rescues have been exceptional, so good that they're better than any other retina study. Again, that has been executed flawlessly.

And then we were told last year that the modifications that we made in SOL-1 would negate the SPA. Well, they haven't. The SPA has been retained because we had complete FDA alignment as you'll hear about today as well. And that has been executed flawlessly.

And then earlier this year, we heard that SOL-1 was going to fail. In fact, we heard from some that SOL-1 had already failed. In fact, SOL-1 succeeded spectacularly and AXPAXLI did something that no other drug has done. It reached superiority against an anti-VEGF, which had never been done with a p-value that had never been gotten less than 0.0006. Again, we executed that flawlessly.

Now today, you've been told that there is no way the FDA will accept a single trial for NDA submission. And in fact, what you'll hear today is that we have complete, formal, and documented. And yes, I know this has been going around, but we do have FDA minutes. We wouldn't be doing this without the minutes, obviously.

Documented alignment with the FDA that we will have a complete package for submission with SOL-1 alone and safety-only data from SOL-R at the end of this year. You will hear the details today. Again, we will execute that flawlessly as well. This is not a new thing. If you look at this, you'll see that there are other trials that have been approved.

In 2025, there are 28 single trial approvals. This is 61% of evaluable approvals, and this is almost half of them are non-orphan diseases. Tomorrow, there will be another narrative. There will be another bear narrative, and we will do what we have done over and over and over again to combat that. We will execute flawlessly as we always have, whatever that narrative is.

So here's what you'll hear today. You'll hear that the further we dig into SOL-1, the more confident we are, the more convinced we are about the impact that AXPAXLI is going to have. The durability and the disease control is absolutely unmatched with a single dose, and you'll hear about that more today.

You'll also hear that there's a clear path to market. You'll hear that we have aligned with the FDA formally on a complete package submission that we will have in the fourth quarter of this year. Now many of you may wonder why we haven't already submitted and why we already haven't already submitted our NDA and filed.

Well, what I said earlier was that we were courageous, we were bold and we're opportunistic. But we're not reckless. Speed without guidelines kills, right? And our guideposts are the U.S. FDA. We have waited until we have full and formal alignment with the FDA, and that is why we're talking to you today.

And we will wait until we have the complete package, and that is why we will submit responsibly and completely in the fourth quarter of this year. The goal here is the same. It's the fastest path to FDA approval with the least amount of regulatory risk. We are doing this carefully, thoughtfully and responsibly.

And because all the time lines have been pulled up, we have to be ready for launch. And you'll hear today that we are absolutely ready for launch, and you'll hear our commercial strategy as well. So what have we learned from SOL-1? Well, what we've learned from SOL-1 is we knew that EYLEA is a good drug. It's a great drug. We also have learned that EYLEA lasts a long time. But we also learned that AXPAXLI is better, much better. It lasts longer and it's a lot stronger. It's much better than we ever thought it would be, and we're thrilled with it.

So when we learned that the FDA did not require the SOL-R efficacy data for our complete package, we had the opportunity to go ahead and not just hit the home run because we already hit the home run with SOL-1, but to go for the grand slam, which is the superiority versus high-dose EYLEA, having already secured the superiority versus regular EYLEA.

And if we are able to do that, this will secure this drug for decades and decades to come. And that's what we're going after and why wouldn't we with newfound confidence. As you go through this today, what I'd like you to understand is not just the things that you're going to hear, but who you're going to hear from.

You'll hear about regulatory from Art Ciociola. There's no one in this planet who has had more drug and device approvals than Art. He is simply the most experienced regulatory person there is. And I wager that the 3 people behind them put together are not nearly as experienced as he is.

I think [indiscernible].

Other than Peter. You'll also hear from David Robinson. There's no better person to lead our launch than David Robinson, who's already led the launch and architected the most successful launch in the retina in EYLEA. These are the people that you'll hear from. And on top of the team that we already have, there are no finer people to do this.

What I would ask of you today is this. It's regulatory heavy, and I realize that, and that's appropriate, and that's the way it should be. But for a successful submission, there are really 2 things that are required, right? We always talk about the one, but not the other. The second one is equally important. The one that's really -- that everybody talks about is speed. And that's important. I get it. But the one that people forget is risk. Speed kills without guideposts, as I said. So today, when you hear what we're going to do, you'll get the details. But for everything we say, think how have they derisked this? How have they derisked the submission? How have they derisked the shareholders? And that's a really important thing because the goal remains the same. We're not just going to be best-in-class now, we're going to absolutely be first-in-class.

Gives me great pleasure to welcome 3 of the finest retina physicians in the planet, who I'm absolutely honored to call my friends, people that I've known for a very long time. Their words matter today. Their words will matter even more when AXPAXLI is approved. And I think you know them all.

Arshad Khanani from Reno, Nevada; Lejla Vajzovic from Duke University; and Darius Moshfeghi from Stanford University.

And now I'm going to go ahead and hand it over to someone that I said last year was the greatest CMO on the planet, and that's truer today than it's ever been, Dr. Nadia Waheed.

Thank you, Pravin. I need a little clicker.

As you have expected.

Thank you so much, Pravin -- and it is an absolute pleasure to be here today, and I'm excited to walk you all through our clinical program for AXPAXLI, starting with our SOL -1 study, highlighting the unmatched durability and sustained disease control shown by AXPAXLI. I'm also going to talk a little bit about why clinicians will use this when it gets to market.

SOL-1, as you all know, is a superiority study designed to compare head-to-head a single injection of AXPAXLI versus a single injection of aflibercept. The primary endpoint at week 36 was the proportion of subjects who maintained visual acuity, defined as less than 15 ETDRS letters of loss from baseline at week 36.

Even though the primary endpoint was at week 36, patients were followed for rescue to week 52 to evaluate the 52-week durability and up to 12-month dosing of AXPAXLI. Patients received a second dose of AXPAXLI at 52 weeks. And the second year of the study was designed to evaluate safety of a Q6-month dosing.

Accordingly, patients continued in their treatment arm and received treatment every 6 months. SOL-1, as Pravin mentioned, is the first successful superiority trial of a novel agent versus an approved anti-VEGF. The SOL-1 study showed AXPAXLI had unmatched durability, sustained disease control and was well tolerated by patients.

And so first, let's discuss in more detail the durability of AXPAXLI. So the SOL-1 study met its superiority primary endpoint with a high statistical significance and a p-value of 0.0006. The study showed an observed difference of 18.3% and also had a highly clinically meaningful risk difference of 17.5% for patients treated with AXPAXLI compared to control in maintenance of visual acuity at week 36.

And I will also show you some evidence downstream on how the Kaplan-Meier curve data is especially exciting for us as clinicians. At month 9, 3 out of the 4 AXPAXLI patients maintained vision with a single injection, demonstrating a strong potential for annual dosing.

And at month 12, we saw 2 out of 3 patients maintain vision with a single injection. 90% of the patients maintaining vision at month 9 continued to maintain vision at month 12, clearly demonstrating both the durability of AXPAXLI as well as the predictability of response in these patients.

And here is the Kaplan-Meier curve demonstrating extended durability, significantly delaying the first rescue injections in the AXPAXLI arm. As you can see, the time to approximately 30% of subjects requiring the first rescue is a whole 6 months later for AXPAXLI than it is for aflibercept.

Now you're all used to seeing some time to 50% event rates in Kaplan-Meier curves. And of course, you're asking why we're using 30% here instead of 50%. That's because AXPAXLI patients never actually hit a 50% rescue rate even at the 1-year time point.

So besides great durability, we also see sustained disease control with AXPAXLI. And so how do we evaluate disease control? So as retina specialists, we rarely just look at vision. We look at anatomy. And specifically, we look at fluid in wet AMD patients. As you may know, sustained fluid control leads to better maintenance of vision over the long term. And so let's discuss fluid control and what that means in clinical practice.

This graph shows time to 75 microns increase in central subfield thickness from week 8. 75 microns is significant because this is often used as a threshold for retreatment in wet AMD clinical trials. Our SOL-1 study showed a 5-month delay in reaching 75-micron central subfield thickness gain from week 8 with the use of AXPAXLI, again, evidence of exceptional disease control in patients. But wait, there's even more.

What's more interesting to look at for clinicians is to look at a threshold of more than -- greater than or equal to 30 micron increase in CSFT. And the reason I say that is because 30 microns is a very small amount of increase in CSFT and because also fluctuations in retinal thickness of greater than 35 microns are associated with fibrosis and worse long-term visual outcomes.

AXPAXLI showed about a 6-month difference in time to a 30-micron CSFT increase from week 8 versus aflibercept, again, demonstrating outstanding sustained disease control. So now that we've covered fluid control, let's move on to vision control. And I think all of you are familiar with this graph. Here, we see the mean change in vision from screening.

AXPAXLI demonstrated strong vision control up to 9 months with much fewer rescues than in the aflibercept arm. As you know, this represents close to 3/4 of the patients in the AXPAXLI arm that remained rescue-free at week 36 versus only 56% of the subjects in the aflibercept arm.

So now that we have dug into the unmatched durability and sustained disease control demonstrated by AXPAXLI, let's discuss how this is tolerated by patients. So AXPAXLI was generally well tolerated in the SOL-1 study. There were no treatment or procedure-related ocular serious adverse events and no subjects discontinued the trial because of adverse events.

Most importantly, there were no cases of endophthalmitis, occlusive retinal vasculitis or non-occlusive retinal vasculitis observed with AXPAXLI. We are now in year 2 of SOL-1, where mask safety data is being monitored while we evaluate 6 monthly dosing and the DSMC recommends trial continuation.

To summarize, SOL-1 results highlight AXPAXLI's groundbreaking profile. SOL-1 is the first Phase III trial to demonstrate durability out to more than 9 months, showed up to 52-week visual and anatomic stability and demonstrated a well-tolerated safety profile.

And so now that we've demonstrated that the SOL-1 results are highly positive, and we intend to submit our NDA based on these results, let's talk a little bit about what value each one of the SOL trials now brings going forward. So SOL-1 establishes efficacy and safety out to week 52 that will be the foundation of our NDA submission in wet AMD.

This trial will support both our U.S. and ex-U.S. regulatory filings while maintaining strong commercial relevance given the strong superiority results of the study and the possibility of bypassing step therapy. Now that SOL-R year 1 efficacy data is no longer a requirement for NDA submission, we are in the extraordinary position of using the SOL-R trial to best serve our long-term strategic objectives for AXPAXLI, which are to be the best-in-disease agent for wet AMD, as Pravin mentioned.

We're now adding a new key secondary endpoint of superiority compared to aflibercept 8 milligrams, HD EYLEA in SOL-R, which will be evaluated at week 96. And we also hope to demonstrate prevention of fibrosis and atrophy with AXPAXLI relative to aflibercept 2 milligrams at this time point.

Moving to SOL-X, our open-label extension study, subjects who have completed 2 years of safety follow-up in either SOL-1 or in the SOL-R study are eligible to enroll in the SOL-X trial for an additional 3 years of safety follow-up. We initiated SOL-X enrollment in April and believe this will be a tremendously valuable program, both from a commercial relevance as well as a long-term safety perspective.

SOL-X outcomes may further expand AXPAXLI's potential by highlighting the need to start AXPAXLI treatment early or potentially risk worse long-term visual outcomes due to potential fibrosis and atrophy that may be seen with today's pulsatile treatments.

And finally, let's talk about how SOL-1 success has impacted our diabetic retinopathy program, which we call the HELIOS program. So as you may recall, we first unveiled plans for our registrational program in diabetic retinopathy during our September 2025 Investor Day. We announced 2 complementary Phase III superiority trials evaluating every 6- and every 12-month AXPAXLI regimens using a novel primary endpoint that we aligned -- aligned on with the FDA, which is an ordinal analysis of a 2-step change status on the diabetic retinopathy severity score or the DRSS as it's commonly known.

Today, we're happy to announce that we will be streamlining this program to prioritize HELIOS-3. This superiority trial will evaluate every 12-month AXPAXLI versus sham, and we will continue to target a broad diabetic retinopathy label by including subjects both without center-involved diabetic macular edema as well as patients with noncenter-involved DME.

And the primary endpoint will remain as the ordinal DRSS 2-step change status. Here is an overview of the HELIOS-3 superiority trial design. We intend to randomize approximately 620 subjects with moderately severe to severe NPDR without center-involved DME. These subjects will receive either AXPAXLI or sham at randomization at week 48.

The primary endpoint will be taken at week 56 from baseline and subjects will be followed until week 96 for safety. As you will notice, we've removed the Q6-month dosing arm from this study. So why did we make these changes to the HELIOS program? Following our strong SOL-1 results, combined with the tremendous evidence that we have already generated in the HELIOS-1 study, we can now confidently say that AXPAXLI will show durability up to 12 months in NPDR, where we know that a once-a-year regimen is highly preferable and therefore, we streamlined the development to focus on this approach. Importantly, HELIOS-3 will also support our global regulatory objectives. And having said that, I'm now going to pass on to Peter to present to you the highlight of the day, which is our regulatory strategy.

Thanks, Nadia. It's now my privilege to share with you our U.S. regulatory strategy in wet macular degeneration. So here's what we're going to cover today. First, what are the FDA regulations and guidelines that clearly support a single trial submission. Second, why does our SOL-1 study meet all these FDA guidelines for a single, adequate and well-controlled study that we could file our NDA.

And finally, what are some of the confirmatory evidence which are required to support the SOL-1 trial as part of a single trial submission. So let's first start with why we can do this. Section 115 of the 1997 FDA Modernization Act specifically amended and defined what the substantial evidence rules were and explicitly allows one adequate and well-controlled trial plus confirmatory evidence to receive FDA approval.

The 1998 and 2023 guidance reiterated that a single trial plus confirmatory evidence meets that statutory requirement for substantial evidence for approval. As was mentioned by Pravin earlier, this is not new. The use of a single trial for FDA approval has been used in the past and in fact, has become increasingly frequent over the past few years. In 2024 and 2025, the majority of CDER approvals actually utilized a single trial approach. Moreover, over 40% of these approvals were in non-orphan designations. So the 21 CFR Part 314 specifically defines what is an adequate and well-controlled trial. A study that uses sham, for example, which introduces bias is not adequate and well controlled and therefore, can only be corroborative and cannot be used as a single stand-alone trial.

SOL-1, therefore, was prospectively designed to meet all the requirements as defined in 21 CFR Part 314. What about this thing, the SPA? Well, a special protocol assessment indicates the FDA has agreed specifically on the study design, clinical endpoints, study size and most importantly, the statistical analysis plan that they are adequate to address the scientific and regulatory requirements that support approval. SOL-1 is the only active wet macular degeneration study that's being conducted under a special protocol agreement.

Is this important for a single trial submission? Of course, it is. And Dr. Boyd at the recent Retina World Congress actually said that a special protocol assessment is an official agreement between a sponsor and the agency that we will accept a certain trial design and if successfully completing that protocol, that this would be highly supportive of the approval of the product.

The Division of Ophthalmology has also stated that p-values less than 0.001 could be potentially supportive of a single trial approval. And at that same meeting, Dr. Boyd reiterated and stated specifically that a single adequate and well-controlled trial can support approval, often with very strong p-values, reiterating less than 0.001.

The division of ophthalmology has also approved drugs like XIPERE, for instance, for noninfectious uveitic macular edema based on efficacy from a single trial. The PEACHTREE trial met its primary outcome with a p-value less than 0.001 and only 96 patients on study drug. The safety package include 296 patients, with those additional patients coming from the open-label AZALEA study.

As Nadia mentioned, the primary endpoint of SOL-1 was highly statistically significant and the p-value was 0.0006. And this was supported further by 6 prespecified sensitivity analyses of the primary endpoint that were also statistically significant. So SOL-1 is the first study to show statistical superiority in preventing vision loss against an active anti-VEGF control.

Moreover, almost 70% of the patients were rescue-free at 1 year. And as Nadia mentioned, there was a 6 months difference in between that first rescue injection between aflibercept and AXPAXLI. Finally, 3 hierarchically controlled secondary endpoints were statistically significant, showing that the clinical meaningfulness of SOL-1 is that we demonstrated the superiority on the primary outcome.

We had a strengthening effect size over time. We had consistent visual and supportive anatomic outcomes. And together, that creates a very highly persuasive efficacy argument. Now the guidelines clearly define that one trial can establish effectiveness. But what they doesn't mention is the FDA still requires adequate safety exposure.

The 2023 guidance tells us that a minimum 300 patients with at least 9 months follow-up are required. So the AXPAXLI safety data set will include more than 300 patients on AXPAXLI for 12 months. How are we going to do this? Well, we're going to take the 170 patients from the SOL-1 study who have 52-week safety results.

We will perform an interim safety analysis of the SOL-R study looking specifically at patients who have passed the 52-week time point, and this will add more than 130 patients to the safety data set. An alpha penalty will be taken for this analysis, but no masked efficacy analysis will be performed on that SOL-R data.

We also maintain SOL-1 masking into year 2, specifically to be able to use this data for labeling purposes. And at the 120-day safety update, we intend to add the year 2 SOL-1 safety data to support repeat dosing. The 2023 guidance also defined what can be used as confirmatory evidence to support a single trial NDA submission.

And we have broad confirmatory evidence to support our single highly statistically significant SOL-1 study. What are some of these? One, mechanistic evidence. We know that the role of vascular endothelial growth factor is one of the primary drivers of wet AMD.

We also have agency reviews that acknowledge axitinib's potent and selective pan-VEGF receptor blockade. Class consistency is another evidence that they look for. In other words, do other members of the same pharmacologic class behave similar to the observed effect in SOL-1?

Is it consistent in terms of mechanism of action, disease, endpoints, direction of effect? There's extensive evidence, obviously, of the use of anti-VEGF and vision and anatomic gains in wet macular degeneration. AXPAXLI's effect in SOL-1 is in the expected direction, magnitude, time course, anatomic relationships and safety for this therapeutic class in the same disease.

We also have strong pharmacodynamic evidence showing axitinib blocks all 3 VEGF receptors as well as both PDGF receptors with very high potency and specificity. And most importantly, this data aligns with the pharmacodynamic evidence from the INLYTA NDA.

Animal models show that axitinib inhibits angiogenesis and paricyte sprouting as well as in the gold standard rat CNV model, it inhibits angiogenesis and leakage -- in a VEGF challenge model where you sustained VEGF suppression is crucial to prevent vascular leakage, traditional extracellular VEGF inhibitors work only in the short term, whereas AXPAXLI shows sustained inhibition of vascular leakage for the entire 90-day duration of the study.

Natural history evidence can be used to support, which shows untreated wet AMD patients lose vision, while inhibition of VEGF maintains vision. Real-world evidence supports the use of anti-VEGF in wet AMD from the IRIS registry as well as in our own analysis of a SOL-1 emulated population where the visual acuity and OCT results were identical or similar to SOL-1, but only required -- but didn't require 9 anti-VEGF injections. So this is what we plan to do.

Per the FDA Type C written minutes, our planned NDA package will include the SOL-1 efficacy data at 52 weeks with no SOL-R efficacy data. The safety database will include both the week 52 safety from SOL-1 as well as the interim safety review from SOL-R to submit a complete NDA with more than 300 patients for safety review.

And then at the 120-day safety update, we will provide the agency with year 2 of the SOL-1 safety data. No additional data will be provided that would trigger any major amendment while submitted during the NDA. And specifically, as mentioned before, no SOL-R efficacy data can be submitted because we will remain masked until our key secondary endpoint at 96 weeks. So this is what the time line looks like.

After our release of our positive SOL-1 study in February 26, we moved very quickly to align with the FDA to derisk our NDA submission. In May, we had our in-person Type C meeting and then we have the written minutes that have reflected what was agreed to at that point, and that was that the FDA agrees we could file our NDA with a single SOL-1 trial plus our confirmatory evidence.

In the third quarter of 2026, we will have a pre-NDA meeting, which is planned to align with the FDA in terms of the formatting and logistics of those final exhibits. The NDA and what is submitted in the NDA has already been agreed to in a Type C meeting.

In the fourth quarter 2026, we're going to perform that interim safety analysis of the SOL-R study, as I mentioned. And once we have that data in hand, we will file our complete NDA package in the fourth quarter 2026. 120 days later, we will provide the year 2 safety data, as mentioned, and no additional data that would trigger a major amendment is planned during the entire NDA review cycle.

Another important aspect of our submission is not so obvious. The normal pathway is the 505(b)(1) pathway. That's a standard full NDA submission pathway for a new chemical entity. In contrast, the 505(b)(2) pathway is a hybrid pathway. This NDA is used for drugs that are similar to, but not identical to an approved drug. This hybrid application relies on the safety and efficacy of the previous submission, and this accelerates approval time lines for new formulations, routes of administration or indication.

Axitinib, as you know, was approved for renal cell carcinoma in 2012, and therefore, we plan to use the 505(b)(2) pathway. Why? Why should we do this? Well, if you submit a hybrid NDA using this pathway, it could speed up the review time by up to 60 days versus a traditional 505(b)(1) pathway, speeding approval time lines.

So Ocular Therapeutix is submitting a complete hybrid NDA package via the 505(b)(2) pathway that meets the FDA's substantial evidence of effectiveness and safety requirements. We have one positive adequate and well-controlled study that was performed under a special protocol agreement with the FDA. That has a highly statistically significant result of 0.0006.

Our data has internal clinical coherence and is consistent with the data in that 3 out of the 5 key secondary endpoints were met with statistical significance as well as many of the other secondary endpoints, which all point in the same direction. We have a sufficient safety package that meets all FDA guidelines, having more than 300 patients exposed for 9 months or longer, and we have broad confirmatory evidence to support the submission of SOL-1 as a single study.

So now I'd like to invite Art to the panel area up here, regulatory head, and we'll have a little kind of Q&A session. So Art?

So one of the things that many of you don't know is who this man standing next to us or sitting next to us is. And he won't talk about himself, so I'm going to do it for him. And he has extensive ophthalmic experience in numerous indications as a regulatory person. He has 35 years in both big and small pharma. He's been at Novartis, B&L, Pfizer, GSK. And most importantly, he has overseen the global approval of over 18 new chemical entities. So we were -- it was a coup for us to get here, but Art -- before you joined us, you were having a very successful consulting career enjoying your "retirement. What made you decide to join Ocular full time?

Well, thank you, Peter, for your kind words. I decided -- I have a small story I want to tell about why I decided to join Ocular. So when I was at Pfizer, there was a drug called MacuGen. And it was the first drug approved for the treatment of AMD. It was first VEGF. It was a co-development agreement with a company called Eyetech, which actually has offices was very nearby here.

And I remember early on, I was introduced to the project team, and they told me about this drug, Aptamer and they said, "Oh, it has to be injected. And I assumed this was some sort of infusion, biologics, they said no. Patients are injected in their eye. It's an intravitreal injection. And I said, patients would accept this. They continue in the trial.

They said, yes, they're not comfortable with it, but they do and so on. Peter, fast forward 20 years. Lots of good drugs approved for AMD, lots of good drugs. Peter, there still remains patients who are injected every month, every other month. And I believe that puts a significant patient burden on them, on the caregivers as well.

And so Peter, I think this drug has that potential. Patients have been waiting, if you don't mind, 20 years for this drug. And I believe this will have a huge impact on patients' lives and patients' families. And I would not pass up the opportunity to join you, the other members, as I look at Nadia, she's waving at me, Jeff, to get this drug approved for our patients in AMD. That's why I joined.

Well, we're glad you're here. Let's jump to the question I think is on everybody's mind sitting in this audience. And so we've talked about our regulatory discussions. We talked about how we can submit an NDA on SOL-1 alone. But I think everybody in the audience wants to know why haven't we submitted the NDA already?

Peter, it's a good point. As you kindly shared with the group, I have multiple NDAs that I have multiple sNDAs. And the key for me, Peter, is this balancing of speed and risk, speed and risk. Yes, we all want to submit these applications as soon as we can. We want our patients to get these drugs as soon as possible. That being said, Peter, if you do not submit a complete comprehensive NDA, FDA will -- they can reject that application, of course. We don't want that. Of course, we don't want that.

But Peter, here's what's really important for me as well is we've aligned with the contents of the submission. The agency understands what we're going to submit. As you nicely described here, we did it under a SPA. We have safety database. We will have established already effectiveness as per the guidance. But what's really important, Peter, is we want to do it in a manner that the reviewers will take our application and review it in a timely manner and not ask extraordinary excessive number of questions, which always delays your application.

So Peter, that is key for us as we go through that is that our development program fully aligned with the agency, their expectations through several meetings over the years, written correspondence and of course, as you described, our recent Type C meeting results.

Well, let's talk about some of those interactions. The most recent one is probably the most important for what we're discussing here. Could you give the audience a peek behind the curtain, so to speak? They weren't in a room where it happened. So what happened?

Yes. It was good. I'm smiling. And many of you know that the -- our previous commissioner, Dr. Makary, he wrote an op-ed article in the New England Journal of Medicine and said that FDA's policy would now go from 2 trials to 1 trial. And I got lots of questions. They said, what does that mean? Is FDA changing their standards? What is that? I said, no. I said, we've always had that option.

Peter, you described since the '90s, okay? There's a guidance -- 2023 guidance that was issued. It's actually very clear guidance. And it says, yes, you can establish effectiveness based on a single, adequate and well-controlled trial. And so Peter, as we discussed that, we said, yes, it's a possibility. And I always said it depends on the results of that study.

FDA will require the ophthalmology division, a highly significant clinically meaningful benefit has to be demonstrated. And Peter? In February, when our results were announced of a p-value of 0.0006 with a clinically meaningful difference of 17% at week 36. I still remember that hearing, oh, no, here we go. This is the basis for our discussions and it meets the substantial evidence of effectiveness based on a single study.

Hence, Peter, we had that -- we requested a Type A meeting. I apologize, Type C meeting. and asked literally a single question. Would the agency accept an application based on our -- I'm pointing at the screen, SOL-1 study data plus confirmatory evidence, Peter. And that was the discussion that we had at FDA.

And during that discussion, FDA said, you have presented a compelling argument -- your data package is significant and that they will accept that application for review. Peter, that's where we are today. And right now, my team is working really hard on assembling that NDA and progressing this as quickly as we can.

Well, today, we shared that in the fourth quarter 2026, we're going to submit the complete NDA. What are some of the gating items that we need to worry about? And specifically, what do you expect the role of SOL-R to play in that NDA?

Yes. Peter, you make a really good point here, as you described there. We have to submit a complete comprehensive data package for FDA to review this in an expedited manner here. Peter, the gating item for us is the adequate safety database.

As per the 2023 guidance, we need 300 patients exposed to AXPAXLI, and that's what we plan to do by the fourth quarter of this year here, and that will be part of that submission. At the time of application, we will submit more than 300 patients. who've been exposed to AXPAXLI for 12 months. That is the real key gating item for us here.

As I shared, I've got a very experienced regulatory team experienced in numerous NDAs. Frankly, Peter, I will look at every page of this application when it goes in. So we're assembling that application now and pulling that together there. And frankly, we're going to give FDA exactly what they have asked for and what they require to expedite the review of this particular application.

That's what's gating us.

Perfect.

Peter, I actually -- I have a question for you here. You just talked about the SOL-R data and the impact on there, the change to week 96 top line data a bit later. I've gotten some questions. Give us some thoughts on that.

Well, when we talk about the SOL-R study, there's a few things that are very important. So first of all, what has not changed? And what has not changed specifically is, first of all, the primary outcome, which is week 56, non-inferiority to EYLEA 2 milligrams and how and when we're going to evaluate that. There's no change to the non-inferiority margin. It's still 4.5 letters and because it's an adequate and well-controlled study with no sham injections per CFR314.

If we had to use a sham injection, that would have reduced our margin. So that's why we didn't use a sham injection. And there's no change to the study conduct. But I think the most important thing that has not changed is our absolute confidence in what we expect SOL-R to show. We expect to meet the primary outcome, and that confidence has only been increased since the results of SOL-1 and specifically analyzing the rescues and the visual and anatomic data from SOL-1 just gives us even more confidence that we are going to hit that primary outcome.

But what has changed? When we received the written guidance or the written minutes from the Type C meeting, everything changed because now all of a sudden, SOL-1 is all we needed for our NDA. So that means we could use SOL-R specifically for commercial advantage. And that's really the important thing.

SOL-1 will hopefully give a superiority label to 2-milligram EYLEA. But if we hit this superiority outcome in SOL-R, then theoretically, we could have a superiority label to EYLEA 8 milligram, which would be an immense commercial advantage. So we have this potential to hit both these things.

Now remember, in SOL-1, we -- the initial primary outcome or the primary outcomes at week 36. And initially, we were going to unmask at week 36, but we decided to hold off. We made an amendment, and we decided to unmask at week 52. And it was really important that we did that because since we were masked, we had an outcome measure at week 52 that we could use, which was specifically talking about the fact that 2/3 of the subjects at 52 weeks were rescue-free. This is an incredible feat and something now that will be a potential differentiator if we were to put that into the label. So had we not changed the masking regimen of SOL-1, we would not have been able to get that into the label. And we're doing exact same thing in SOL-R. We want to maintain masking for that key secondary outcome of superiority to EYLEA 8 milligrams. And by doing that, that would allow us to be able to put it into the label. So that was our thinking behind doing that.

Makes totally understandable, Peter. Let me just ask a follow-on question here. Why don't we just -- I've gotten this question. Why don't we just look at a comparison of EYLEA HD at our week 56 time point?

Well, so if you look at anything when you do a study change like that, you put -- there's a lot of thought put into it. And first off, when you're doing a superiority evaluation, the first question you should ask yourself is, do you have enough patients to meet that superiority outcome? And so the answer to that question is, of course, yes, the SOL-R was sized specifically for this purpose. It's not something we talked about in the past, but we did do this on purpose.

Second, the test should be performed when you have the highest likelihood of success. So our highest likelihood of success in SOL-R is meeting a non-inferiority versus EYLEA 2-milligram Q8 at 56 weeks. Superiority to EYLEA 8 milligrams at 56 weeks would be a hard bar. Why? Because if you remember, everybody was reinjected at 48 weeks. So that would be 2 months later, we would be doing the superiority test.

In contrast, at the 96-week time point, the previous injection of EYLEA HD would have been 6 months prior. So in terms of hitting a superiority outcome, the highest chance of hitting that superior outcome would be at week 96 not at week 56. And so because of that, we decided we really want to -- we hit a home run as Pravin says, we want to hit a grand slam. The home run is superiority to 2 milligram. The grand slam is superiority to 8 milligram, and that's our goal by moving our key secondary to week 96.

That's good. Thank you for that, Peter.

Now Art, there are some confusion about the way we're going to be doing this and specifically, this 120-day update. Perhaps you can comment what is expected at the 120-day update from the FDA.

Absolutely. Thank you for that. Just for folks in the audience, as you -- many of you know, a 120-day safety update is a regulatory requirement. It's outlined in, as Peter, as you said, 21 CFR 314 as well. And frankly, the intent of this really is to update the agency on any new safety risks that have been identified.

I mean think about it. It's now 4 months after the application has gone in. Your database cutoff is prior to that. So the agency wants to know anything new that has been observed in clinical studies here. Now Peter, importantly for us, as you outlined here, is that at the 4-month safety update, and that was discussed with the agency at our Type C meeting is that we will be submitting the SOL-1 2-year data. Which will provide us evidence to support repeat dosing in our labeling. And that is really important for us.

The agency will want to see this long-term safety data, hence, that 2-year data that we will submit at the 4-month 120-day safety update as such. And the SOL-R data, as you pointed out, Peter, SOL-R efficacy data will not be submitted in that. I know there have been discussions about that as well. That being said, Peter, by doing it in this manner, this is the fastest regulatory pathway to our approval.

So anyone can submit an NDA at any time. But the question is, will the FDA actually accept that submission for filing? And based on everything we know so far, based on all our discussions with the FDA, sort of what is your confidence level that the FDA will accept the submission, number one.

Number two, are you worried about RTF refusal to file? Or are you worried about having to do any major amendments?

Yes. So thank you for that, Peter. As you probably can understand, my expectations and confidence in accepting this application, the agency, it's incredibly high, incredibly high. Given what we've done, outlining all of the criteria, the SPA agreement here, the statistical analysis, the results, our interactions with FDA, incredibly Peter, you're making me smile with the refusal to file, okay?

There are many reasons for refusal to files. Peter, as you shared, I've done a number of submissions, NCEs. I've done dozens and dozens of other sNDAs as well, sBLAs as well. Peter? I've never gotten a refusal to file. So I'm smiling as you ask me that question here.

So hence, I'm confident, as I shared with you, we will ensure that, that application is complete, comprehensive, all the hyperlinks work, everything. I not only have an experienced regulatory team. Peter, I also supervise the quality team, who will also do QC on this application as we go through this. So I'm very confident we will not get a refusal to file.

Perfect. Glad to hear that. So we talked about this third quarter pre-NDA meeting. And some people will say, well, everything they just told us is complete BS. They haven't agreed to anything. They still have to do this NDA meeting, pre-NDA meeting and everything could change at this pre-NDA meeting. So for those of us in the audience who don't understand what a pre-NDA meeting is, what do you expect the FDA to say or do at that meeting?

Yes. It's a good question, Peter. And pre-NDA meetings, I have every single application that I've submitted, we had a pre-NDA meeting. And basically, these are operational meetings in that you align with the agency on the formatting, okay? It can be font size. It can be any of those types of things. That's what the focus will be on what are the agency's expectations and how they want to see the data positioned. That will be the focus of these meetings here.

So it's not what we've already talked about.

No, no, no. That will not change. That will not change. We have this in our written meeting minutes, as you know, and that will be the content of our NDA. We want to make -- we want to ease the review of the reviewers. We want them -- we want to present them with the data, how they want to see it presented, and that is the key. And Peter, as you know, if the reviewer has questions, doesn't understand what they'll do, they'll ask the question, they'll put your application aside, they'll move on to somebody else. And I want to minimize that. Our goal is to minimize those numbers of questions. So having that pre-NDA meeting, and I've asked for it to be in person, and I want to sit across from the reviewers and say, hey, how would you like this? hey, how would you like that? That's the focus. It's an operational perspective.

Perfect. So you've said multiple times today and even Pravin has mentioned that we actually have the meeting minutes in hand. I'm curious, can you tell us anything about what's in the meeting minutes that may help us here?

Sure. Absolutely, positively. I mean, the key for me, Peter, in the meeting minutes was that FDA stated, they concluded that Ocular has presented a compelling data package and that this application would be reviewable.

They didn't say it would be approved or anything like that? Kidding, kidding. They don't put that.

No, sir.

Another thing that people have said is why don't you do a rolling submission? Wouldn't that be easier? You just follow what you have with SOL-1. And when the data comes in from SOL-R later in this year, you just put it in. And wouldn't that be faster?

So yes, Peter, I'll answer your question here. I mean, rolling submissions are an option, of course. The key here, Peter, for me is for rolling submission and a lot of people don't realize, with a rolling submission, you can submit various modules as you go through. Here's the but part. But the FDA will not start their review until the application is complete, not until it's complete. Peter, I think what we've outlined today is the fastest and derisked regulatory approach here. We've aligned with the agency. They know what they're going to get from us in that application here. We will support that with confirmatory evidence. We have an agreement on our safety database, 300-plus patients exposed AXPAXLI for 12 months. Peter, this, I believe, is a complete comprehensive submission package, and it's the fastest way to get this new medication to our patients.

Well, I really thank you, Art. Before we wrap, any final comments, closing comments?

Peter, I think we've touched on a number of points here. I mean, to me, it's balancing the speed and risk aspects of it. We've talked about this. We've discussed this many times as we go through that. And frankly, I think we've optimized our pathways as we go through that here. And I'm most excited about this application, the approval so that we can provide a longer durable treatment with better visual outcomes to our AMD patients. Peter?

Thanks, Art. Appreciate it. Get back to work. So now it's my pleasure to invite David Robinson, our Global Chief Commercial Officer, to the podium. David is one of the most accomplished commercial leaders in retina with deep experience in launching therapies and building franchises. He was the key architect for the EYLEA launch during his time at Regeneron, arguably the most successful launch in retina history. He has end-to-end launch experience, including strategic strategy, planning, execution and market access. Most recently, he was the Chief Marketing Officer for Global Ophthalmology at Merck, where he helped lead the global ophthalmology strategy and franchise.

So it's my pleasure to hand the podium to David.

Thank you, Peter. And there's nothing that makes a commercial guy happier than somebody with the enthusiasm of Art Ciociola. I have to say, nothing makes me any happier. So one of the things that I'd like to speak about today is not only preparing for a successful launch, but to give you a little bit of background. As Peter said, I started in the retina space in 2011. And one of the things that always is stuck with me is that patients love usually their retina specialists. They love the therapy. They love the fact that they had not only a therapy that would stabilize their disease, but in many cases, improve their disease.

So I was always taken aback by patients and physicians always ask us when we come in the office, can you improve the number of times I have to come into the office a year? Can I come less? Can we -- how can we do that? So one of the things that EYLEA gave us was the opportunity to increase the opportunity not to have to come into the office so often. But again, it was only 8 weeks. So if you take a look at what we talked about today, Peter just discussed -- been discussed many times today, following a successful Type C meeting, we will be filing the NDA in fourth quarter of 2026 and preparing for our launch in 2027, assuming approval.

If you take a look at AXPAXLI's potential. This is one of the things I'm the most excited about. This is a $15 billion market, but it's commanded right now by short-acting VEGFs. And we have an opportunity to drive this market with AXPAXLI with a change in how often patients have to be seen by their physician. And if you think about that, marginally, if you look at VABYSMO, they have seen a small durability change drive a big market. And after year 3, they had already generated $4.4 billion in revenue. We feel that the durability of AXPAXLI is unmatched by other current agents. You've heard a number of times today, 12 months with a rescue-free rate at 69% rescue-free rate after 1 year. And that gives us the opportunity to have up to a 12-month dosing parameter and gives us the opportunity to have a label that's 3x that of the current market today.

The question I usually get is, well, what's your market? Where are your patients going to come from? If you look at how the market breaks down, it breaks down in 3 big buckets. That is, number one, patients that are on therapy and within the PI, patients that are on therapy and not within the PI, either shorter or longer than, and then a group of patients that discontinue. In fact, I always have felt it's interesting the fact that there's a 44% discontinuation rate even after year 1. And we feel that AXPAXLI gives us the opportunity to bring patients back into the market keep patients on therapy longer as well as have an opportunity to switch those patients that are currently on VEGF on label and ones that aren't on label.

So if you look at where we feel like we can go with AXPAXLI, in the beginning, we feel like it will be switches from current anti-TNF (sic) [ anti-VEGF ] patients. And in the longer term, we feel like we not only have an opportunity to continue to get switches from VEGF, but an opportunity as well to take the naive patients starting on AXPAXLI and continuing on the drug longer. And since we have been -- since we released SOL-1 top line results, we've been talking to many, many retina specialists getting feedback from them. And one, physicians are telling us that this product will be rapidly adopted. Greater than 90% of retina specialists would adopt AXPAXLI within the first year of launch. Broad utilization and the fact that retina physicians say that improved disease control and predictable greater than 6-month duration will drive broad use.

And it's easily incorporated into a retina physician's office and into the practice. By that, what I mean is the prefilled intravitreal injection is ordered, it is stored and is delivered in the same way as an anti-VEGF. So you put it into the practice and incorporate it quickly into the full account. And in fact, retina specialists post-SOL-1 have told us that 80% of them would use the product based on SOL-1 results alone. So if you think about that, 80% of physicians, 4 out of 5 say they will use AXPAXLI broadly when they have SOL-1 data alone. Our payer team has been out proactively calling on payers. In fact, so to date, they have seen 100% of the carriers that cover Medicare Advantage in Tier 1. They have also seen 100% of Tier 1 commercial lives payers as well. And payers are telling us that they acknowledge that a label with superior durability potentially transforms the market and could command premium pricing in the market.

So a little bit about launch preparation. If you look at the current challenges in the market, we have no superiority label in the market today. That means approvals have, up to date, been based on non-inferiority design, which means minimal differentiation in durability between agents or efficacy. And Peter cited that lack of differentiation is making it difficult to choose between treatments. Biosimilar entrants into the market, increased competition to discount or rebate means that the focus is a lot of times on financial and not safety, efficacy or durability parameters. We feel that, that gives us a clear market opportunity to differentiate based on a superiority label with predictive, durable dosing and positive long-term vision maintenance outcomes.

And we feel that the market is perfectly set for a product like AXPAXLI. There's 1.8 million wet AMD patients in the market today, but they are seen by a very concentrated call point. They are between 2,500 and 3,000 retina specialists. But more important than that, when you dig under that, about 600 physicians account for 80% of the utilization in the market according to claims volumes. Not only that, but there's a very high initiation rate in AMD because of the fact that it can be a catastrophic disease as well as a high switch rate. And that's among physicians and patients requesting a switch to particularly a more durable, longer-lasting agent.

Our team is ready today. We have a team out there in the field right now of 65 people, 50 salespeople as well as 15 reimbursement people. And that's our DEXTENZA team, been in the market, still in the market, very stable in the market as well as a world-class retina leadership that's been responsible for decades of combined experience in the industry as well as in retina.

Here are some of the key launch preparations that are ongoing. Nowhere close to an exhaustive list, obviously, but in 3 major buckets: commercial strategy and predominantly their launch scenario planning. We looked at a number of scenarios based upon all the work that's been done. And this change of looking at our new filing, et cetera, has really pushed us up, and it's really meant that our teams have had to do extra work, but I have to say, this is one team that I've worked with, and I haven't worked with a team like this in a long time of preparation, really being ready to go and really working on differentiatable plans and differentiatable programs in this market, and I'm very proud of this team. Launch infrastructure, especially looking at patient support hubs. As you know, patient support hubs help patients get on drug, help physicians' offices get patients on drug. And then organizational enablement, particularly looking at talent planning and organization as well as training readiness. We are very committed to have our team ready to go day 1 when the product is ready.

This gives you just a view into what we're looking at as far as our path to commercial readiness. Obviously, every line here, every arrow here has 100 arrows under it. But they're really in 3 big areas: preparing our team, preparing our market and preparing our product to be ready for launch. So we feel AXPAXLI has the potential to redefine the retina market. It's a large market size, and there's a global opportunity attached to AXPAXLI. AXPAXLI redefines the retina treatment dosing in the market. Superior label positions us to put AXPAXLI in a class of one. And all of that delivers to our payers, physicians and patients economic predictability.

Thank you very much. And with that, I want to introduce Dr. Jeff Heier, our Chief Scientific Officer at Ocular. Jeff?

Thank you, David. As I sit in the audience for events like this over and over, I'm repeatedly grateful to have the opportunity to be with the team of such exceptional and passionate experts, experts like Pravin, Nadia, Peter, Art and David and our teams back home. And on top of that, to be part of the team that can bring such an important and impactful drug to really the patients I've dedicated the last 3 decades of my life to caring for.

Over the next several minutes, we will review key design elements of SOL-R that align with FDA guidance and increase the likelihood of study success, and we'll follow that with some concepts of outcome analysis. As we've really discussed in depth over the past 2 years regarding the SOL program, alignment with the FDA, both in terms of the 2023 draft guidance and public and written communications is critically important to derisking the regulatory process. The FDA guidance for non-inferiority trials allows for the investigational agent to be compared to label dosing of either aflibercept 2 mgs or ranibizumab 0.5 mgs with a noninferiority margin of minus 4.5 letters. AXPAXLI dosed every 24 weeks is compared to aflibercept 2 mgs dosed every 8 weeks.

However, the FDA guidance also states that a comparator arm should have the same dosing schedule as the investigational drug. And for that purpose, one arm has aflibercept 8 milligrams dosed identical to AXPAXLI with the same dosing regimen and intervention criteria, satisfying the desired masking intention. As both Nadia and Peter have described earlier, AXPAXLI will be compared to 8 milligrams aflibercept dosed every 6 months for superiority. In addition, sham injections are not recommended due to inadequate masking, and this has been emphasized several times by the FDA, both in our communications and in public settings. And as such, there are no sham injections in SOL-R.

While SOL-R was designed entirely in line with FDA guidance, given the strength of SOL-1 that you've heard repeatedly today and our recent FDA feedback, year 1 efficacy is no longer a requirement for NDA submission. Because of this, we are amending the design of SOL-R and extending the masking period to week 96 to evaluate new important secondary endpoints. At week 96, we hope to show potential superiority in best corrected visual acuity over aflibercept 8 milligrams, and we hope to demonstrate prevention of fibrosis and atrophy with AXPAXLI relative to 2-milligram aflibercept. Why are we not taking these measures at week 56? Well, in addition to what Peter described, 8-milligram aflibercept's dosing interval in wet AMD was recently expanded for up to every 5 months after 1 year of treatment. This new key secondary endpoint will be evaluated at week 96 to align as closely with aflibercept 8 milligrams year 2 approved dosing interval as possible.

Let's talk about the importance of patient selection. Many, if not most studies encounter hard-to-treat patients that can disrupt outcomes, and this has been apparent in numerous non-inferiority studies. Several of the leadership team at Ocular were intimately involved in this analysis of patients with early persistent fluid from the aflibercept VIEW Phase III program. When you look on the left, when this fluid is present, patients required monthly aflibercept for the best outcomes, and this was superior to every 8-week aflibercept or monthly ranibizumab. When you look on the right, however, without early persistent fluid, all 3 arms practically overlap.

In the Kodiak DAZZLE trial, which was conducted with the old formulation of their drug, patients were placed in dosing regimens based on disease activity. However, the subjects with the most disease activity could not be treated more frequently than every 12 weeks. And not surprisingly, this wasn't adequate for some patients. And in fact, per Kodiak's own commentary, this was insufficient for some patients. Each of these last 2 programs that I've shown you had patients with high need that could readily disrupt non-inferiority outcomes. The SOL-R criteria were carefully selected to exclude those high-need patients that typically require more frequent injections regardless of the intervention. Such patients have been seen in virtually every study and are most likely to disrupt non-inferiority outcomes.

In SOL-R, following 3 monthly anti-VEGF injections, subjects were observed for 8 weeks without treatment and had to have a retinal thickness of less than 350 microns and could not increase by more than 35 microns from the lowest CSFT or retinal thickness at any prior visit. Both of these criteria select for stable, well-controlled subjects.

Another component of study design involves monotherapy following randomization. The trials for the first- and second-generation anti-VEGFs, EYLEA, Beovu, Vabysmo, EYLEA HD dosed only investigational product post-randomization in the active arm. Non-inferiority trials for agents aimed at extended duration on the order of 6 to 12 months and longer are often preceded by anti-VEGF therapy in a loading phase, but then rely upon investigational product only post-randomization in the active arm. This is the case for SOL-R as well as SUSVIMO, the port delivery system. Some studies do include mandated supplemental injections with controlled product post-randomization, but run the risk of being considered combination therapy, especially if additional supplemental injections are required. Keep in mind that once considered combination therapy, a superiority study is typically required and the bar for such studies is quite challenging to achieve as we have seen with some recent failures despite them having early phase promise.

Given these considerations, how should the outcomes of non-inferiority trials be interpreted? The SUSVIMO FDA review highlighted that efficacy outcomes may be impacted in patients who receive rescue or supplemental therapy. Key considerations include not only the number of rescues, but their cadence and timing relative to the primary endpoint. Subjects requiring rescue therapy, especially more than a single rescue, may be considered either treatment failures or combination therapy. The implication of either of these designations can have a significant impact on regulatory review of efficacy outcomes.

In addition to the number of rescues, the timing is equally, if not more important. Rescues close to the primary endpoint and certainly within the 3 months leading up to the endpoint garner more critical scrutiny. Such rescues are believed to have a visual acuity impact, meaning they artificially increase the visual acuity measurements, making this a significant review issue for regulators. Needless to say, such factors are critically important to obtaining a clear interpretation of trial outcomes.

So let's summarize this section and identify key components to understanding a non-inferiority trial evaluating extended durability agents, and we will highlight a few key points. First and foremost, did the trial meet its non-inferiority endpoint? This is both obvious and intuitive. Next, one should look at the rescues, how many subjects were rescued? And if rescued, how many subjects required more than a single rescue? Of rescues, how many were in close proximity to the primary endpoint, especially within 3 months. And of course, was the trial protocol in alignment with the FDA? This includes attention to the comparator arm, study interventions and rescues and masking. And along these lines, does the use of other agents, both mandated and rescue or supplemental constitute combination therapy requiring a superiority design? All of these factors contribute to the interpretation of study outcomes and require careful analysis in order to fully understand and appreciate study success.

So thank you. With this, I think it would be appropriate for us to step to the question-and-answer session. As Pravin already introduced, we have an exceptional panel of key opinion leaders, clinicians, clinical trialists, and Arshad, Lejla and Darius, and we're going to move right to them.

So I'm going to ask all of you this. As you heard earlier, we met with the FDA and have alignment on submitting our NDA based on SOL-1 efficacy alone in the fourth quarter of this year. Were you surprised when we shared this news with you?

Arshad, let's start with you.

Jeff, thanks for having me here. It's great to see everybody. I think this is fantastic news for the field. It's fantastic news for our patients, their caregivers, physicians and payers. But it's not surprising to me because Peter presented very nicely that you need -- it's a very high bar of evidence that you need to submit one trial for approval and SOL-1 met that. And the reason for that is the first superiority study. It's adequate and well controlled because of the SPA, does not have sham injection because it follows the guidance. So as a clinical trialist, and you do a lot of clinical trials, you've been doing much longer, Jeff, than I have.

Much longer than anybody in this room, except Pravin.

So for -- I've been doing it for the last almost 2 decades. And this is a very unique thing for the field. And I think this is what's going to drive the field forward where many others will try to get there. But it's a very high bar. You and I've been with many trials that have failed. Superiority is not easy. So yes, very excited about it. And now Monday morning, I can go back to my clinic and tell my patients that something is coming sooner than I was telling them. I was telling them 2028. Now there's a potential to have this in 2027. And this provides great hope for our patients.

Thank you, Arshad. Lejla, I'd love your thoughts.

Thank you. Thank you, Jeff. True pleasure to be here with all of you. I will echo what Arshad just said. And for the first time I heard the statistic you just mentioned on the survey, I would agree that -- and I'm going to join my colleague, retina specialists, that 80% of us are comfortable using this product on day 1 after approval. And why am I so comfortable and why I'm going to fit into this 80% positive report is because the data is confident, giving me confidence to do -- use it on day 1. I'm excited by not only efficacy, but definitely safety.

And when we talk about PAT surveys, The American Society of Retina Specialists does a yearly survey for retina specialists. And they ask us what is the biggest unmet need. We always talk about safety being one. This trial gives me confidence in safety. But second thing is going to be duration and treatment burden. And to see the efficacy and durability of this product is very exciting. And I think coupled all of this gives me great confidence to use it on day 1. And I'm super excited now to know that we may have this option earlier than we thought.

Thanks, Lejla. Darius, anything you want to add?

I was completely unsurprised by that announcement. The data is very compelling, rigorous, well-controlled study addressing a superiority outcome against the undisputed market leader, the actual gold standard aflibercept for the last 15 years with a meaningful clinical outcome, which is maintenance of visual acuity, not just any kind of visual acuity, excellent visual acuity. You're losing 4.5 letters at 52 weeks at a baseline of 80 letters. There's no study that has ever exited at 75 letters at the end of 52 weeks. It's crazy vision.

And then on top of that, you're exiting -- you're controlling for the 40% or 50% of patients that we lose in year 2 and 3. They're off the -- they're just disappearing from us. And we've got 6 months, 9 months, 12 months. We have 80%, 75% and 2/3 of the patients are making it to that -- those time points with excellent fluid control, great vision control, and that's an extra safety measure, and that is not lost on the FDA. So for me, it's a no-brainer. You made an agreement with the FDA. You delivered on your end of the bargain. It's delivering for the unmet need. Why wouldn't they want to get this approved?

Thank you, Darius. Arshad, over the last few months since the results have come out, there's been a lot of discussion about the SOL-1 results. Can you comment on the significance of the trial hitting its superiority primary endpoint? Why is that different?

Yes. Jeff, as I said earlier, we have been involved in so many trials, and it's a very high bar to hit superiority. So I think there are 3 things I want people to keep in mind. Number one is this is a treatment that is superior to standard of care, as Darius says, aflibercept. This is the first time we are comparing head-to-head durability based on FDA guidance. And this is the only trial that has shown 9 to 12 months durability in clinic injection. So I think those 3 things are super crucial because that has not been shown before.

Now what do physicians care about? Physicians care about OCT and anatomic control. And the data we have seen with patients with less than 30 microns of fluid, majority of them had that until 1 year. So if you have good anatomic control, you have durability head-to-head. So there's no marking the water with anti-VEGF rescues. This is clear durability, head-to-head and safety. And we saw the safety that is well tolerated. So those 3 things on top of the efficacy, I think it's very, very compelling from this data set. And I think as Lejla said and David said, like 80% are excited to use it and physicians are going to use it the way they think it's best for their patients.

Great. Thank you, Arshad. Darius, as we've heard over and over, SOL-1 is a first-of-its-kind study. And in some respects, the results have been different to interpret than others. When you've been at meetings, what type of questions have you heard regarding the study? And what issues or what types of results seem most unclear?

Yes. It's really hard when you have something new and it changes your perspective on what's going on. So I really just try to focus on, when I'm talking with my colleagues, about the 3 things that really stand out to me about this study. Just because it's a new study, it doesn't mean it's not going up against a high bar. So we focus on the superiority outcome right off the bat. You're beating the -- again, the gold standard in a meaningful clinical outcome, which is maintenance of excellent visual acuity.

Then the next thing is safety. There is no safety signal here whatsoever. You have 94% and 97% of patients completing enrollment all the way through. There's no cases of endophthalmitis, intraocular inflammation of any severe kind. You don't have any occlusive or non-occlusive vasculitis. And then, of course, you get the durability. And we felt very confident coming out of the Phase I trial monotherapy, AXPAXLI, you got patients making out to 52 weeks with good vision and fluid control. And why is that 52 weeks important? Because if you want to get to a 36-week outcome, you got to get a majority of your patients to 52 weeks in order to make that 36-week outcome. So we felt very confident.

But working in conjunction with the FDA, you got to make sure that it's safe for the patients. So how do you make it safe? You choose a responder population. And in this case, the responder population is both on -- you get at minus 8 and minus 4 weeks, you get aflibercept and then you test to see if you get the 20/20 vision or gain 10 letters, then you can qualify on the functional aspect. And then you also have to make it on the disease control aspect with respect to OCT fluid. You have to get below that 350 microns and show that you're a fluid responder. And interestingly, this results in this very nice group of patients with the best fluid control, 220 microns roughly at baseline and visual acuity of 80 letters. And what does that mean? It means you can only go downhill with respect to vision. And so they push back at me and say, hey, you got randomized to AXPAXLI or aflibercept.

But that's not how I treat my patients. I said, really, frankly, I don't care how you treat your patients because you're not going to get a better outcome even if you're treating monthly with aflibercept because when you look at the MARINA data with ranibizumab or other data from aflibercept, if you do monthly treatments at 6 and out to 12 months, the best you can do if your vision is at over 75 letters is lose 5 letters at 6 and 12, okay? And so we're giving -- and that's with monthly injections. And so here you are, you're going out there and you're getting 1 injection and you're going out to 52 weeks and you're giving up 4.5 letters. And then the light goes off because now they see, hey, this is actually paradigmatic change that's meaningful and wait for it, I'm walking away at 75 letters of vision, higher than any other trial has ever achieved. For me, once they see this and get it and they start thinking about it, now they get it.

Great. Thank you, Darius. Lejla, what, probably among the data that's considered most impactful to clinicians has been the time to first rescue. In this room and on the webcast, we have many of the top investors in the country, if not the world. How should they look at this data and interpret it?

Well, Jeff, I completely agree. The time to first rescue to me is really the most clinically meaningful measure. Why? Because it really gives us a practical measure of durability in clinic. When the retina specialists look at this data, they really see evidence that rescue-free rates for AXPAXLI were significantly better than aflibercept rescue-free rates. As a matter of fact, if you look at the data itself, you see that AXPAXLI outperformed aflibercept by a measure of 6 months. So we're giving ourselves duration of 6 months flexibility for our patients.

And when we talk about, in general, recurrent treatments, patients missing appointments, missing treatments, we know that, unfortunately, all of that leads to poor visual acuity outcomes. And when we now have a 6-month advantage over currently approved and most commonly used therapy, I would say that is going to yield a really remarkable outcome in the real world. But injection-free or rescue-free rates, I would say, are measure that we talk about in clinical trial. But how about the real world?

When I see a patient, I'm not thinking when was the last time injected. I'm looking at the OCT in front of me. As a matter of fact, my patient is asking me how is that OCT looking because we are all focused on anatomy. And from the current data, what I see is that OCT, that anatomic measurements were very much solid all throughout the program and at 9 months, really barely variated within a 30-micron difference. That data for me is even more significant because it really is going to mimic my real-world use of this therapy.

Yes. And Lejla, you mentioned the OCT and how we use that to gauge our treatments. When patients come in and look at the OCT, I tell them fellows have spent 2 years learning how to read the OCTs. And then they tell me, well, I've been with you for 8 years. So I feel I'm an expert as well.

Arshad, there's been discussion around how to interpret and understand the patient population of SOL-1. As we've touched upon, this patient had -- this patient population had the best starting visual acuity of any study we've seen. How do you interpret that from your clinical population?

Yes. Being part of dozens of naive wet AMD trials, this patient behave like what they usually do. They got the 2 aflibercept injections. They gained vision as expected. So they were at peak vision. And after randomization, the goal was to maintain vision. They're not going to gain any more vision. So that's one thing. The second thing is that when I started recruiting for this study, and I know a lot of patients in almost all trials, but especially here, the recruitment was really fast because the patients coming in with naive wet AMD are much earlier now than what they used to be back in the day. And in this study, we allow good vision patients. And what that did was led to very fast recruitment of the trial.

So this kind of reflects the real-world patient population that we have in our clinic, which means that when we see this data where 2/3 of the patients are going 1 year in it, it translates into very quick adoption in clinic. So I think the only difference here, obviously, as I mentioned, is that patients started at randomization with very good vision, but I'm not surprised. I mean, this is what patients do. They gain vision and our goal was to maintain it, and we were able to do that.

Yes, I agree with you. We see now more frequently than not, these are the patients. This is how they present with wet AMD.

Yes, because optometrists have OCTs, we image them much earlier than what we used to and catching the disease early actually is beneficial for patients.

Absolutely. So Darius, you've talked in the past about how durability itself is a safety feature. Can you describe what you mean by this?

Yes. Again, another excellent question. I may be unfamiliar to a lot of you guys for a couple of reasons. One is I'm a pediatric retina specialist by training and love. That's what I do. And the second thing is my niche has always been safety. I've served on over 20 data safety and monitoring committees. In fact, when I first started working with these guys, I was the independent rescue monitor. And that's what attracted me to this company is its commitment driven from the top by Pravin to ensuring patient safety. And when you look at this drug and what it offers is it gives us peace of mind.

And what do I mean by that? Well, Nadia, you and everyone here on the panel has alluded to that we monitor patients with OCT technology, okay? We either use fluid as a proxy to intervene or we use visual acuity. And if we see either of those things, then we can treat right then and there. And if we don't, we feel safe in extending their -- the next time they're going to come. And we extend in 2-week intervals. Keep in mind that the longest currently approved interval for a single bolus injection is 16 weeks in this disease, okay? So we feel comfortable extending you out to plus or minus 2 weeks in that window. Otherwise, you could lose vision. You could get too much fluid and get permanent loss of vision. You could get too much hemorrhage and get permanent loss of vision.

Now think about this. We're talking a drug now that goes out -- we're measuring outcomes in months and years, okay, not weeks. We're sitting there at 9 months and 1 year. We have 80% of patients are making 6 months, 3/4 of the patients are making 9 months. 2/3 of the patients are making it out to a year on a single injection, okay? And now I know that if my patient has an accident, has difficulty getting in either because they can't afford it or because a family member isn't available because they want to go to a wedding, they're traveling or they just want to live their life, they can go out there, and I can very happily know that this patient is safe. They're going to -- when 75% of my patients are going to make it out to 9 months, if they miss their 6-month appointment, I'm not sending out SEAL Team 6 to hunt down that patient and ensure that they can come back in and not be at risk for losing vision. That's what I'm talking about safety. It's complete peace of mind.

So do you have any safety concerns at all, not just about the durability?

Yes. So like I was involved in almost every single rescue call along with Barry, and there's no safety signal here. I mean, right off the bat, all you have to do is look at how many patients completed the trial. It was essentially 94% and 97%. There's no cases of endophthalmitis, occlusive or non-occlusive vasculitis. The floaters were related to the drug platform breakup. The timing was consistent with that. There were no visual acuity impacts from that. And that last follow-up, all of the drug particles that spontaneously resolved. There is no safety signal here. The 9 cases of intraocular inflammation were mild or spontaneously resolved on their own accord. This is a complete -- as completely safe a drug that has been introduced in the last 15 years as a guy who sat on over 20 data safety monitoring committees.

Thank you, Darius. So I'm going to ask each of you this question. If you had to simplify the takeaway message from SOL-1, for practicing retina specialists, what's the single most important message from SOL-1? And a corollary to that is, given what you've seen from SOL-1 and submission of a single study, is there enough here for you to initiate treatment?

Jeff, for me, it is durability 9 to 12 months. I mean I think we have never seen that in our field for an in-clinic easy injection. And I think that correlated with anatomic control and the well-tolerated safety profile that Darius mentioned, I think it's enough for me as a retina specialist to start using AXPAXLI as soon as it's approved. Now SOL-R is important for redosing and more for commercial reasons.

But I have a question for the audience. You came to me if you had wet AMD or your parents have wet AMD and I offered you a 2-month drug versus a 9- to 12-month drug. How many in the audience will take a 2-month drug? Raise your hand. Zero. How many will take a 9 to 12? So majority will be untreated, it looks like. We don't not treat by AMD. Let's do it again.

They're filming in the back.

2-month drug. Okay. 9- to 12-month drug. Okay, majority, right? Simple answer from a retina specialists as well as the patients.

Lejla?

I mean, really well said, Arshad. I would completely agree, disease control, not only disease control, but maintenance of really good vision, visual acuity and all of that coupled with great safety, no questions. And Arshad is asking me, but really my patient is going to be asking me to use this because they very well will come to me saying, doctor, I want the 9- to 12-month drug.

Yes, 100%. Darius?

Yes, absolutely. I mean, it's the durability plus, it just raises the entire visual acuity floor, if you will. We're maintaining excellent vision out to 52 weeks. We have durability that's 125% to 200% more than any currently approved dosing regimen on the market today. And who knows, it might even go longer. Jeff, we didn't hit that 50% rescue at 1 year. So we're going to learn a lot more about this drug, hopefully, pending its approval. But I think there's -- this is just -- my phone has been ringing off the hook from my patients, like when can that drug be available for me.

Great. So Darius, we've just been finished talking about SOL-1 superiority. How do you -- now as we look at SOL-R, which is a non-inferiority, how do you look at the difference between non-inferiority and superiority trials?

Yes. This is an interesting one. I think we all get superiority. This drug is superior to that drug. Non-inferiority is a little bit trickier. You weren't superior, but you weren't inferior, you were non-inferior. What does that mean, okay? And so when I look back on 30 years of clinical medicine, I've never once had a patient, not once, come into my clinic and say, hey, doc, can I have the non-inferior drug, okay? Just hasn't happened. And they ask me for the best drug and they ask me for the long-acting drug, okay? Just like you all said you wanted the durability, my patients want the durability.

And so when we look at non-inferiority trials, they are aimed primarily at getting to the secondary -- key secondary outcomes, okay? And one of those is durability. So what they do is they give you this metric and they say, hey, the functional outcome, maintenance of visual acuity is a primary outcome, okay? And that's assessed at a certain time point, let's say, 52 weeks. And typically, they give you a non-inferiority margin anywhere between 1 to 5 letters, and it's usually on the minus side. So let's say you make it to minus 5 letters at 52 weeks, then hey, you're non-inferior to the gold standard and immediately, the discussion shifts to the key secondary outcome. My drug made it 8 weeks, your drug made it 4 weeks. I'm superior on durability, and that's what moves that product in the market, okay?

However, you got to remember that little visual acuity tax you paid 5 letters because the FDA is keeping track of that. And so every 52 weeks, you're going to lose those 5 letters. And so the FDA says, hey, you got to protect the patient somehow. So they give you rescue criteria, which is where I come in because then I deal with the sites to help them adjudicate these rescue criteria. And so if you get too much fluid or you lose too much vision, then we give you a rescue therapy, typically with the gold standard. And that goes towards your evaluation of did you make the durability.

And so the second tax that the patient pays is how many rescue therapies did you get. So you went to 52 weeks, you lost 5 letters and you got 3 rescue injections, but your durability was longer. Is that a win? I don't know. We have to leave that up for the patients to decide. But in superiority outcomes like AXPAXLI, we don't have to worry about any of that. We beat them. We're superior, and we give the greater durability.

Great. Thanks, Darius. So Arshad, how should we think about rescue treatments when we're looking at non-inferiority studies?

I think Darius made some good points. I think the key is that we need to make sure that we pretty much have no rescues or minimum rescues. As you said, and recently, many of you were at clinical trials at the SUMMIT, and we had Wiley Chambers and asked him the question in a panel, I was the moderator, how many rescues are allowed and the timing of the rescue? And he said, any injection given after randomization is considered rescue. So imagine if you are giving -- randomizing a patient and giving in your drug plus an anti-VEGF versus EYLEA, that's a rescue because this is post-randomization. They don't care about the run-in phase, but after randomization.

So imagine if you have your own drug and you have aflibercept Q8 weeks, the delta if you're giving a 6-month drug is only like 4 injections in the middle, right? The other one group for a year will get 6, your 6-month injection will get 2. So the delta is very small. And if you're giving 2 injections or you're giving an injection a month before primary endpoint, as you said, Jeff, it's going to change your BCVA. So Wiley Chambers said, anything after 1, you get a penalty. And then the rescue has to be greater than 3 months from the primary endpoint.

And also for us, right, a clinician, if you are giving 2 or 3 rescues and giving another treatment, it really doesn't address the unmet need of durability and treatment burden. So I think the non-inferiority design, as Darius said, is an easy way to go, but it comes with a lot of criteria because we don't want a drug that will need a lot of rescue because it's -- we already have good drugs. So I think that's why superiority design is ideal, but it's a high bar for approval or to win in terms of primary endpoint. So yes, it was very enlightening for me because I've been hearing from a lot of people, so I asked Wiley Chambers myself directly. And he was very, very strict and very to the point.

Yes. Lejla, can you comment on the -- the design of non-inferiority trials with regards to the selections of patients, one, and the use of multiple drugs after randomization. Arshad sort of touched on it there.

I echo what both of my colleagues here have said. First, it is very confusing for non-inferiority trials. And certainly, we don't talk about that with our patients. They want the best track most certainly. But when we are digesting this information, you really have to look at 2 aspects, very important aspects. First is the loading phase that can happen pre-randomization and times post. But when you load pre-randomization, you are selecting for the right patient to enter that randomization and continue the trial. And that we have done in prior trials, Archway, for example, in one of them and most certainly in SOL-R. Now that is a key aspect and really gives us a clean data to understand and for us as retina specialists to really digest.

But I think what it gives us even cleaner data now that we randomize the patient is this co-administration. If you give monotherapy post-randomization, you are really looking at the efficacy of that drug alone. You will fully understand what is efficacy versus if you're co-administering, you're administering the study, the targeted drug versus what is approved currently on market. And one may wonder which drug is really truly giving the efficacy down the road? Is it what we're studying? Or is it really the therapy that's already improved in market? So I think that really muddies the waters. And from a clinical perspective, from scientific, from regulatory, it is harder to tease out information when you have co-administration of the drugs.

And how does this apply to clinical care on just general real world? Well, I can tell you and assure you that co-administering drugs on the same day in clinic is impossible. There's no way any of us will be able to accomplish that. And why do I say that? Because it's simply logistical nightmare. It's also approval nightmare. There's no way that insurance currently allows us to prove 2 drugs on the same day to give to the patient. I'm not sure how that's going to change in the future, but I doubt it would.

Yes, Jeff, I just had a follow-up on that. Even with our complement inhibitors, patients who have GA and neovascular AMD, I'm not treating the same day because it's hard to get paid for it. And even though there are 2 different codes. Here, if you are doing 2 injections at the same time, you have to use a wet AMD code. And so injection, you're not going to get paid for, forget that. But I don't think the drug will be covered either because you're injecting 2 drugs the same day for same indication. So I don't think that's very practical and also a busy clinic and patients don't like 2 needles.

And then we may suggest come back for another day to do this, but let's be quite frank. We're talking about minimizing number of injections for a patient, minimizing treatment burden. Anytime we're talking about additional procedures, we're just adding the complexity.

Yes. And then there's a 28-day thing that you cannot do wet AMD treatment less than 28 days based on the current anti-VEGF injection. So I think it's going to be very -- actually impossible to give 2 injections the same day.

Yes. And I think the point about separate days in Boston, they'd rather go to Europe than come from Cambridge and come back to Boston. So let's switch gears to some commercially oriented questions. Darius, how should investors think about the real-world questions of treatment burden? And we've talked a lot about the unmet need. So is this -- is there truly an unmet need from treatment burden?

Absolutely, there is, Jeff. As you pointed out earlier, we're doing OCT-guided treatment, 97%, 98%, I think, for the most recent Preferences and Trends Survey from the ASRS. So we look at the OCT, we were making a determination, which means we're giving every single patient individualized care, okay? But you may have 5,000 patients with this disease. So that's 5,000 different treatment plans. And then on top of that, every one of those patients has a varying degree of fluid control, predictability responsiveness. And it is completely unpredictable from patient to patient. You just showed up there the data from the VISION (sic) [ VIEW ] trial. If you had fluid early on and -- VIEW VISTA -- I'm sorry, VIEW, VISTA trial, where you had fluid early on that adversely impacted how the patient would respond later on. And so here, what you have now is the potential, and it seems counterintuitive and maybe not what you would like to move away from individualized care and to standardize the practice.

And what this leads to is predictability. If I can get 80% of my patients are going to make 6 months, I want to see that patient twice a year. It's easy. It's going to promote ease of scheduling. It's going to promote inventory control in my office. It's going to clear up my parking lot. It's going to be very predictable as to who's going to be there. You guys laugh at that. But parking right now, people spend 2 hours circling around the Byers Eye Institute at Stanford looking for free parking. And so it's a big deal when you're moving 550 patients a day, and you never really think of it. But if you can have predictability and normalization with maintenance of excellent visual acuity, no safety concern and no worry if the patient misses the appointment but wait for it, 3 months, they're still under control. This is a game changer for how we are going to kind of transform the clinical practice and make it more predictable and less reliant on the OCT.

It's interesting. You said they'll drive around for 2 hours to look for free parking in Boston, they'll drive around for 2 hours to look for $50 parking. Arshad, if AXPAXLI were to be approved on SOL-1 alone as our NDA submission, where do you see it fitting into the treatment paradigm for your wet AMD patients?

So Jeff, that's a great question. And I think the answer is majority of the patients, right? So when I think about my patients and a new drug, we have all these patients, hundreds and hundreds of patients in the clinic that are on injections, right? So we have 2 buckets. We have the one who are high need 4 to 6 weeks, and then we have the ones that are stable on the second-generation treatments anywhere from 2 to 4 months. So if I have a patient going 2 to 4 months and I tell them, I gave you this new treatment that can go 9 to 12 months, they're all in. It just like our audience. And then you have these patients who on 4 to 6 weeks very active treatment, you will give AXPAXLI to them. And because of sustained disease control, they may not need supplemental. And if they need supplemental, then we are going to give supplemental injection on top, but they're not going to be coming in every 4 to 6 weeks, but maybe every 3 to 4 months, right? So it's addressing majority of the patients that are in our clinic.

And then the third is the smaller number is naive patients, right? We do a lot of trials, so many of them go into clinical trials. But if they don't, they'll come in, they'll get an anti-VEGF and then 1 or 2 and then once the disease is controlled, you'll give them AXPAXLI.

And I think Darius made a really good point. I treat patients differently than Darius. I don't do fixed dosing. I do treat and extend. So our experience with port delivery system is the same. I have patients who only come and see me once a year for their refill. And then I have patients who come in every 6 months. And I have a few that need supplemental in between their refill. So I think I'm more of a treat and extender, and I won't be surprised that with AXPAXLI, I have those 3- to 4-month patients now coming in once a year to see me.

Yes, it's a good point. And given the results of SOL-1, I've looked in my clinic in a similar manner, and I agree with you. I think the large, large majority of patients are going to benefit from AXPAXLI.

Lejla, given SOL-1 had a unique patient population, we've talked about it earlier diagnosis, better vision. How do you think about the potential impact of AXPAXLI if approved in the broader population?

Well, first of all, Jeff, while we call it a unique patient population that was enrolled, I would say that is really the patient population that's representative of the modern practice. What do I mean by that? Well, all of us are much more aware of disease itself, the awareness of wet age-related macular degeneration in our community among our optometric referral, our general ophthalmologists and our retina specialists is much further than it has ever been. That's leading to earlier diagnosis.

But what's leading to even earlier diagnosis is actually OCT, amazing imaging technology that we have accessible, readily accessible everywhere. I mean one day, I'm sure going to be available in grocery stores to be imaged. So we're diagnosing patients earlier, identifying patients. And now we're actually talking about great visual acuities because we're diagnosing them earlier, and we are saving and maintaining the visual acuity long term. So the bar is very high for SOL-1. So I do say -- I do feel comfortable that this patient population is very much the one we see in our practice. And on top of it, we do know that results were quite impressive, but also the enrollment was exceeding expectations. So clearly, the rest of the retina specialists agree that those patients are very much seen in our practices.

But when you talk about broad label itself for wet AMD, I will just kind of look at historic trials. When I look at, for example, for approval for geographic atrophy drugs, IZERVAY being one of the great examples, patients enrolled in that trial were extrafoveal GA patients. They showed efficacy and the drug approval is for general patient population, geographic atrophy. So it gives the retina specialists liberty to use it for geographic atrophy alone and for us to learn in a real-world setting how that behaves.

Now I know this is -- we're talking about superiority trials, and it's very unique to now have a positive superiority trial. And why is that beneficial? Because I hope that it's going to translate to greater access for me to utilize this drug for any patient that I deem that would benefit from. And I think that's the biggest mutation now we have. It's really having to go through step therapy and get there. And I hope the superiority trial is going to allow us to now have this accessible to all our patients.

Great. Well, to wrap things up, I'm going to ask each of you this question. We've talked a lot about retina specialists and investors how they've interpreted the SOL-1 data set. What impact would a therapy like AXPAXLI have on long-term patient outcomes if we're dealing with the improvement in adherence, follow-up and disease control.

Arshad?

Yes. I think our hope as a field, right, and all of you are here doing this because we want to optimize the outcomes for our patients. So I know that patients who come less often are more compliant than patients who have to come every 4 to 6 weeks. And not because sometimes they don't want to come, it just life comes in the way. They don't have a driver, they got sick, they got admitted and they miss 1 or 2 or 3 injections, they come in with a catastrophic hemorrhage and now they're blind and we cannot recover that.

So that's my hope, right? We are doing this because we want to have better vision for our patients. And based on the SOL-1 data, right, it's clean data set. That's the key is there's no contamination. It's a clean data set. We have a drug that can go up to a year in 2/3 of our patients with good anatomic control and safety. So I think that's the bottom line that the excitement is there from the retina community after they understand the trial, and I think patients are waiting for it.

Great. Lejla?

I'm going to tackle on the adherence question, portion. The real-world studies over and over tell us that we lose about 50% to 60% of our patients in year 1 to 2. And that's primarily due to adherence, missed appointments because real life happens, accidents happen, hospitalizations, other events would certainly do. So now to have a drug that's going to be a safeguard for my patients, so in case that life event happens, they will have therapy that's controlling their disease. And I think that really truly in the long term, I hope going to translate to even better real-world results than what we see in clinical trials.

Thank you, Lejla. Darius will give you the final word.

I always like that, Jeff. I look at it very strategically for the patient population overall. The problem with bolus therapy and increasing durability is that we know that the more injections you give, the better your visual acuity is and the converse is also true. The less -- the fewer injections you give, the worse your visual acuity is with current bolus anti-VEGF therapy. We've seen now with 2 studies, the surgical implant and now with AXPAXLI that if you have continuous drug release, you can maintain visual acuity for up to years going out, okay? And this addresses one of the central fallacies of the treat and extend OCT-guided regimen, which is that you should only treat for fluid and there's no functional benefit from continuous VEGF inhibition.

The visual acuity decline is a late drop-off, okay? Fluid comes first and then you lose it. And so if you only always wait until fluid, you're always behind in the functional outcome score. I think if you look 5, 7 years down the road, you're going to see what I see with my patients. I was just preparing a case report the other day of a patient that I have done about 140 injections originally with ranibizumab, then with aflibercept and now with VABYSMO over the last 10 or 12 years, that patient has fluid in both eyes, convex foveal contours and he's 20/25 in both eyes.

You continuously suppress a patient on monthly or every other month injections for a long term. And what I see happening is that guy who's getting 130 injections 10, 12 years in could get by with 20 injections. And that is a win for the entire patient population, okay? Not just here, everywhere that we have wet AMD. And I think that if you look at the IRIS database, which is run by the American Academy of Ophthalmology, and you go and say, hey, look at the visual acuity between 2015 and 2025, and we see that patients eventually lose vision because they get fewer injections, what you'll see is they're going to get fewer injections and the visual acuity is going to go up because we're having continuous suppression with long-term predictable durability.

Great. Well, I want to thank the panel. Your insight and expertise is invaluable. And with that, I'll invite Pravin to come back up and give us a summary and takeaways.

Thanks, Jeff, and thank you. Great job. As you guys move around for the Q&A part, please go ahead. What I would -- I'm not going to take long with this. You heard me say when I started out, look, there are 3 characteristics that define us. We're courageous. We're bold, we're opportunistic. But I also told you that I hope you take away from this that we're careful, we're thoughtful, and we're methodical in what we do. We look after this company like no other. We look after what we do step by step, even if you may not hear it, every day, the fact of it is that we're not just going fast. We're going fast but with very, very firm guardrails. I mean, at the end of the day, I hope you realize how deeply infused that is in our culture. I mean, how many times today did you hear the word derisked? How many times today did you hear the word FDA alliance? I mean how many times today did you hear the word Peter from Art?

Okay. So thank you for being here. Look, I hope you realize with this. Our hope here, our intention, our goal when we're right on track is not just to be best-in-class, it's to be first-in-class. And we'll do that quickly, but we'll also do that responsibly and thoughtfully.

So let's just go to the Q&A. Please go ahead, Biren, go ahead.

Yes. And congrats to the Ocular team. A lot of updates. So a wonderful job. And I got to admit, you guys always keep us on our toes with all the updates. I've got like a list of like 10 questions, but maybe I'll just go with a multipart.

That was #9.

All right. There you go. Maybe to start on the requirement for confirmatory evidence for the NDA submission. Will the pre-NDA meeting in Q3 discuss the confirmatory evidence that you shared with us? Or have you already shown that to the FDA? So that's first question.

Second question, of the 6 components, that made up the evidence for confirmatory evidence, were there any weightings assigned to the -- so is there a preference of order, for example, such as SOL-1 IRIS data? And then I guess in the context of SOL-1 study, what's the weighting of the confirmatory evidence relative to SOL-1 data set that the FDA is going to apply to that section?

All great questions. Let me have Art start off and then maybe Peter would like to jump in because Peter is kind of an Art wannabe. So go ahead, Art, why don't you go ahead?

Let me answer your question. Thank you for your question. As I stated a little earlier, we've always agreed with the agency about what the content of that application will be. That is the SOL-1 data plus the confirmatory evidence plus our 300 patients' worth of data. And the agency, as I shared with you, has confirmed that this is a compelling package and that it will be reviewable. So the pre-NDA meeting is -- and I've done a lot of these pre-NDA meetings, really more about the formatting of those same data. In other words, I want to sit across the table from the reviewer and say, we're going to format it this way for this table. Is this acceptable? And that will be the discussion. So it's really an operational aspects of the formatting of that application. I hope that answers your question.

Okay. So this like asking a man starving of thirst across the Sahara desert to be water critic.

Peter, anything to add?

Just a few things. So first off, yes, we have presented to the FDA confirmatory evidence. In terms of weighting, that would be asking crystal ball in terms of what they would want for the weighting. Certainly, the most important is a positive, well-controlled study with high statistical significance. That's what matters most. The confirmatory is that. It's confirmatory of that study. The fact of the matter is it's the breadth of our confirmatory evidence that probably made the agency say the things they said in the minutes. Now does it -- again, doesn't mean we get approved, but it just bolsters our position, I guess, is the best way to put it.

And do you want to repeat what Bill said regarding SPA?

Yes. I've been to many FDA meetings, certainly more than Pravin. And usually, when you get to the end of these meetings, they have a gajillion questions. And really, the fact of the matter is, as Bill probably said at least 3 or 4 times that our presentation, or evidence, et cetera, is very compelling. And that word actually shocked me. And the next thing that shocked me was they only had really one question, which was when can you file? And to me, that statement and the fact that there were no questions to us was an incredible meeting, quite frankly.

Go ahead, Nadia.

So I will say the big differentiator for our program was that we went in with data. And we had obviously benchmarked against what has been published before previously by the FDA as well as what Dr. Boyd had said. But we did go in when we went into that meeting with our data in hand and with the confirmatory evidence in hand. And so we were able to have a conversation that was not theoretical, but more benchmarked in what is already available.

Very important point. We went in with data. Anything else to add, anybody? Okay. Next question.

You say your name [indiscernible].

I'm Tara Bancroft from TD Cowen. So that was all super helpful context, especially in underscoring your confidence in this particular pathway. But we also have to understand contingency plans in the however, unlikely event of a refuse to file or a CRL. What would that plan be? Like would you say that it's a CRL at the time? Like would you wait for 2028 SOL-R data? Would you unmask SOL-R at the time, something else? Anything to describe what would happen in these events would be super helpful.

Yes. I'll -- let me try and take a crack at it and then maybe Jeff and Nadia, Peter or anybody else can answer as well. Look, it's very important to state that our confidence in SOL-R is greater than ever. I can't say that enough. I used to say that because of the ramp, which is extraordinarily well designed by this group. But now I can say that more factually because of what we've seen in SOL-1. And let me just repeat that because it bears repeating. Realize that using the SOL-R rescue criteria in SOL-1, 80% of patients at 6 months were rescue-free. And that's remarkable. It's even more remarkable when you think about the patient population.

This is exactly the opposite patient population that one would choose for SOL-R, right? For a non-inferiority study, you'd want a patient population that's absolutely stable. For SOL-1, we had a patient population by design that was absolutely unstable. They were designed to lose vision. And despite that, we have an 80% rescue-free rate at month 6. So clearly, when you go ahead and look at the ramp and you look at the way we've super enriched and super selected patients for stability, we fully expect that number to rise, and that's with good reason. So our confidence in SOL-R has not changed. It's gotten greater, if anything, by far, right? That's the first thing that I would say.

The second thing that I would say is we're not doing anything to SOL-R, right? As far as the primary endpoint is concerned, we're not changing anything. We're still masked and it's still running. That's available to us at any time. It's entirely flexible. But I will reiterate that it became very clear to us that a complete package for the FDA has nothing to do with the SOL-R efficacy data. That's it. So that gave us the green light to really use that data for the best leverage we can get in the community. Why would we repeat the same trial and do and show the same results? Why not show with our newfound confidence in AXPAXLI that we can actually hit a grand slam when we've already hit a home run by going all the way and showing superiority to high-dose EYLEA. That's logical, and that's exactly what we're doing.

Anybody else want to add? Peter, Jeff, Nadia, Art, anybody?

I think just to reiterate, the flexibility is tremendous here. We haven't changed anything. We're still running the study exactly the same, but the opportunity to demonstrate superiority to 8 mgs aflibercept at 96 weeks is just too great to not take.

And Tara, I also realize that we have the opportunity at that point also to look at atrophy and fibrosis, right, under masking. And if we're fortunate enough to show a delta there, which we think we will, there's potential of including that in the label as well. And imagine if we're fortunate enough to do that, what that gets you, a label where you're shown to be superior to EYLEA and high-dose EYLEA potentially with a delta in fibrosis and atrophy. I mean, that will corner the market for decades to come. Nobody is going to do a superiority study, I don't think, based on what we've done. So it will absolutely solidify the market for decades. And why would we pass up that opportunity.

Bill? Who's next? Go ahead. Sorry, I can't see because I've got the lights shining right on me here.

Daniel [indiscernible] from Bank of America. I had a question on your confidence that the submitting the 104-week data from SOL-1 will not trigger a major amendment for the review? And then is that something you discussed with FDA during the Type C meeting? And also, how should we think about ex-U.S. regulatory path? Do you think you will need SOL-R for that?

Yes, I can take a crack at that, and maybe I'll pass it on to Art and Peter or anybody else that wants to comment. Look, the words major amendment was never ever discussed in any of our meetings. It's a totally different path. It's -- there's nothing to see, there's nothing to show. We're masked, right? I don't see any way that there would be a major amendment whatsoever when we're not unmasking data at all. So I think that's completely off the table. That's never come up, right? As far as the OUS part goes, David (sic) [ Daniel ], that's a great question. Look, we are -- to be very honest with you, in a company such as ours, our job is -- I mean, we're not a large strategic that can fire everything at once. Our priority unabashedly has been the U.S. FDA.

Now that that's there, we will continue and intensify our engagement, which has already started with OUS agencies. And having data that goes all the way to 96 weeks in this kind of a study will only add leverage to that. And they would love to see that kind of data with a fairly familiar study design, but with twice as much information, right? So that actually is completely aligned with what we expect in our early conversations with OUS agencies.

Art, any more about the major amendment?

I can just add something quick. During our Type C meeting, we did not discuss the SOL-R. And our strategy was focused on single trial, adequate, well controlled, meeting the evidentiary standards for effectiveness and then our safety database that we would add to. So that was our focus. I'll give you our OUS perspective here. I mean we have -- we're working through that strategy now. And as you know, European and other health authorities have a very, very different perspective than FDA at times. So I really just think it's moving forward as we pull that strategy together and have those conversations with those regulators.

But they would love a study where you can provide 2-year information.

Yes, Lisa, go ahead.

Really appreciate all the detail here, especially on your thoughts on the regulatory path and the rationale. Just a couple of questions for me. So your competitor has a non-inferiority trial ongoing right now that's going to read out soon. Should this fail either due to efficacy or a safety issue, would you consider unmasking SOL-R under this scenario? Or could the FDA ask you to unmask your ongoing SOL-R trial?

So Lisa, yes, thanks for the question. Look, this has nothing to do with anybody else that's out there whatsoever. We're doing our thing because we have a study result that nobody has ever been able to achieve in the history of this planet. It has nothing to do with anybody else. I have no idea what they'll be doing. Good luck to them.

But at the end of the day, no matter what happens, the way that I see it, what you've heard today, I think we'll all agree, has completely immunized us from anything that happens to anybody else, which is exactly what we want to have. We want people focused on us, what we're doing because what we've achieved is something no one else has achieved. And whatever happens anywhere else, we're completely immunized from.

Bill? Sorry, I can't -- I've got to go like this because I can't actually see anything from the spotlight.

Serge Belanger from Needham. So first question for the company. Based on the regulatory path you outlined today, what are your expectations for the label? And more specifically, how do you think it will reflect the product's duration as well as the repeat dosing that you're looking for?

Yes. Serge, it's a great question. Let me use this as -- I'll give you a quick response, but let me use this as a way to bring in our 3 KOLs as well in terms of what a label means to them and what -- how they would use the product. But look, from our point of view, with this strategy, I don't see why we can't get the label that we are hoping for, which is a label that is the first and only superiority label with dosing from 6 to 12 months. They'll have all the information for that. And as Art outlined earlier on, there's a lot of redosing information that they will have as we continue with this strategy. So again, we haven't had labeling discussions with the FDA. It's premature to do that. But I think the other impact of this is how will the label impact the use of this drug, right?

And what I'll also remind you is, look, the label is very important and not -- in my perspective, at least when I was practicing, not necessarily from how you use the product. I mean, all of these KOLs and everybody in my field goes to tons of meetings. Nobody uses any drug that I know of in my field per label or per the Phase III trial. I mean, nobody does, right, at all. At the end of the day, this company's goal because we are -- we always say this, we're for retina by retina. This company's goal is to have this product in the community period, and they'll figure out how to use it. And they will. And we're not -- there's lots of questions to answer. They'll answer all of them. We believe that this will be the most impactful drug in the history of retina, but how it will exactly be used is going to be determined by them.

Lejla, why don't you start off and then we'll go from there.

No, happy to. So exactly what you said. We're going to use it most likely off-label because -- I completely agree, all of the drugs that are out there approved are -- we really use at liberty to help our patients. And what is the help we currently need? What is the community asking for? Longer duration therapy that's maintaining visual acuity for our patients. So yes, I will feel comfortable based on the trial design and efficacy I see that I will feel comfortable using in my brand-new patients that are diagnosed with wet AMD, and I want to maintain the visual acuity long term.

But I also feel very comfortable to use it in all my patients that are currently being maintained on therapy. And that's the majority of my patients. In a 50 day -- 50-patient day in the clinic, probably 1 or 2 of those patients are newly diagnosed wet AMD. But the rest of them are really kind of continued therapy and maintenance dose for patients. And I assure you we very well feel comfortable using those patients, especially based on the efficacy and the safety I'm seeing on that. But all of them, literally all of them, new or recurrent patient will very much ask for longer duration therapy for me.

I agree with you. And then I think for me, this label is a little bit more important than others because of superiority because we have about -- when I started 16 years ago, in Reno, we had about 80% to 90% Medicare straight patients. Now we have about 50% Medicare. and then others are mainly Medicare Advantage. So we have to go through the step therapy of Avastin to biosimilar Lucentis, biosimilar EYLEA, EYLEA, VABYSMO and then EYLEA HD. And then we are seeing that with the port delivery system that I offer that to my patients and many of those programs are not accepting as an option because they want you to go through the steps.

So I think the unique thing here is that if we can get the superiority label in there, that's going to make a huge difference for the patients, right? Because now and practitioners, we can get this drug on demand anytime we want, and now we can use it as a monotherapy switch as a layered therapy for our patients. So I think here, that's the part I'm more interested. And the other one is flexible dosing, right? We saw with HD EYLEA, I always said even before the data came out, we want monthly and every 6 weeks, and they did not have it, and that impacted the adoption, and they had to do the ELARA study to get the 4-week label because we had to go 7 weeks. And when an anti-VEGF bolus comes out, we usually go with the high knee patients. So I think superiority will be huge if you avoid step therapy and number two, would be every 6 months dosing. Those are the 2 things I'm looking for.

Darius?

Yes. Both of them brought up the excellent point. The key is the flexibility on the downside. the 6-month dosing, not because I am worried about patients who are going to fail at 6 months because I want to bring them in, standardize, normalize my operation. I want to see them twice a year, give them the injection, take them off the board forever and then have always 6 months of vision safety in my pocket, okay? They want to go on Safari, they want to go up to Mars, whatever it is that they want to do. I don't have to worry about them. They're off the board, okay? And as a safety kind of guy, that's how I view it. And if I don't have that and I have 9 months or 12 months, which seems amazing, but it's actually impacting how I manage my patient.

That's because your patients live in Marin County, right? That's why they like that. So -- I hope nobody lives in Marin County. But the other thing that I would say is, look, we have a -- I keep saying this to people, in my 30 years that I did this, we have never had a single drug with good reason that goes from a Phase III to the community with better results. Logically, it shouldn't happen because what you're doing in the Phase III is selecting the best patient population. And we also have a need when we launch to make sure that the first experience is really good. This is exactly what's going to happen with this drug. This is going to be the first drug that ever is going to do better in the community than it did in the Phase III study, meaning SOL-1.

And clearly, the first experience the doctor has with this drug is going to be fantastic. And let me just explain that. In the SOL-1 study, what we did was we picked patients who are designed to lose vision on purpose, right? That's not your regular patient population that you see. If this drug did this well in that patient population, it certainly will do a lot better in a stable population. So in a regular doctor's office, the doctor may see 50 patients, let's just say, of those, I don't know, 1 or 2 may be new, right? The other 49, 48, 49 are going to be patients that the doctor has been seeing on a regular basis and are stable. And they're frustrated, but they're stable.

So the first interaction will go something like this, hey, Ms. Jones, I've got a drug that I just got, the results look great, and I know you're really frustrated that you have to be taking EYLEA every 2 months or 5 years. Let me see if this drug can help you. But I still want you to come back in 2 months. And that patient will come back and the doctor will say, wow, you're looking great. Well, let's just extend that a little bit more, and let's just extend that a little bit more. And if you can take a patient who's been on EYLEA for 5 years every 2 months to every 6 months, they're doing backflips. They're thrilled. So the bar for success for this drug with the first experience with the first encounter is very, very low. And that's exactly what we want. We want everybody to have their first encounter to be absolutely fantastic for the patient and the doctor, and that's exactly what we're set up for.

Pravin, can I just jump in there? So Pravin has alluded to it that it's a patient population that's designed to lose visual acuity. This patient population at best is quartile 4, okay? It's 20% to 25% of the overall patient population. They lose vision because their vision is so good to begin with. The remaining 75% to 80% of those patients, they all gain vision. They have not been exposed to this drug yet. Those patients are going to lock in high and they're going to carry it forever. It's going to be transformative when this gets out into the wild.

And I just have to add one more comment is our interest is real-world studies, TRUCKEE, TAHOE, SUMMIT. So I'm already designing the study. Maybe we'll call it the Dugel study or something, and we'll do it because we want to know, understand how the drug delivers in the real-world patient population. And as you said, majority, almost 90%, 95% start would be previously treated patients. So I think there we'll learn, right? And that's what we learned about VABYSMO, right? VABYSMO had TENAYA and LUCERNE at different lanes in naive patients, 8, 12 and 16, we had no experience on previously treated patients, and we found out through TRUCKEE that we were adding 2 weeks on top of EYLEA 2 milligram with VABYSMO and that really helped the community understand the anatomic control and now it's a blockbuster. So we will do that study, and we also want to establish real-world safety. So I think those studies are going to come. We just need the approval.

Well, just make sure that you start the Dugel study early because now clearly, it's going to be pulled up a little bit now.

Yes, Bill? Sean.

A couple of questions for me, maybe require a little bit less pontificating. I know the study is masked through 96 weeks. But will the DSMB notify you if SOL-R hits or misses the primary endpoint at 56 weeks? If so, will you communicate that to investors? And if it misses, does the study start or will continue to -- or stop does it continue at week 96? And then can you speak to your handling of rescues in the SOL-R stats plan?

Yes. So what I can -- the first part, I can handle and then I'll maybe have Nadia step in here for the second part. What I would say is, look, it's a masked study, right? So the unmasking is going to happen at week 56. The DSMC (sic) [ DSMB ] hasn't made any comments, thankfully, at all. 96, I'm sorry, 96. And that's just a pure safety committee. So the answer to your question is that it will remain masked because we want to preserve the integrity of the study until it's unmasked at week 96.

Nadia, do you want to handle the second one?

Yes. I mean I think it's a very traditional non-inferiority study, and that's what our stat plan seeks to. We have had discussions with the FDA and Art can probably talk about this a little bit more, but we have a standard non-inferiority margin of 4.5 letters. Outside of that, everything is detailed in our confidential protocol and discussions with the FDA. So I'm going to stop over here.

Yes. Sean, I think it's a very standard way that we're going to look at things. And what I would say is you've heard today from Jeff, and Jeff, you may want to comment what the FDA has said. I think it's very, very clear. They haven't changed, right? And what they've said, if you don't have a combination agent, and that's a big -- if you don't have a combination agent, the first rescue is going to be allowed as long as it doesn't impact the primary endpoint, and they traditionally consider that within 3 months of the primary endpoint. Every other rescue thereafter is going to be under review.

Now I don't know that it could be any more clearer than that. And what I would say is that in any non-inferiority study, what you would want is you would have -- you want the whole gamut of information as Jeff very nicely put out the check box, which is to say, look, we want to know the number of rescues. We want to know when the rescues occurred. And it's good to know how many patients required multiple rescues. And I think those are standard questions that will be answered by us and should be answered by any other non-inferiority study.

Jeff?

Yes. I think it's pretty clear. We've heard it from the FDA in communications, but you've also seen it at meetings such as the CTS this weekend that the injections that are different than the investigational product matter. And when you -- if everybody gets one, that's a rescue. If you get them throughout the course, those are additional injections. And when you get them close to the primary endpoint, those are viewed differently as well. So they all matter.

Unfortunately, we only have time for one more question, but we will have a cocktail reception to follow up for any follow-up.

Lachlan, you're the only thing that stands between their happy hour and the question, but go ahead.

All right. I'll go to the long one then. Lachlan Hanbury-Brown, William Blair. Maybe another on the confirmatory evidence. I think historically, the level of confirmatory evidence is sort of inversely related to the strength of the main trial. You obviously outlined several lines of confirmatory evidence that you have. Did the FDA tell you that you need all of those lines of evidence or that you need a particularly strong degree of confirmatory evidence? Was there any language to that effect or talking about the level of confirmatory evidence that you need?

Well, what I can tell you is, look, I'll give this to Peter. Knowing Peter, if there's one line of evidence, he'll give you 50 just to make sure that you got it. So I think that's exactly what we did to the FDA.

Peter?

Yes, I agree. It wasn't like they said, this is what we want or this is what we need. It was more like we presented everything that we presented. And they were like, yes, that's great. To me, as you said, if you have a weak primary study, then you need stronger confirmatory evidence. We have the -- we have both. We have strong confirmatory evidence and we have a strong study. So it just adds to the package. And yes, like I would do anyway, we're going to give them absolutely everything and more.

Peter is learning how to be a regulatory officer and Art is teaching him, by the way. So again, we have a cocktail party over there. Please go ahead and proceed over there. Hopefully, the lines will be good. And thank you again for coming here. This is a fantastic day for us. It's a milestone and to share it with you is really an honor and a pleasure, and thank you for being here. We'll make ourselves available as we always do after this.

So if you have any questions, we're around, please let Bill Slattery know. We are -- we'll be happy to be on calls with you, answer any questions. As always, look, you'll find us to be about as available as any company, and we're happy to answer any questions and invite any questions from you. Thank you again.

Ocular Therapeutics. Presenting for Ocular today and sitting up on stage with me is Dr. Pravin Dugel, who is, of course, CEO of the company. Dr. Dugel, I call you Pravin. Thank you for making the trip out here.

Tazeen, thank you. Thanks for having us here. It's always a wonderful meeting and really appreciate the opportunity to speak with you and to be in this meeting. Thank you.

I should actually refer to you as Dr. Dugel because..

No, you should refer to me as Pravin.

Okay. So for those who might not be as familiar with Ocular, can you give us an overview of the company, the platform, and we can go into the specifics of AXPAXLI right after that.

So we have 2 targets. One is wet macular degeneration. The other is diabetic retinopathy. There is a receptor that called VEGF that is inhibited that we know is effective in both wet macular degeneration and diabetic retinopathy. The need that we've known about for almost 4 decades is that though we have a receptor that we know works almost miraculously well, take wet macular generation, for instance, after 4 decades in this country alone, 40% of patients drop out in the first year, which is not just a tragedy from a human point of view, but also has enormous social impact.

We also know that even in those patients who continue treatment, after about 2 to 5 years, inevitably, they end up losing vision and getting worse than baseline. And they get worse than baseline not because of rebleeding, which is what we thought would happen, but because of fibrosis and atrophy.

And we know now from a lot of evidence that, that fibrosis and atrophy occurs because of the pulsatile nature of our treatment, which is when we give these injections monthly or bimonthly, there's a lot of the medications, so the macular at the back of the eye gets thick and thin and thick and thin. And that's akin to having multiple concussions, which leads to fibrosis and atrophy.

So although we know the target and although we know the target works very, very well, there's a tremendous need in terms of sustainability as well as long-term outcomes. And the purpose of Ocular Therapeutics is to go ahead and put a tyrosine kinase inhibitor in a proprietary hydrogel format to address both of these problems, which is that of sustainability as well as long-term outcomes.

Okay. Can you just remind us of the recent -- fairly recently released SOL-1 results is one of the 2 pivotals?

Absolutely.

I assume it's the be pivotal.

Yes, let's assume it's the pivotal. The SOL -1 study is the first study that has ever been successful against the anti-VEGF for superiority. A lot has failed. This study has a scar, and we hit the primary endpoint with a p-value of 0.0006. So a very robust p-value.

The way to look at this study is in 2 different ways. This study was really designed in many ways and certainly validated by the FDA because this was a known track that the FDA validated with a SPA for a superiority label potentially. So from a regulatory point of view, we hit the primary endpoint, the first time ever for a superiority primary endpoint with a very robust p-value.

The primary endpoint was the percentage of patients who maintained vision and vision loss was described as 15 letters or more. From a clinical standpoint, one can look at that endpoint and say, that's not what is done normally from a clinical standpoint, which is to wait until a patient loses 15 letters or more. And that's very understandable.

So what we've gone out of our way to do is to address the clinical value of this product, which is disease control. And the way we measure disease control is by OCT. And what we've shown, we believe, with the SOL-1 data addressing specifically the clinicians in terms of disease control is really quite spectacular.

What we've been able to show is that with a single injection in 9 months, 75% of patients are rescue-free and in 12 months, 66% of patients are rescue-free, and that's never been done before. But perhaps more impressively, what we've been able to show is that with a single injection at month 9 by the OCT, which is the ultimate barometer of disease control, that a majority of patients are within 30 microns of fluctuation by OCT.

And that's audacious. That's unheard of to have that kind of disease control. So the way to look at the results of SOL-1 from a regulatory point of view is that we hit the primary endpoint, which is a superiority primary endpoint for the first time ever with a robust p-value from a clinician's point of view, it is unprecedented disease control and durability.

Okay. On the point of durability, what are you thinking the average dosing frequency will be in a real-world setting? Or do we need to see SOL-R for that?

Yes. That is a great question. And let me answer it this way. What we do right now is something called treat and extend. What that means is that we have a patient come in, knowing that a patient can't come in per label because nobody treats per label, which is either every month or every other month, saying, look, I have no idea how often I need to treat you because we have no genetic biomarkers, we have no anatomic biomarkers.

We are 75 years behind oncology and rheumatology. So we do it by trial error. So we say, look, let me just give you an injection and then have you come back at a certain point and see if your diseases come back or not. the way we treat is misaligned with every discipline in the medicine.

I mean you don't see an oncology doctor saying, let me just wait for the bladder cancer to come back to figure out when to treat you or you don't see a cardiologist saying, let me wait for your first heart attack to figure out when to treat you. And we also have really no evidence for treatment extend, and it means different things to different people.

So ultimately, I think what's going to happen is that we're going to be aligned with the rest of medicine in having fixed dosing. And ideally, this comfort level that we have and the patients have is seeing a doctor with a chronic disease every 6 months, right?

So for a drug to be effective every 6 months, that drug has to last for 9 to 10 months in case the patient gets sick, the doctor is not there, et cetera. And that's exactly what this drug is designed for. So ultimately, I think what's going to happen is that this is going to be the ideal drug to be given on a fixed basis every 6 months.

Now doctors will get to that in different ways. Some people may look at this and say, wow, I've got enough evidence, I'll go right -- I'll dive right down to every 6 months on a fixed basis. Others may look at this and say, you know what, I'm very comfortable with treat and extend. I'll just keep on extending until I'm comfortable with every 6 months.

However, they get there, my prediction is that doctors will get to every 6 months fixed dosing, and this will be the ideal drug for that.

Okay. And how important will it be to overlay SOL-R maybe we could talk about what SOL-R is on top of SOL-1 for real-world usage?

That's a great question. It depends on who you're asking that about, right? So just so that everybody knows, SOL-1 is a superiority study that has succeeded. Our intention is to file with SOL-1 alone. SOL-R is the second Phase III study.

It's a noninferiority study that is still ongoing. We have no intentions of changing SOL-R. SOL-R is going to be running as efficiently as it is. If you're asking from a clinician point of view, I don't think there's a single clinician that's going to say, look, I really like this drug. I love the results of SOL-1, but I'm not going to use it until I see SOL-R.

I don't think that ever happens. I don't -- there's not a single drug, and I've challenged people with this. I don't think there's a single drug in my field in retina that is used per label or per clinical trial period. I mean everybody does click treat and extend, as we discussed, and treat and extend has never been done in a Phase III study.

It's never -- it's not in any label, but yet we do that. So doctors will figure out how to use this drug. This drug just needs to be in their hands, and they'll figure it out. I think SOL-R is a nice to have. I don't think that it's a gating item for doctors to use this drug whatsoever.

Okay. So at the beginning of the conversation, we talked about SOL-1 being the pivotal study that you plan on using for applying for approval. So can you talk to us about how discussions with FDA are going on that particular topic to the extent that you can?

And the update that we're seeing today that Dr. Makary is no longer going to be Head of FDA, he co-authored an editorial in New England Journal with Dr. Prasad, who is also now no longer there. So the second part of the question is being that the 2 authors of the editorial who suggests that for most indications, you only need one study no longer there, how does that impact your view of being able to apply with one study?

Yes. So let me answer the first -- the second one first and then talk to you about our discussions with the FDA. Look, I don't think what is happening with the FDA is dependent on 1 person or 2 people. The change that has gone on in the FDA in the last year or so has been tremendous and it's got bipartisan support.

And the bipartisan support is to get innovation to patients as quickly as possible. And that's really what drives it. And if people are wondering whether this is simply lip service or this is really happening, one ought only to look at press releases that were there maybe about a few weeks ago for AstraZeneca as well as Amgen.

And what's happening with AstraZeneca and Amgen is that -- there are real-time clinical trials that are being conducted. And to me, having worked with the FDA for 30 years, that's mind-blowing. And what that means is that CRO is uploading information to the sponsor at the same time that they're uploading information to the FDA.

So theoretically, the time to approval is 0. It's real time. And that's mind-blowing. That's already ongoing. The other thing that's already happening are things such as digital twins. The FDA is making use of AI to not make control and a control arm necessary based on disease stratification where a digital twin can be used instead of a control arm.

And those things are already ongoing, and that's not something that's going to turn back. I don't think the toothpaste is going to be put back in the tube. That momentum already exists.

It's not dependent on 1 or 2 people. And that's consistent with our discussions with the FDA. We've been very, very blessed to have the ophthalmic division of the FDA that we have. We have a SPA for both our targets for both wet AMD as well as for diabetic retinopathy.

We have a novel primary endpoint for diabetic retinopathy. Everything that we have done, including major modifications in our trials have been supported by the FDA, and we're completely aligned with the FDA in our discussions. And look, we've been saying this from day 1, which is our intention is to go ahead and discuss with them the potential to file with a single study, and that's what we've been doing, and we're more confident than ever that we'll be able to do that.

Okay. So thank you for all that color. So if you think about between now and the end of the year, what are the important updates to be expecting? Can you maybe walk us through both expectations for, let's say, additional data at a medical meeting from SOL-1? When to expect feedback from FDA on your discussions? You've announced an Analyst Day as well. So there's a lot going on. Maybe kind of frame the importance of each of those things.

Yes, there indeed is a lot going on. And to take it one by one, look, we certainly will give you updates on the clinical trials, both in wet macular degeneration as well as in diabetic retinopathy. We have a lot more data from SOL-1 that will be particularly clinically relevant that we think is very exciting that we'll show you as well.

We will also show you our commercial plan, which we haven't done before. Look, we're building a stand-alone company. We're scaling up. We haven't talked about that a lot, both in terms of hardware, and I'm talking about buildings as well as automation, et cetera. We're doing that all in the U.S. in Bedford. We manufacture the hydrogel ourselves. And that's all being scaled up very, very well. We'll discuss that.

As far as the regulatory part is concerned, look, the cadence of how and when we discuss that is really -- needs to be aligned with the FDA, and we will let you know when appropriate. And look, what we have said, and this is very important, in the press release as well as in our discussion in the earnings call is that we have ongoing formal discussions.

These aren't informal discussions. These are formal discussions. And those formal discussions are continuing. And we are very, very happy with the direction that they're going, and we will continue to inform you as appropriate.

Okay. So let's talk about the market data research maybe that you've collected so far. So wet AMD, it's an established market, right? You're retinal surgeons, so you already know what options are available for patients. We live in a world now where there are generics of the VEGF and the VEGFs were transformational in their time.

And now we have longer-acting versions of those VEGFs. Where in the treatment landscape do you think, based on what you're hearing from physicians, AXPAXLI could fit in? Is there a particular subgroup of wet AMD that might be more willing to be treated with less frequent injections than, let's say, the rest of the population if for whatever reason, they're just comfortable with whatever they have.

Willing is a weird word. I mean, I think everybody will want to be treated less frequently. I'm not sure who wouldn't want to be treated less frequently, right, as a patient. Here's what I would say.

Look, let's look at the historic data and see what first there is for anything that's incrementally longer lasting and history will tell us. I'm old enough that I remember Lucentis as a miraculous drug, and it really is a miraculous drug. And Genentech is one of the finest scientific companies ever, right?

Genentech and Lucentis had a 7-year head start on EYLEA and Regeneron. Regeneron was an unknown company at that time. A 7-year head start in our field is Infinity. And EYLEA is not safer, it's not stronger. It may last a week longer. And based on that incremental durability, it dominated the field.

And we see history repeated again with Vabysmo, for instance. Vabysmo is not safer, it's not stronger. It may arguably last for another couple of weeks, and it's doing great. That's the thirst that exists for sustainability, let alone long-term better outcomes. We're not talking about weeks.

We're talking about a drug where in 66% of patients, they're rescue-free for a year. We're in a different orbit altogether. And the thirst for a drug like this is enormous. And it's completely derisked because what we're targeting is a receptor that has been known for 40 years to work. We're not reinventing the wheel. We haven't really even talked about the long-term outcomes, which is the other part of this, which is the second goal that we're trying to reach.

And what we have is something called the SOL-X study, which is an extension study. The most important part about SOL-X is going to be the crossover patients. These patients are going to be crossed over to AXPAXLI after 2 years of pulsatile treatment.

We don't think those patients are ever going to catch up. We know that in 90 days by OCT, you can see changes with atrophy and fibrosis. After 2 years of pulsatile therapy, we don't think those patients will catch up.

So now not only will we have a drug with greater sustainability, but we will have evidence to show that this drug should be started from day 1 for the best long-term outcomes. I think everybody will want to be on this drug. I don't think there's a subgroup of patients. I think the question that is appropriate to be asked is to say, look, is this a first-line drug or is this a maintenance drug?

And I think that's an appropriate question. And we're not answering that, quite honestly. I can give you my opinion, but it's just an opinion. And my opinion is, look, this, I believe, is a first-line drug based on a few patients and admittedly a few patients in our study in Australia, where this was used as a first-line agent in treatment-naive patients, and they did as well as one would expect from commercial-grade Lucentis or EYLEA. But quite honestly, it really doesn't matter if it's a first-line agent or a maintenance drug because the projections won't change. It will still be the most impactful drug that we've ever had if it does what we think it will do.

But that will be answered, that amongst other questions by the community when this drug goes out there. My job is to make sure this drug gets approved as quickly as possible.

Yes. I asked that specific question because just given how big the EYLEA market itself is, even if ocular were to penetrate a small portion of that market, the dollar value of that is meaningful, right?

And for whatever reason, there's going to be patients, we see this across all therapeutic categories that even if there's a less frequently dosed version available, either insurance pushes back on it or doctors are more comfortable because they know it for a long time, whatever the reason is, you don't get necessarily 100% conversion.

And I don't think -- and you can feel free to disagree with me. I don't think you need to have 100% conversion in order for AXPAXLI to have a really strong launch. So I guess I'm asking, is there -- in your market data research, obviously, nobody wants to be injected in the eye frequently.

But is there within that group of patients, a subgroup that you think would be lower-hanging fruit easier to get to at least initially?

So look, it's a great question. In the 30 years that I've been on the other side doing hundreds of clinical trials, there hasn't been a single drug that has done better in the community than it did in the Phase III trial. And that's logical.

I mean you want to have the best performing patients in your Phase III trial and almost expectedly, the drug is not going to perform as well when it goes out in a much more heterogeneous patient population in the community. This is going to be the first drug where it's going to be the opposite because what we did in this study in SOL-1 was arguably to use -- to test this in the hardest patients there are.

These patients, as you know, Tazeen, were specifically designed to lose vision. That's not necessarily what exists every day in the community. So how is this drug going to be used? Well, as soon as the drug is available, I believe it will be adopted like this because there's nothing new to be done. There's no equipment to be bought. The workflow doesn't change. Everything is exactly the same. If you look at a given doctor, they may see 50 patients in a day. Of those 50 patients, 2 may be new patients. The other 48 are patients that this doctor has been seeing over and over again.

So the conversation is going to go like this. The doctor is going to sit there with Mr. Jones and say, Ms. Jones, I've been treating you with EYLEA every 8 weeks for 3 years now. And I know you don't like that. I know you're frustrated. What I think I have here is a better drug that has more durability, but I've never used it before. So let me go ahead and try that out. But I still want you to come back in 8 weeks. And they come back and go, wow, Ms. Jones, you're doing great. Well, let's make it 12 weeks. And they'll extend and extend and extend.

And Mrs. Jones or a patient like Mrs. Jones is going to be the easiest one to make happy because it's all a durability play. For someone that's been on EYLEA and stuck on EYLEA every 8 weeks for 3 years, just a little bit more durability is going to make her thrilled and it's going to make a doctor thrilled.

So this is going to actually perform far better in the community than it even did as impressive as it was in the Phase III study. It's going to be adopted seamlessly, and I think it's going to be adopted ubiquitously in all patients. I don't think there's a particular patient subtype who wouldn't want a more sustainable drug that has better long-term outcomes.

Now on the point of physician preference, how are you envisioning that doctors would prefer something that's less frequently dosed given that they're paid per injection, is the price point going to be a little bit reflective of that?

So it's a great question again. But this is one of those rare things that's a win-win-win.

Okay. Let me just step back and talk about payers and doctors and patients. And I really think it's a win-win-win for all 3. As far as payers are concerned, and by the way, we've done a lot of research on this, still continuing. We have lots of payer boards.

And I've been on 2 payer boards. The most expensive disease to treat and payers are actuaries. But the most expensive disease by far is blindness. It's not cancer, it's not strokes, it's not heart attacks, it's blindness. And the reason for that is because the mortality doesn't change. The use of resources go shy, but the mortality doesn't change.

Each blind patient in this country costs over $66,000 a year. You know that in this country, despite having these fantastic drugs, 40% of patients drop out in the first year. All of those patients go blind. The cost for the payers is enormous. If we reduce that dropout rate by even 10%, which we can easily do, that's 0.25 million fewer patients in this country every year that will not go blind.

And it's not just a human impact, but the cost savings of that for the payers is tremendous. The payers love this drug, which will allow us a higher pricing point, a greater ASP, which will be now translated to the doctor.

And if you talk to the doctors, they may say, look, I make my money out of injecting and I may make less because I'm injecting less. But at the end of the day, there are far more patients that they can inject with potentially a higher ASP. The patients will be a lot happier because they don't have to keep coming back as often as they do.

And everything we're talking about Tazeen is just wet macular degeneration, right? This doesn't even include diabetic retinopathy, which I think is a completely untouched field that's 3.5x greater than wet macular degeneration. But to answer your question, look, this is a win-win-win situation.

And with the superiority label, there is a potential. It's not automatic, but there's a potential to bypass that therapy because we will have the first and only superiority label. So if you ask the doctor whether they'd want to have a drug that they want in the first place without watching a patient fail, everybody would want that.

So it has great benefits in terms of a superiority label in terms of not having pricing pressures and also in terms of patient satisfaction.

Okay. So how should we be thinking about the investment in infrastructure that's going to be needed vis-a-vis marketing and sales as you get ready to potentially launch next year?

Yes. I think one of the things that people don't realize is what a small community retina is. It's a huge market, but the community itself is small. And I remind people, and they're shocked when I tell them that when Lucentis was selling at its peak, there are only 55 reps. It's not thousands and thousands, there's 55 reps, but those -- every one of those has to be like really connected and really, really good.

We already have that. We already have a commercial arm. And we've recently hired David Robinson, and David is the architect of the most successful launch in the history of our industry, which is EYLEA. So we've got everything in place already. We are scaling up in terms of our production. We've increased our hardware, the buildings, the automation. We obviously have IP that goes till 2044. We are increasing our additional IPs with materials and methods, et cetera.

So that scale-up is already going on. We are ready for the launch, and we're building a stand-alone company, and so we're ready for that.

Okay. So in the few minutes that we have, let's talk about diabetic retinopathy, which is also a sizable opportunity. We spent rightfully so most of our time on the upcoming launch, but you aren't just trying to just launch this one indication and this one product, you've got plans for a whole pipeline. So maybe let's start with that. Where are you in development with diabetic retinopathy? Can you just remind us of the sizing relative to wet AMD, for example?

So diabetic retinopathy, the field is at least 3.5x bigger. The tragedy of this is that there is nobody is being treated, although we know of a derisked receptor, the same receptor as VEGF. And the reason that nobody is being treated is because patients who are asymptomatic have to come in every month or every other month to get injections. Nobody is going to do that. And if they don't come in, there's a potential of a rebound effect.

What we have shown in our HELIOS study is that with a single injection, the risk of vision-threatening complications year upon year go from 30% to 40% to literally 0. I mean that is phenomenal. And we as clinicians saw that data and we said, holy cow, we would use it today if we had it. That's absolutely doable. It's a derisked receptor.

We already know it works, it's VEGF. It's a single injection. It's once a year. So the conversation would be you'd be sitting with a young person who's either in their workforce, they may be a lawyer, they may be a physician, they may be a male carrier, they may be a truck driver.

But you say, if you come to see me, but once a year, like you go to your dentist for teeth cleaning, I can reduce your risk of a blinding complication, which currently is 30% to 40% year upon year to literally 0, that's sustainable. And that market is enormous, and we're really excited to go ahead and investigate that, and we believe that we will be absolutely successful.

What we've done is launched a HELIOS program with 2 studies. We have a SPA in one of the studies. Very importantly, we have a primary endpoint that is novel and that is validated by SPA. It's an ordinal endpoint. And without getting too technical, what it basically does is to allow us to be credited for patients regardless of whether they improve or don't get worse or maintain.

So we think it's very clinically relevant. It's a novel endpoint. And again, it's validated with a SPA.

And when should we expect to see data?

So we haven't guided you to when the carturner will be, but what we have said is that, that study is recruiting. The physicians are thrilled to do that because there's no one else doing this. And based on the HELIOS results, which we think are spectacular, physicians are very, very excited to enroll their patients in the study.

Okay. And then last question really quickly is cash position and balance sheet strength.

So we are in a great position very conservatively. We've said that we have cash to get -- to go into 2028. In our last announcement and earnings call, we said that we had a cash and cash equivalents position of over $666 million.

Okay. Perfect. With that, we are just about out of time. So thank you, Pravin, for spending the last 30 minutes with us. Thanks, everybody, for listening.

Thank you, Tazeen, for having me.

Good morning, and welcome to the Ocular Therapeutics First Quarter 2026 Earnings Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded and will be available for replay on the Investor Relations section of the Ocular Therapeutics website.

I would now like to turn the call over to Ocular's Vice President of Investor Relations, Bill Slattery, Jr. Please go ahead, Mr. Slattery.

Good morning, everyone, and thank you for joining us today. Earlier this morning, we issued a press release and filed our quarterly report on Form 10-Q outlining our financial results and business updates for the first quarter of 2026. During today's call, Ocular's Executive Chairman, President and CEO, Dr. Pravin Dugle, will summarize recent business highlights before we move to our question-and-answer session. Joining Dr. Dugel for the Q&A portion of the call will be Donald Notman, Chief Operating Officer; Sanjay Nayak, Chief Strategy Officer; and Steve Meyers, Chief Commercial Officer. We refer everyone to this morning's press release and our Form 10-Q for a comprehensive update of our first quarter 2026 financial and business results.

During today's call, certain statements we will be making constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially as a result of a variety of risk factors, including risks and uncertainties identified in the Risk Factors section of our annual report on Form 10-K and our other SEC filings.

With that, I'd like to hand the call over to Dr. Pravin Dugel to review our recent updates. Pravin?

Thank you, Bill, and thank you all for joining us this morning. 2026 is off to a tremendous start for Ocular Therapeutics. And I want to begin by stating this clearly. SOL-1 has fundamentally changed the conversation in wet AMD. In February, AXPAXLI became the first novel investigational therapy to demonstrate superiority to an approved anti-VEGF agent in a Phase III wet AMD trial. That has never been done before. The magnitude, consistency and statistical strength of the data with a p-value of 0.0006 for our primary endpoint are giving the retina community great confidence in the robustness of the result and the probability of a potential approval as we prepare to submit our NDA based on SOL-1 week 52 data, subject to ongoing formal discussions with the U.S. FDA.

But beyond the statistics, what truly excites us is the clinical significance of the data. AXPAXLI delivered unmatched durability and sustained disease control with substantially fewer rescues. In 2/3 of the patients, just a single AXPAXLI injection maintained vision for an entire year. That is not incremental progress. That is true differentiation. Most importantly, we're not slowing down. Just last week, we announced the initiation of enrollment in SOL-X, our long-term extension trial in wet AMD designed to explore AXPAXLI's impact on the long-term outcomes that matter most to patients and retina specialists.

Since the top line announcement, we have continued to analyze the SOL-1 results and each successive data presentation only strengthens our conviction, both at the Macular Society and most recently at the Bit Buckle Society Annual Meeting, we presented additional 52-week analyses that further reinforce AXPAXLI's unprecedented profile. For example, when we look at time to fluid volume increases, specifically thresholds of greater than 30 and 75 microns from week 8, subjects treated with AXPAXLI took about 5 to 6 months longer to reach those thresholds as compared to subjects in the aflibercept arm. This is exceptional disease control.

So why does this matter? Fluid is the key marker of disease activity in wet AMD. Lower fluid accumulation reflects slower anatomic progression and slower anatomic progression reflects sustained disease control. And that has important implications for the long term, which we are further evaluating in SOL-X. Over time, inconsistent or pulsatile VEGF suppression as we see in today's real-world clinical practice may contribute to irreversible changes such as fibrosis and atrophy. What AXPAXLI may offer is something fundamentally different, continuous zero-order drug release and consistent disease control, which we believe could significantly alter the long-term trajectory of disease.

What we have seen to date in SOL-1 with AXPAXLI is not just durability in terms of dosing intervals. It is also durability in terms of disease control. And that distinction will continue to be important. Furthermore, when you consider the patients who were randomized in SOL-1, it becomes even clearer that what we have demonstrated with AXPAXLI is simply remarkable. It's worth remembering that SOL-1 enrolled what may be the best seeing wet AMD population ever studied in a Phase III trial.

As you will recall, treatment-naive subjects needed to reach 20/20 vision or gained 10 letters over 8-week screening and loading phase to be randomized into the trial. Since we started recruitment, we've consistently said that this population was intentionally selected specifically because they are expected to lose vision. And yet, with a single injection of AXPAXLI, nearly 75% of patients maintained vision at 9 months and 66% maintained vision all the way through 12 months. That is simply profound.

We also saw a meaningfully delayed time to first rescue compared to aflibercept. Incredibly, the rescue rate observed in the aflibercept arm at week 28 was not reached in the AXPAXLI arm until 6 months later at week 52. Just think about that. We're talking about a 6-month delay in clinically meaningful disease change. In wet AMD, that kind of separation has never been seen before, and it speaks directly to the durability and sustained disease control that define AXPAXLI's profile.

Most importantly, AXPAXLI was shown to be well tolerated in SOL-1. We have made a conscious decision to be extremely transparent with regards to safety simply because it is so important in retinal vascular diseases. In our Macular Society and VBS presentations, we went so far as to provide subject level detail showing that AXPAXLI is performing as exactly as expected and is eluding drug and bioresorbing when it should. We did not observe a single treatment-related serious ocular or systemic adverse event such as endophthalmitis or vasculitis that would be cause for concern.

Instead, when you combine our superiority, durability, sustained disease control and a reassuring safety profile, you begin to see the profile of a product that retina specialists could adopt with confidence. If approved, we believe AXPAXLI has the potential to become a foundational therapy in wet AMD.

Based on the strength of the results, we remain on track to submit our NDA relying on SOL-1 week 52 data, subject to ongoing formal discussions with the FDA. The FDA continues to publicly communicate plans to move to a single registrational trial as the new default option for approvals. The agency's Commissioner recently noted that he expects this new framework to be phased in over the next few months or so, aligning with our goal of bringing AXPAXLI to patients as soon as possible.

We intend to leverage the 505(b)(2) pathway, which may further allow for a shortened review time line. Importantly, we are accelerating commercial readiness in parallel. We're building the infrastructure, engaging payers, refining our commercial strategy and preparing for what we believe will be one of the most important launches in retina in many years.

Turning to SOL-R. We completed randomization of 631 subjects in December 2025, exceeding our original 555 subject target. Because of this swift enrollment, we recently accelerated our guidance for SOL-R top line data to the first quarter of 2027. This trial was specifically designed to complement SOL-1, whereas SOL-1 demonstrated superiority, SOL-R evaluates non-inferiority in a derisked population. Importantly, our 24-week screening and loading phase occurs prior to randomization, and this is designed to screen out those subjects with high fluid fluctuations, which have notoriously derailed prior non-inferiority trials.

The design reflects real-world clinical practice and incorporates rescue criteria more closely aligned with how physicians treat patients. It is powered to provide additional data supporting rapid clinical adoption. Retention in SOL-R is strong and site engagement remains tremendous. Based on the success of SOL-1, our confidence in SOL-R has never been higher. In addition to SOL-1 and SOL-R, we are thrilled to have recently announced the initiation of enrollment in SOL-X, our open-label long-term extension study in wet AMD.

Following the remarkable results from SOL-1, where AXPAXLI demonstrated unmatched durability and sustained disease control, SOL-X is designed to evaluate the long-term outcomes that matter most to patients and physicians. Subjects who have completed 2-year follow-up in SOL-1 or SOL-R will now have an opportunity to receive AXPAXLI for an additional 3 years in SOL-X, bringing the total follow-up to 5 years. And that is critical because wet AMD is a chronic disease.

In clinical practice, we see the consequences of inconsistent disease control over time, progressive damage that can ultimately limit long-term visual outcomes, including through fibrosis and atrophy. Because all subjects in SOL-X will ultimately transition to AXPAXLI, we will have a unique opportunity to observe the consequences of delaying AXPAXLE treatment. Patients initially treated with aflibercept in SOL-1 and SOL-R are exposed to what we would describe as pulsatile VEGF suppression, where disease control can fluctuate over time compared to the continuous suppression we have observed with AXPAXLI.

If that difference translates into worse long-term outcomes for patients who begin on aflibercept and switch later, it would provide physicians with a clear rationale to initiate AXPAXLI earlier in the disease course rather than waiting. If successful, this has implications far beyond durability. It has the potential to improve long-term vision outcomes, reduce cumulative treatment burden and importantly, keep significantly more patients on therapy over time, which we believe could meaningfully expand the overall market.

So when we think about AXPAXLI, we're not just thinking about a more durable therapy. We're thinking about a therapy that has the potential to be transformative over the long term. And SOL-X is a critical step in potentially demonstrating that.

Beyond wet AMD, our HELIOS-3 trial in diabetic retinopathy remains ongoing. This is a superiority study designed to support a broad label across diabetic retinal disease. It allows enrollment of patients with non-center involved DME, reflecting the continuum of disease in clinical practice. On June 17, in New York City, we will host an Investor Day and plan to provide several important updates across our portfolio. We will provide regulatory updates regarding our NDA submission plan in wet AMD, detailed updates on SOL-R and SOL-X, program updates on diabetic retinopathy and a first look at our planned commercialization strategy for AXPAXLI.

In addition to ocular leadership, we will feature leading retinal KOLs who will share their perspective on the SOL-1 data, expectations for SOL-R, the evolving wet AMD treatment landscape and how AXPAXLI could be adopted immediately if approved. We hope you all plan to join us either in person or virtually for what we expect will be an important day outlining the future of Ocular Therapeutics.

As of March 31, our financial position continues to remain strong. We ended the first quarter with approximately $667 million in cash, which we expect to provide us runway into 2028. That provides us the flexibility to advance the NDA submission, complete the second year of SOL-1, continue SOL-R, SOL-X and our HELIOS program and accelerate commercial readiness. However, our cash runway does not include the full expenses we anticipate we will need to support the commercialization of AXPAXLI. We remain disciplined stewards of capital while investing strategically in what we believe is a transformational opportunity.

Before we turn to Q&A, I'd like to close with a few important messages summarizing our incredible position coming out of the first quarter. AXPAXLI has now demonstrated through SOL-1, the first successful superiority outcome for a novel investigative agent in wet AMD against an approved anti-VEGF. Unmatched durability with sustained disease control through 1 year, a safety profile that supports broad clinical adoption.

In addition, with the initiation of SOL-X, we now have a clear path to evaluating long-term outcomes with AXPAXLI and its potential to fundamentally alter the trajectory of disease. Together, we believe this combination has the potential to redefine the retina experience. Our organization is energized. The data are compelling. Execution remains exceptional, and we're advancing with urgency toward our planned NDA submission and potential commercialization.

Thank you all for your continued support. Operator, we can now take our first question.

[Operator Instructions] We'll take our first question from Tazeen Ahmad with Bank of America.

Thanks for all of the clarification on time lines. Pravin, I just wanted to get a sense of how the discussions with FDA are going. So a couple of things. You've been confident on your view that you can apply with just SOL-1 to get approval. But today, you provided the good news that SOL-R has enrolled at a pace that you're going to be able to have data in the first quarter. So maybe can you walk us through the scenarios of what the time line differences would be if it's decided that you can apply with SOL-1 versus a decision that it might be better to wait for SOL-R?

Tazeen, thank you so much for the question. Very appropriate question. Look, what we've said today and what we've said in the past is that we have ongoing formal discussions with the FDA. We couldn't be happier, and I want to stress, we couldn't be happier with the collaboration that we have with the FDA. We feel we're more aligned with the FDA's goals than ever. We check all the boxes. And what's been demonstrated to us over and over again in our discussions and in the writings of the FDA is that there are 2 things that are really important with this single trial submission that I think everybody ought to note.

First of all, it's a default position for the FDA. And second, the FDA views this as an elevation of the standards for a clinical trial. This is not a lowering of the bar. This is a raising of the bar. And as such, SOL-1 checks all the boxes. It has a SPA. It checks all the boxes in terms of the superiority standard that was reached in terms of safety. So we're more aligned than ever.

In terms of your question regarding SOL-R, look, we haven't disclosed the time lines as yet. We will when appropriate. But I remind you that we have a lot of flexibility here in terms of SOL-R. Nothing is changing with SOL-R. We're continuing with SLA with the same kind of efficiency that we've always demonstrated. We are very, very happy with the engagement of the PIs and the enrollment of SOL-R and nothing has changed. And again, I want to reiterate, we have ongoing formal discussions with the FDA. We couldn't be happier. And when the time is appropriate, we certainly will update you.

Thank you, Tazeen, for that question.

And we'll take our next question from Biren Amin from Piper Sandler.

And I just want to welcome back Donald. Great to have you back, Donald. So regarding the ongoing formal discussions with FDA, Pravin, can you maybe just talk about if you've had the pre-NDA meeting with the FDA? So that's the first question. And then the second question, for SOL-1 in the past, you provided a snapshot on patient discontinuations and patient retention in the study. I was wondering if you could discuss these dynamics for the SOL-R study. Thank you.

Thank you for the personal note regarding Donald. We too are absolutely thrilled to have Donald back, and he's essential part of our team, and we couldn't be happier that he's back with us. In regards to the FDA meetings, again, I want to emphasize what I said earlier on, Biren, which is that we are not in the habit of disclosing the details of our FDA meetings as is true for most sponsors. Suffice it to say that we have ongoing formal meetings that we're very, very pleased with.

The collaboration with the FDA today and as has been demonstrated historically could not be better. You recall all the modifications that we've had and have preserved our SPA with this study. We also recall the modifications that we've had with the SOL-R study. All of those have been done in collaboration with the FDA, and we couldn't be happier with their support and their collaboration. And as I said earlier, when appropriate, we certainly will update you regarding the time lines.

In regards to SOL-R, again, a very appropriate question. As you recall, we had a phenomenal retention rate and execution with SOL-1. That has not changed in SOL-R. We are very, very pleased with the execution. We're very, very pleased with the stats that we have in regards to patient retention. And you'll hear the details of that in our upcoming Investigator Day. And I hope that -- Investor Day, I'm sorry. And I hope that all of you will be present for that in New York City on June 17. Thank you for that question, Biren. Back to the operator.

We'll take our next question from Tara Bancroft with TD Cowen.

So I'm going to stick on this theme, if I may. I understand you can't give exact timing and all of that, of course, to preserve the integrity of the discussions. But I was hoping maybe you could go over with us what has to be done ahead of a filing just to get a better sense of the process as you understand it? And then kind of separately and related, potentially timing to when we could get an update on data from SOL-X and whether this is going to be part of that review that's expected for the NDA?

So Tara, thank you for the question. Look, in regards to the FDA, again, I'll repeat that we check all the boxes. We're completely aligned. And I think everything that you've seen from the FDA is in line with their intention of getting drugs to patients faster and making sure that the trials or the single trial approval process is validated. You've seen all the editorials or the editorial in the New England Journal of Medicine. You've seen the criteria that was laid out by the commissioner. We check all the boxes. And in our discussions with the FDA, we're more confident than ever that we check all the boxes.

In addition to that, as I said earlier, SOL-R also provides us a tremendous amount of flexibility. It's important to note again that nothing has changed with SOL-R. We're moving with SOL-R as efficiently, as quickly with a great deal of integrity. And nothing is going to change with that. So we're moving with that and preserving the flexibility of whatever the FDA should desire.

In regards to your question regarding SOL-X and the updates, we will provide more updates in our meeting in June in New York City. Important to remember that SOL-X will provide some very, very important information in regards to the long-term effectiveness of AXPAXLI. As has been mentioned, SOL-X will provide a lot of data. Probably one of the most important data points that SOL-X will provide are the crossover patients. We said earlier that there is as great deal of evidence in our field that what causes long-term decrease in vision is atrophy and fibrosis that is caused by the pulsatile nature of our treatment.

I've also mentioned several times that that's akin to having multiple concussions because after all, this is neural tissue. We believe that with continuous suppression that AXPAXLI will provide and by eliminating these pulsations, we will have a much better long-term outcome by having less fibrosis and less atrophy. And remember, in SOL-X, patients will cross over to AXPAXLI after receiving 2 years of pulsatile treatment.

So we don't think those patients will ever catch up. And we believe that we'll be able to demonstrate not only the remarkable sustainability and absolutely incredible disease control that we've seen with SOL-1, but we believe we'll also be able to provide substantial evidence that it will provide a better long-term outcome by having continuous suppression. And again, more details on that, Tara, in our meeting in June in New York City, which I hope you will attend. Thank you again for the question. And back to you, operator.

We'll go next to Sean McKesschon with Raymond James.

This is Yang on for Sean. Maybe can you speak to the optionality of adding SOL-R to the safety database for the NDA submission and also the risk of unmasking SOL-R is left on the table as it relates to maintaining the integrity of SOL-R for global approvals?

Yes. And thank you again for the question. A very appropriate question. So I don't want to speak again, as I said earlier on to the details of our conversations with the FDA. Again, suffice it to say that they're very collaborative, supportive, ongoing and formal. What I will say is we have no intention of doing anything different to SOL-R whatsoever. The flexibility that, that provides us in terms of the safety database is enormous, let alone the fact that we also have the HELIOS study.

It's important to remember that in SOL-1, everybody at week 52 has been redosed. So in SOL-1 alone, there's a great deal of redosing experience. Obviously, there's a great deal of redosing experience in SOL-R as well. So again, that affords us a great deal of flexibility. On top of that, it's important to note that what we're filing is a 505(b)(2) because both of these entities are previously FDA approved. So this drug has a lot of familiarity with the FDA. And on top of that, we have a SPA, which we believe will also add to a very efficient filing. But thank you for your question. Again, back to the operator.

We'll go next to Lisa Walter with RBC Capital Markets.

Congrats on the progress this quarter. A couple for me. On SOL-R, just wondering if you can walk us through the secondary endpoints that you expect to share? And maybe could you tell us how you are measuring reduction in injection burden as well? Any color here would be helpful.

Lisa, thank you again. In SOL-R, we certainly will plan to share the details with you of what we will study in our meeting in June. So wait for the details for that. In terms of injection burden, obviously, we're going to be measuring the rescue rates. And again, we'll share the details with that in our meeting in June. It's important to state that I think a lot of the questions that you've asked that you're concerned about, which is very appropriate, have already really been answered in SOL-1.

In SOL-1, we certainly see the disease control of AXPAXLI. It's important to remember the patient population difference in SOL-R and SOL-1. In SOL-1, patients were specifically and intentionally selected to lose vision. And that's important to understand. And I think that's something that has often been neglected. Despite that patient population, we saw an almost 75% rescue-free rate at week 36, and that's quite remarkable. Perhaps more remarkable and perhaps even more clinically relevant is that with a single injection despite that patient population, 56% maintained a stable CST within 30 microns.

Again, I emphasize 30 microns at that time point, and that's unheard of. And you remember, using the SOL-R criteria, almost 80% of patients were rescue-free in SOL-1 at 6 months. And we feel that those 20% would perhaps be excluded in SOL-R given our very long ramp and given the fact that we have 2 opportunities to observe patients for fluctuations. We expect an even higher rescue-free rate in SOL-R, and we believe that AXPAXLI is very well positioned to succeed in the non-inferiority SOL-R trial. Lisa, thank you again for your question. And again, a lot of those details will be addressed in the meeting in June in New York City, which I hope you will attend. Thank you again. Back to you, the operator.

We'll go next to Jon Wollanden with Citizens.

Just wondering, Pravin, if you could talk a little bit about the feedback you received and how retina specialists plan on potentially integrating AXPAXLI in the practice based on SOL-1 and how that might change with the SOL-R readouts?

Thank you for the question. Great question. And that's the discussion going on right now. My colleagues expect to have this medicine in their hands. And the discussion that's going on right now is how will they be using it and how will they be introducing it to their patients, which is a great discussion to have. I think ultimately, what I think at least, and this is just my hypothesis is that this is the ideal drug to be every 6-month fixed dosing drug.

And as I've said, to have a drug that lasts -- that is a fixed dosing confident every 6-month drug, one also has to be confident that, that drug will last beyond 6 months, maybe 9 to 10 months. Now in case the patient gets sick, the doctor is on vacation, that kind of thing. So this is the ideal drug for that. Now how doctors will get to that fixed dosing is something that I think will be explored by the community. Some feel that they'll directly go to fixed dosing. I've had those discussions with my colleagues. Others feel that what they will initially do is to have an extended treatment extend that will continue to give them more and more confidence to go to that every 6-month fixed dosing.

However they go there, I believe that, that's where this drug will end up. And I think that will transform the way we treat patients with wet AMD. And in fact, I think that will align us with the rest of medicine. I've always said that treat and extend, which is what we do now, is sort of opaque. If you ask your 10 KOLs what treatment extend means, you'll get 10 different answers. And there's really no study on treat and extend in a Phase III program. Treat and extend is not on any label. And it certainly is not aligned with anything we do in medicine.

You don't go to your cancer doctor and say, look, I'll wait until your bladder cancer comes back before I decide how often to see you. And you certainly don't go to your cardiologist who says, look, I'll wait for your first heart attack before I figure out how often to treat you. So this type of fixed dosing, I think, is aligned with medicine. I think there's good scientific data to support it. And I think that this drug is ideal for every 6-month dosing.

The other important thing is that the adaptability, I think, will be very, very quick, and it will be seamless nothing changes for the doctor. The workflow doesn't change. The experience doesn't change. It's a self-sealing 25-gauge needle. There's not a single new piece of equipment to buy. There's no added overhead. So I think the adaptability of this will be absolutely seamless. And I know that in talking to my colleagues, they are very enthusiastic to use this drug as soon as it's marketed. Thank you for your question, and back to the operator.

We'll go next to Yi Chen with H.C. Wainwright.

Pravin, could you comment on whether there are any patients who have dropped out of the SOL-1 trial and whether any patients from SOL-1 who are eligible to enroll into the SOL-X trial have chosen to do so. So if not, what are the reasons for not enrolling into the SOL-X trial?

Thank you again for your question. We haven't given the actual numbers, but suffice it to say that the retention rate is absolutely remarkable. And I'll go so far as to say that the retention rate is probably better than any other retina Phase III study that we know of. This speaks to the enthusiasm not only of the patients, but also the doctors. And historically, this is borne out, right? I go back to Lucentis and EYLEA, for instance. Lucentis had a 7-year head start. Eylea came in 7 years later and extended the durability by maybe a week or 2 and absolutely dominated the market.

And you see the same kind of thing with VABYSMO now. This is a real need in our community. Doctors know this, patients know this. and seeing the data that they've seen with SOL-1 makes it very, very easy for patients and for doctors to stick with this program. So there's been an overwhelming amount of enthusiasm. We haven't given you the actual numbers. But again, the retention rate of this program, I'll go so far as to say, is higher than any other Phase III program that I know and the enthusiasm is through the roof at this point. Thank you for your question. Back to the operator.

[Operator Instructions] We'll go next to Lachlan Hanurry-Brown from William Blair.

Truman Dunkley on for Lachlan. I just wanted to ask, for the HELIOS-3 study, can you remind us if there's a certain proportion of patients that you will need to enroll with non-CI DME to ensure that you have enough data to get DME in the label?

No, there is no -- again, thank you for the question. There is really no such requirement that we have guided you to. What I will say is we are very confident that we will not need to do another diabetic retinopathy study to cover all of diabetic retinal disease. And I say that because remember, what we're doing is enrolling patients with moderate to severe non-proliferative diabetic retinopathy with non-center involving diabetic macular edema with an ordinal endpoint, which captures every facet of change with non-proliferative diabetic retinopathy.

Now the FDA historically has given approval based on the disease as opposed to the clinical trial. We absolutely believe that we will have a label that will cover all of diabetic macular edema. And you've seen evidence for this over and over again. If you go way back to Anchor and Marina, for instance, there was a restriction in visual acuity in enrollment. And you see that for Lucentis, there is no restriction whatsoever. You look at Panorama, there is no restriction for a stage of non-proliferative diabetic retinopathy in the label.

And most recently, my last company, Iveric Bio, I recall that we didn't treat a single patient with center-involving geographic atrophy yet if you look at the label for IZERVAY, it allows for all of geographic atrophy, foveal involving and non-foveal involving. And in the same way, we believe that with the label, eventually, AXPAXLI will cover all of diabetic macular edema, central involving and non-center involving. And also recall that everybody with diabetic macular edema, everybody also has non-proliferative diabetic retinopathy.

So all of diabetes will be covered, we believe, by the label. Again, I will add that, obviously, we haven't had labeling discussions with the FDA. It is far too early for that. But we firmly believe that this will be the only trial that will be necessary in the HELIOS programs for a broad label encompassing all of diabetic retinopathy. Thank you again for the question. Back to you, operator.

Thank you. At this time, there are no further questions in queue. So this concludes our question-and-answer session. I will now turn the call back to Dr. Pravin Dugal for closing remarks.

Thank you. Once again, thank you all for joining us today, and thank you for your continued support. We hope you will join us on June 17 in New York City for our upcoming Investor Day. In the meantime, if you have any questions, please reach out to Bill Slattery, our Vice President of Investor Relations. Have a great day, everyone, and thank you.

Thank you. This brings us to the end of today's meeting. We appreciate your time and participation. You may now disconnect.

Good morning, and welcome to the Ocular Therapeutix SOL-1 Data Review Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded and will be available for replay on the Investor Relations section of the Ocular Therapeutix website. I would now like to turn the call over to Ocular's Vice President of Investor Relations, Bill Slattery, Jr. Please go ahead, Mr. Slattery.

Good morning, everyone, and thank you for joining us today. This past Friday, February 27, 2026, we presented detailed results from the SOL -1 Phase III clinical trial of AXPAXLI, also referred to as OTX-TKI in wet AMD at the 49th Macula Society Annual Meeting. We refer everyone to the Macula Society presentation slides and video recording for a comprehensive update of the clinical data released. The presentation is available on the Events and Presentations section of our Investor Relations website.

Today's conference call will begin with brief prepared remarks from Dr. Pravin Dugel, Ocular's Executive Chairman, President and CEO; Dr. Peter Kaiser, Ocular's Chief Development Officer; Dr. Arshad Khanani, Director of Clinical Research at Sierra Eye Associates in Reno-Nevada and Steering Committee Chair for the SOL program; Dr. Darius Moshfeghi, who is a rescue monitor in the SOL-1 trial and is Chief of the Retina Division Byers Eye Institute at Stanford University School of Medicine; and Dr. Jeffrey Heier, Ocular's Chief Scientific Officer. Following the prepared remarks, Dr. Sanjay Nayak, Ocular's Chief Strategy Officer, will join our presenters for the question-and-answer session.

During today's call, certain statements we will make constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially as a result of a variety of factors, including risks and uncertainties identified in the Risk Factors section of our annual report on Form 10-K and our other SEC filings. With that, I'd like to hand the call over to Dr. Pravin Dugel. Pravin?

Thank you, Bill, and thank you all for joining us this morning. It has been nearly 2 weeks since we announced positive SOL-1 top line results. And as we've continued to analyze the data set, our conviction has only strengthened. The message remains simple. We have a drug, a drug that is active, durable and well tolerated, delivering sustained VEGF suppression with evidence of activity up to 12 months in 66% of the AXPAXLI treated subjects. That is simply unprecedented, and it cannot be matched by our nearest competitor. This is not incremental progress. This is not another modest extension in dosing interval. This is transformative durability with continuous predictable disease control.

At the 49th Macular Society Annual Meeting, we answered several questions raised after our top line announcement. We demonstrated just how difficult it is to achieve superiority in wet AMD and reinforced that the endpoints most relevant to clinical practice strongly favor AXPAXLI. Remember, no other novel mechanism has ever demonstrated superiority to anti-VEGF in an FDA-aligned Phase III study. We believe this represents a lasting point of differentiation since very few, if any, sponsors are likely to take on this difficult challenge. With positive SOL-1 data in hand, we are now preparing for our NDA submission. The transformative durability, continuous VEGF suppression and safety profile demonstrated in SOL-1, combined with a seamless workflow integration likely positions AXPAXLI for immediate and rapid adoption pending FDA review and approval.

Most importantly, it provides new hope for patients who have lived with the burden of treatment injections and fear of irreversible vision loss for far too long. With that in mind, it is my pleasure to hand the call over to Peter Kaiser, who will spend a few minutes on AXPAXLI's mechanism of action presented this past Friday at Macular Society. Arshad Khanani will then talk about the detailed SOL-1 efficacy results, followed by Darius Moshfeghi, who will provide an update on AXPAXLI's safety profile. Finally, before we move to Q&A, Jeff Heier will speak more about our plans to submit our NDA for AXPAXLI with SOL-1 alone. Peter, please go ahead.

Thanks, Pravin. Ocular Therapeutix is and will always be a company grounded in scientific evidence, first and foremost. With that in mind, let me explain why AXPAXLI is fundamentally different from the anti-VEGF therapies we use today. Current anti-VEGF drugs work outside the cell in the extracellular space. They bind specific VEGF molecules, primarily VEGF-A outside cells, preventing them from activating receptors that drive abnormal blood vessel growth and leakage. This approach has transformed retina care, but it's also incomplete. Multiple VEGF receptors are involved in neovascular AMD, particularly VEGF receptors 1 and 2 and blocking just one ligand like the most pathologic VEGF-A may allow other pathways to compensate.

For example, VEGF-C can become upregulated when VEGF-A is suppressed. None of our current anti-VEGF agents address that. Axitinib, the active drug component of AXPAXLI works very differently. Instead of blocking VEGF outside the cell, axitinib works inside the cell at the receptor level. It blocks activation of all VEGF receptors by targeting the ATP binding site, effectively shutting down the signaling cascade that drives leakage, inflammation and neovascularization irrespective of the concentration of VEGF in the extracellular space.

In simpler terms, it's a more comprehensive blockade of the VEGF pathway. And it does this with very high potency and selectivity. Independent kinase profiling performed under physiologic ATP and drug conditions shows that axitinib produces greater than 90% inhibition of all VEGF receptors with almost complete inhibition of the pathologic VEGF receptors 1 and 2. In addition, axitinib produces greater than 85% inhibition of all the PDGF receptors, which are involved in vessel stabilization and fibrosis. Coupled with this targeted selectivity, when tested appropriately at physiologic ATP levels and therapeutic drug concentrations, axitinib does not inhibit off-target kinases like JAK1 or Type 2. In fact, none of the TKIs in development for retinal diseases meaningfully inhibit the JAK pathway at physiologic ATP and therapeutic drug concentrations. The bottom line is that axitinib is very potent and selective for the receptors that lead to retinal vascular diseases.

The second part of the ocular story is drug delivery. AXPAXLI combines axitinib with ocular's tunable ELUTYX hydrogel platform, a platform leveraged from our FDA-approved product, DEXTENZA, which has been safely used in more than 700,000 eyes. The ELUTYX hydrogel technology is a tunable and fully bioresorbable polyethylene glycol platform. It does not leave any hydrogel remnants for 12 to 18 months like some other programs. It is injected through a standard 25-gauge needle and does not require surgery. The hydrogel releases axitinib in a controlled, predictable manner with 0 order kinetics, providing continuous drug levels in the retina and choroid for up to 9 to 12 months. That sustained, steady axitinib delivery is what allows for consistent VEGF and PDGF pathway suppression over time. Unlike other polymer systems, drug release and hydrogel resorption are synchronized.

Physicians know when the drug is gone and when redosing may be appropriate. So when you combine a highly potent pan-VEGF intracellular inhibitor with a strong pan-PDGF inhibition delivered through a bioresorbable hydrogel platform that provides predictable, long-duration release over 9 to 12 months, you get a therapy designed not just to compete in the market, but to redefine it. What I've shared is a scientific foundation behind the positive SOL-1 clinical results, which I would now like to ask the Steering Committee Chair, Arshad Khanani, to speak more about. Arshad?

Thanks, Peter. It's a privilege to work through the efficacy results from SOL-1 that were presented on Friday with the benefit of the expanded data set now in hand. What I'd like to do today is to focus on not just on the numbers, but on what they mean clinically. First, it's important to remember who the 344 subjects enrolled in SOL-1 were. These were not poorly seeing patients with scarring and fibrosis. After 2 aflibercept loading injections, on average, subjects were randomized with approximately 20, 25 vision, approximately 2/3 of the subjects had gained 10 letters or more from enrollment to randomization.

In other words, this was one of the best seeing Phase III populations we have ever enrolled in terms of BCVA. This was by design because the trial sought out a population that was expected to lose vision over time. Against that backdrop, AXPAXLI met the primary endpoint in SOL -1 convincingly. At week 36, 74.1% of AXPAXLI subjects maintained vision, defined as losing fewer than 15 ETDRS letters compared to 55.8% in the aflibercept arm. That reflects a 17.5% risk difference and a P-value of 0.0006. At week 52, 65.9% of AXPAXLI subjects maintained vision after a single injection with statistically significance over aflibercept and a p-value of less than 0.0001. That represents sustained disease control over an entire year in a population selected to fail.

If we were to look at the proportion of subjects who lost greater than or equal to 10 ETDRS letters, this key secondary endpoint also emphatically favors AXPAXLI. Only 1/3 of AXPAXLI subjects would have met this threshold at week 36 compared to over half of the aflibercept subjects with a nominal P-value of 0.029; by week 52, still less than half of the AXPAXLI subjects would have lost more than 10 letters. Now let's talk about anatomy because that's how we actually practice. Treatment decisions are typically driven by fluid on OCT. In SOL-1, AXPAXLI delivered consistently tighter atomic control. At week 36, 55.9% of subjects maintain central subfield thickness within 30 microns of baseline compared to 37.8% with aflibercept. That separation persisted through week 52. We also saw lower total fluid volumes and reduced fluctuation over time. And when you look at specifically at patients who were dry at baseline, over 80% maintained vision at 9 months with AXPAXLI. That level of predictable fluid control is what gives clinicians confidence to extend intervals.

Rescue data reinforces the durability story. At week 36, 74.7% of AXPAXLI subjects were rescue-free. At week 52, 68.8% remained rescue-free in each case based on the on-protocol rescue criteria. The Kaplan-Meier curve is particularly striking, showing meaningfully delayed time to first rescue for AXPAXLI compared to aflibercept. For example, the higher rate of rescues in the aflibercept arm at week 28 was not reached in the AXPAXLI arm until 6 months later at week 52. If we were to consider subjects who had 0 or 1 rescue treatment in the AXPAXLI arm, 81.2% of AXPAXLI subjects made it to week 36, while an astonishing 72.4% made it to week 52. When looking at the ITT BCVA curves, I think it's important to step back and ask what those curves are actually capturing. The ITT analysis is confounded by rescue interventions with many more rescues taking place in the aflibercept arms.

Remember, at week 52, roughly 2/3 of AXPAXLI subjects remain rescue-free compared to a minority in the aflibercept arm. We also know that AXPAXLI's hydrogel bioresorption occurs around week 36. So some softening of effect beyond that point is biologically expected. In that context, it's actually quite encouraging that so many AXPAXLI subjects maintain control out to week 52 without rescue. And importantly, in SOL-R, all subjects will be proactively redosed at 6 months. Seeing this level of durability without mandated redosing gives me even greater confidence in the fixed interval paradigm being prospectively tested in SOL-R. Taken together, what do we see? We see superiority on vision. We see sustained anatomic stability. We see high rescue-free rates, and we see durability extending toward a 9- to 12-month treatment horizon. For a single injection in an FDA-aligned Phase III trial, that combination is unprecedented. With that, it's my pleasure to hand the call over to Darius to talk more about safety. Darius?

Thank you, Arshad. It's great to be speaking with everyone again today. In retina, you can have compelling efficacy and impressive durability. But if retina specialists are not completely comfortable with the safety profile, adoption stalls. What gives me confidence in AXPAXLI is simple. There is nothing in this data set that would make me hesitate to use it in my own patients. Let me be very clear. There were no treatment or procedure-related serious adverse events and no safety events that commonly derail retina programs. No endophthalmitis, no occlusive or non-occlusive retinal vasculitis. There was one singular nontreatment-related ocular SAE, a cataract with greater than 30 letter loss at detection, but the patient's vision quickly recovered after routine cataract surgery.

Cataracts are common in this age group, and this did not represent a concerning safety signal. Some have focused on the higher rate of nonserious ocular events, and the main driver was vitreous floaters in 12.4% of AXPAXLI subjects. It's important to understand that the timing of these small floaters correspond to the tunable hydrogel dissolution and drug elution. They did not adversely affect visual acuity. They were not associated with inflammation, and they were not associated with cataracts. When recording adverse events, we rely on classifications from the medical Dictionary for regulatory activities or MedDRA. At the time of SOL-1, there was no MedDRA code for drug particles. So our expectation is that they were recorded as floaters. That can inflate the category, but clinically, this is not a concerning signal.

Beyond floaters, there has been some discussion of cataracts in 7.1% of AXPAXLI subject. Cataract rates were consistent with what we see in wet AMD trials in this older population. Again, nothing novel, nothing alarming. Intraocular inflammation was observed in a small number of cases, but these were all mild to moderate and resolved with topical therapy or observation. People seem to forget that the Lucentis package insert includes a 19% rate of vitreous floaters, 11% rate of cataract and 13% rate of vision blur or vision disturbance, yet more than 12 million doses of Lucentis have been administered since it was approved in 2006. Moreover, in the real world, missed visits are common. These are elderly patients. They get sick, their spouses get sick, transportation falls through, life happens. With current anti-VEGF therapies, missed treatment visits can result in irreversible vision loss.

A therapy that maintains disease control for up to 12 months like AXPAXLI showed in SOL -1 provides a significant buffer against that risk. From a clinician's perspective, that is powerful. Just as importantly, AXPAXLI is likely to require no surgery, no concomitant steroids, no implant retrieval, no special monitoring for remnants. It is delivered through a standard intravitreal injection exactly how we already practice. Based on the SOL-1 data, I believe AXPAXLI has the profile to support immediate and broad use in wet AMD because it has a reassuring safety profile, continuous disease control, superiority and the potential to meaningfully reduce treatment burden. From where I sit as a clinician and as someone who closely monitored this study as a former rescue monitor, there is nothing rate-limiting here. On the contrary, I see a therapy that has the potential to meaningfully advance the standard of care. Jeff, over to you.

Thank you, Darius and Arshad. We are lucky to have you both as collaborators as we continue to communicate the strength, consistency and real-world relevance of the SOL-1 results. Before we move to Q&A, I want to take a couple of minutes to explain why we believe AXPAXLI is exceptionally well positioned for NDA submission and potential FDA approval based on SOL-1 alone. As many of you have seen by now, the FDA recently announced in the New England Journal of Medicine that one adequate and well-controlled pivotal trial is the new default option for FDA approval when supported by confirmatory evidence. This includes factors such as statistical significance, alignment with the FDA and totality of evidence.

When we look at SOL-1 through that lens, we believe it checks every box. First, the SOL-1 superiority trial was designed in direct alignment with the FDA's 2023 draft guidance for neovascular AMD clinical trials. The guidance recommends that one comparator arm have the same dosing schedule as the investigational drug, and SOL-1 did exactly that. This gives us clean, unbiased evidence of relative efficacy and durability. There is no inference required. The FDA has also stated that sham injections are not recommended due to inadequate masking and potential bias. SOL-1 did not use sham injections. Second, this was an adequate and well-controlled study. And importantly, it was conducted under a Special Protocol Assessment or SPA agreement. That means the FDA aligned in advance on the trial design, patient population, control arm, masking endpoints and the statistical analysis plan, which was included with the SPA submission and agreement.

Third, the magnitude and statistical strength of effect are compelling. The primary endpoint at week 36 achieved a P-value of 0.0006. The key secondary endpoint at week 52 achieved a P-value of less than 0.0001. Across visual, anatomic and rescue-based measures, the consistency of results is striking. Fourth, confirmatory evidence. The VEGF pathway is one of the most well-established mechanisms in all of medicine. AXPAXLI targets a validated pathway that has defined the standard of care in wet AMD for over 2 decades. We also have extensive real-world evidence showing that in the U.S., up to 40% of wet AMD patients discontinue anti-VEGF therapy within the first year alone, largely due to the injection burden.

A therapy that meaningfully extends durability like AXPAXLI did in SOL-1 directly addresses that unmet need. And finally, we will be filing via the 505(b)(2) pathway, leveraging prior FDA findings on axitinib systemic toxicity. Axitinib is already FDA approved in nonocular indications. Its pharmacology and systemic safety are well characterized and our manufacturing is U.S.-based, a priority for this administration, both of which support regulatory efficiency and reliability. We are actively preparing our NDA and plan to submit following our planned meetings with the agency. Our goal is simple: to bring AXPAXLI to patients as quickly as possible. With that, operator, we are ready to take our first question.

[Operator Instructions] Our first question comes from the line of Tazeen Ahmad with Bank of America.

Congratulations on presenting really positive updated data. I wanted to ask about commercial preparation. So now that we have a clear picture of what the product looks like and you believe that you can get approval with this one study, you pulled forward your efforts for preparation. Can you give us a sense about what kind of size of the sales force you think you would need? Just remind us what EYLEA and Lucentis type of drug marketing teams look like? And if you think you would need the same size or a different size, and then have you scheduled your meeting to actually talk about the data with FDA?

Tazeen, this is Pravin. Happy to answer that, and thank you for the question. We are building a company that is a stand-alone company to market this product globally. We've always said that. We've committed to that and the actions that we've taken really validate what I've just said. As you know, recently, we announced the hiring of David Robinson. We're very fortunate to have David. David is the architect of the EYLEA launch, probably the most successful launch in our industry. As far as the sales force question is concerned, we are very, very well supplied with that. As you recall, we are selling DEXTENZA. We have a very capable sales force that we're very proud of. At the peak of Lucentis sales, I believe that Genentech had about 50 to 60 reps, we're already there.

It's not so much the number of reps. It's really the networking, it's the concentration within ophthalmology. And that's one of the very big reasons that we've kept DEXTENZA under our umbrella. We're really proud of the commercial team that we have and their capabilities. So we're very well set up for commercialization here. We're also scaling up, as I've said before, through automation, et cetera, not only for wet macular degeneration, but also for diabetic retinopathy, which is 3.5x the size of that. Now with the single submission, we've also accelerated the entire program. So in terms of the commercialization as well as the scale-up of manufacturing, all of that has been significantly accelerated because our goal is to get approved with a single trial. But thank you for that question, Tazeen. Back to the operator.

We will move next with Biren Amin with Piper Sandler.

Now that you've had time to analyze SOL-1 fully, I want to get your thoughts on read-throughs from SOL-1 to confidence that SOL-R could achieve non-inferiority against aflibercept 2 milligrams every 8 weeks. So that's the first question. And second question, I think on regulatory, would you expect FDA will want you to identify patient populations that benefit from AXPAXLI? Or would you expect a broad label based on the SOL-1 trial data?

Thank you again for your question. For the first one, which is the translation of the SOL-1 data to SOL-R confidence, Arshad, maybe I can ask you to start that. And then with the FDA question, maybe I can give that to Jeff afterwards. But Arshad, if you can go ahead with the first question that Biren asked, which is the translation of SOL-1 data into greater confidence for SOL-R.

Thank you, Pravin. Thank you, Biren. Good morning, everyone. So I think that's a very good question, Biren. And I think looking at the SOL-1 data, it provides me high confidence that we'll be able to potentially achieve non-inferiority in SOL-R. And the reason for that is, as you recall, we have a long run-in period in SOL-R to actually exclude patients that are high need. So you get 3 anti-VEGF and then you wait for 8 weeks. And if they have accumulation of fluid or disease activity, they're exited from the study. So they are not randomized.

So as you recall, in SOL-1, we have a whole spectrum of patients, the VEGF responsive patients, most of them gained 10 letters or more, but that doesn't screen out all the high-need patients. And of course, the number we shared before, 77.1% would have been rescue-free using the criteria for SOL-R, even though we are including the high-need patients from SOL-1. So the totality of the efficacy data we have seen, I'm very confident that we'll be able to potentially meet the non-inferiority in the SOL-R study.

Yes. Thank you, Arshad. Jeff, I think -- do you want to go ahead and add to what Arshad might have said as well?

Yes. I think that as we've looked at different studies and we've seen the responses in these types of studies, I think we are confident that the patients we've treated in SOL and we've looked at the analysis will translate very well to SOL-R and the treatment responses we see there look like they'll do very well. And I think the fact that we've selected out the patients that are most likely to be the most challenging that have the highest anti-VEGF need will give even more confidence to SOL-R. There was original work out of View 1 and View 2 that Peter Kaiser, Namrata, Andrew and myself were instrumental in performing the analysis, and it shows that there's a small group of patients who have a very high need. And if you eliminate -- if you take those patients out of these analyses, and that's for all drugs there all of the anti-VEGFs, you have a much greater response rate.

So we're very confident that this will translate well. Biren, to your second question as to what do we expect on the label, I would not expect any sort of restriction on the label at all. I would expect a very broad label. And none of the approvals for the anti-VEGFs to date, despite different inclusion and exclusion criteria, we've never seen a restriction on the label. And I think not only when you look at our SOL-1 data, but even when you look at our previous studies like the treatment-naive patients in the Australia study, these patients respond well. So I would not expect any type of limitation or restriction, and I would expect a broad label as we've always seen previously.

Jeff, thank you. And Biren, thank you for the question. From my perspective, let me just say for both the parts of the questions that you asked, the translation from SOL-1 to SOL-R, one of the things that we tend to forget is the patient population. Remember, in SOL-1, we specifically picked a patient population that was going to lose vision that was thoroughly anti-VEGF dependent. It's almost the exact opposite for SOL-R. Here, we have a patient population that has a large ramp, the biggest ramp that I think we've seen to ensure stability to make sure that they're actually not anti-VEGF dependent. So it's really quite the opposite. The way I look at this is that, look, if we can have a rescue-free rate in this patient population that is the opposite of SOL-R, arguably the most difficult to treat in the sense of having patients who are designed to lose vision who are anti-VEGF dependent and have a rescue-free rate of nearly 80% when we have meticulous selection for stability as we have with 2 opportunities to observe, I can't help but believe logically that, that rate will be much higher than that.

So I think the confidence that we can take from the SOL-1 results and translate into SOL-R is really quite significant. And we haven't had much time with this data set. I think you will see, I can tell you very confidently further data cuts coming up, which will give you even more confidence in SOL-R. And I think this is really an all-time high as far as our confidence is concerned, again, not just for SOL-R, but also for our diabetic retinopathy studies. As far as the FDA question is concerned, what I would say is the FDA has said very clearly for decades now that the label that they would give, and obviously, we're not in labeling discussions with them, but the label that they give is based on the disease and not based on the clinical trial. And this has been shown over and over again.

If you go all the way back to ANCHOR and MARINA, there are restrictions as to vision. And clearly, you see that with Lucentis, there is no restriction in the label whatsoever. If you look at PANORAMA, there are restrictions as to the severity of diabetic retinopathy. Eylea has no restrictions as far as the severity of diabetic retinopathy is concerned. And most recently, my last company, remember, we haven't treated a single patient with [indiscernible] involving geographic atrophy, not a single patient yet the label of Izervay is very broad, allowing for treatment for all of geographic atrophy. That's going to be no different for us, I believe. And remember, we have a spot to back this up, assuring us at least validating a superiority track forward. So thank you again for your question, Biren.

We will move next with Colleen Kusy with Baird.

Maybe first for Dr. Khanani, Dr. Moshfeghi, just based on the overall data that we've seen, how would you plan on incorporating AXPAXLI into your practice? What type of patients would you use it in? Would you not use it in? And maybe you could just comment -- I know you -- obviously, there was a large meeting of retina specialists over the weekend at the Macula Society. So if you could just comment on kind of how your colleagues are thinking of adoption as well.

Colleen, thank you again for the question. This is Pravin, and that's a perfect question to ask both Arshad and Darius, as well as Peter and Jeff because they're all practicing physicians. But let's start with Arshad first. Arshad, the question was how would you incorporate AXPAXLI when it becomes available in your patient population?

Thank you, Colleen. It's great to hear from you. So looking at the totality of the data, I'm thinking about my clinical practice, and we have a large number of patients that are on Q 8-week or less frequent dosing. Those patients that are maintained on current treatments carry a very high treatment burden. So AXPAXLI is automatically going to help those patients as a monotherapy, reducing their treatment burden to maybe 6, 9 or 12-month injection with just a single treatment. These patients are looking for better treatments coming in the future because they're getting tired of getting 6 injections or even less or more.

So that's the maintenance population that's already in my clinic. Then looking at the data, there's 2 other patient subtypes that I will definitely use AXPAXLI on. Number one is treatment-naive patients. When a treatment-naive patient comes in, you tell them you're going to get 2 or 3 monthly injections and then we'll extend them. And then they say, well, how long can I go? And my answer is it depends on the need. You may go 6 weeks, you may go 8 weeks, you may go 10 weeks. But majority of them are stuck between 8 to 10 weeks even if they're not high need. So those patients, if they are dry after the 2 anti-VEGF injections, as we saw in the data, 80% -- more than 80% went 9 months in terms of maintenance of vision. So it's really exciting to see that if we have a treatment option in these patients who respond well to anti-VEGF we can give them hope that now you can go 6, 9 and 12 months instead of a few additional weeks like we currently do.

And then the last patient population is a high-need patient population that's getting injections every 4 to 6 weeks, even with the VABYSMO in EYLEA HD. What we can do for them is to use AXPAXLI to treat and extend them to an extended interval. Instead of coming every 4 to 6 weeks, they may be able to go every 3 to 4 months with a foundation baseline therapy with sustained delivery and sustained disease control. And last thing I would say, Colleen, is that retina specialists will figure out the way they want to use AXPAXLI for their patients. They may be fixed dosing every 6 months or we treat and extend. So I think I'm really excited to have it in our hands. And my talk with all the physicians at Macula Society, which is a very high membership-only society, I got so many messages after looking at -- after sharing the efficacy data that they're excited to use AXPAXLI in their clinical practice. Back to you, Pravin.

Thank you, Arshad. And maybe I can go to Darius. It's a really important question, and thank you for asking it, Colleen. Maybe I can ask Darius to answer that. And after that, I know Peter and Jeff also practice, so maybe they want to answer that as well. But first, Darius and then maybe Peter and then Jeff. Darius, go ahead.

Thank you, Pravin. I think it's a great question. In my own practice, for the last 20 years, I've been a strong believer in continuous dosing. Most of my patients are being treated on a Q4 to Q8 regimen. Some of them have been stretched out recently to Q12 weeks, but I'm a believer in trying to maintain visual acuity as opposed to keeping fluid away. And we've seen throughout many, many different studies with anti-VEGF agents that continuous anti-VEGF inhibition, irrespective of the presence of fluid is the #1 predictor of great visual acuity. So when I look at the patient population of patients with wet AMD, I think my entire population is eligible. And I'm going to incorporate it right away, whether that's previously treated or incoming patients.

The second aspect of that is that a lot of stuff happens in our patients. It's an elderly patient population. They travel. They have spouses who may or may not be also compromised with respect to their overall health. They may be far away. And when I have something that can lock in visual gains and maintain absence of fluid over a long period of time, I view this as a safety extender as well as a primary treatment intervention. If I can get my patients on a 6-month to 9-month to a 12-month dosing, that's good for them, and it's also good for my overall practice.

And regarding my practice, like many of the people here where you're just busting at the seams, this is something that I can incorporate immediately into my practice without having to do any special evaluations, interventions, leave and go to the operating room. No, I can do this all within the context of my clinic. Similarly to Arshad, Jeff and Peter, I was down at the Macula Society, and it seems like there's a lot of interest in this medication moving ahead, and everybody is excited to see how it moves through the regulatory process. I'll return it back to Pravin.

Darius, thank you. And maybe, Peter, and then Peter, why don't you pass it on to Jeff to answer this question? Why don't you go first?

Sure. Thanks, Colleen, for the question. As you know, Jeff and I still see patients in our clinics. I'm at the Cole Eye Institute seeing patients. And when you talk to patients, unlike what many physicians will tell you, the thing they hate most are injections. And so when you think about it, anything we could do to reduce that is something they're going to absolutely embrace. And the other big thing here, which is lost on most physicians, most physicians in their back of their brain think, well, there's no question that the results of my patients are as good as clinical studies. And the reality has been shown in numerous publications. It's not one. Every publication on real-world data shows that nice improvement that we all see, and then a tail off over time.

And if you look at our data from the SOL-1 study, that tail off occurs early, right? We see a slight tail off, but then you see a stability over time. And that stability is what I think is really going to be important for our patients. It allows us not to have to worry if we're going to be missing a visit or they miss a visit because of what life happens, and so they're going to miss visits all the time. And currently, when I see that happen, even with some of our second and third-generation longer durability drugs, their vision drops and sometimes drops very precipitously.

We have them covered with AXPAXLI, allows us to go much, much further.

So to me, I personally would be using this in the majority of my patients because to me, this is exactly what they want. Whether to use them in treatment-naive patients because I think the label, as Jeff mentioned earlier, is going to be unrestricted. We do have data in totally treatment-naive patients with the treatment with OTX-TKI from baseline from our Australia study. But I don't really think that's how we're going to use it. I think in the future, we'll probably be drying the patients and then getting this on board to maintain patients over the long term. So I'll pass it on now to Jeff.

Yes. Thank you, Peter, and thank you, Colleen, for the question. Every -- what you've heard from the 3 before me is there's clearly a significant need, and we see the potential to use this in virtually all of our patients. The one thing that keeps going over and over in my mind is when I'm in clinic, the recurrent theme of burden not only to the patient, but to families and caregivers, the constant negotiation with patients that they want to keep stretching it out. And when you speak to clinicians individually, they say, well, I'm really good about maintaining the follow-up on my patients, but we constantly underestimate the misses, the adherence to schedule that goes on with patients.

And so not only the confidence to be able to extend patients long, but the confidence to know that when those unforeseen misses happen, when there's an illness, when there is an injury, when patients can't get in and then don't reschedule for another 3 months, having drug on board to control the disease will be absolutely invaluable.

Thanks, Jeff. Colleen, let me just give you 2 more of my thoughts over here. One is that, remember, we have a second goal with this drug as well, which is to have better long-term outcomes. One thing that hasn't been mentioned is that we believe that we're going to have less fibrosis, less atrophy and that's going to result in better long-term outcomes as well. So I don't want that to get lost there. I'm sure we'll be doing other data cuts that will look into that. The last thing that I would say, in the 30 years that I've been doing this, there's not been a single drug that has been tested that has not done worse in the community than in the clinical trials. And there's a good logical reason behind that. Obviously, you want to have the best patient population, the most derisked patient population who are going to respond as well as possible in the clinical trials.

But in the community, the drug will really never do as well. It will always do a little bit worse. I think this will be the first drug, at least in my career time that will actually do better in the community than in the clinical trials because of the way the trials are designed. Remember, the patients that are selected, as I've said before, are patients who are designed to lose vision. So when this drug is out there in the community amongst patients that are stable, as you've heard from others, patients that are not necessarily as anti-VEGF dependent, the results actually will be better in the community than even in the clinical trials. Thank you for your question.

We will move next to Sean McCutcheon with Raymond James.

Congrats on the data. For me, can you give a bit more detail on the floaters, the origin, how they were found and classified, whether they were seeing in the visual field and the window during which the drug particles were observed and subsequently cleared?

Great. Sean, thank you for your question regarding floaters. Maybe I can pass that on first to Darius to explain a little more detail about the safety data. And then after Darius -- after that, maybe you can pass it on to Peter because I think Peter can talk a little bit more about the mechanism of the dissolution of the drug itself. But first, to you, Darius.

Sean and Pravin, thank you very much for that question. First off, vitreous glitters are very common in these anti-VEGF approaches and intravitreal injections in general, you'll recall that the rate was 19% on ranibizumab and the timing of this was in the window that you were referring to is around the time of between 24, 36 weeks is when we would expect the dissolution of the device inside the eye over time. And then the classification of floaters corresponds to that. The MedDRA classification does not have currently for drug particles. And so we believe that this was the time that the device was dissolving and the time line corresponds to that and then the patients had no adverse events associated with this. Back to you, Peter.

Thanks. Very good question, Sean. It's something that's been asked by many people. First and foremost, if you look at vitreous floaters and adverse event, you have to understand how they're like monitored in a clinical study. Usually in a clinical study, and I've done way too many. Patient comes in, you ask them how they're doing, anything that's bothering them. And then if they say, yes, I'm seeing floaters, then you put it down as a measure term that they saw floaters. In contrast, in this clinical study, we specifically had a webcast with our investigators. And in that webcast, we went over how this drug works, how it dissolves over time or bioresorbs over time, when we expect to see drug elution and what that drug elution looks like. We had pictures from Phase I that we showed the investigators. And we actually even had a case report form where the unmasked investigator had to at every visit say, do I see the implant? Do I see any drug elution? And that has to be filled out at every visit.

So unlike many clinical studies where vitreous floaters are described by the patient in this study, they're put on to the adverse event table by both the patient as well as the physicians. So that's one big difference. And despite that, the numbers are consistent in SOL-1 versus all the other clinical studies out there. That's number one. But number two is sort of what you alluded to with your question, which is what is this? Is this just like vitreous because you put something into the vitreous, the vitreous has been changed in some way? Or is this something else? And -- when we really looked at the data and we presented this at SOL-1 as a scatter plot, the majority of these patients, the floaters occurred right about when we expected drug elution to occur, about 27 to 29 weeks.

And people say, well, is this a big snowstorm effect? What's happening to these patients? No. They're not noticing this. The change in visual acuity is essentially nil, less than 1 letter. And the second part of the question is, does this disappear? And we expect it will, and it's something we will be looking at in the 2 weeks ahead to prepare for this talk. We certainly didn't have time to pull all of those patients case report for. Remember, this was happening relatively late, really up against the 52-week cutoff for the study. So we really are going to look very closely as to the resolution of this. Vitreous floaters and other clinical studies don't disappear. In our study, we'd expect they would. And it's something we will obviously be looking at and let you know in the future.

Peter, thank you. So Sean, again, thank you for the question. The rate is very much in line with other studies. If you just look at that as a whole. These are all physician reported. We asked physicians to look for them, had no impact on vision whatsoever, not patient reported, no impact on vision. And the floaters were there because of the MedDRA coding. There is no code for drug. Although because of all of this, we will have a code for drug in the MedDRA classification, I think, starting next summer. So again, I think it's an issue that has been very, very clearly addressed head on. Let's go to the next question, operator.

We will move next to Lisa Walter with RBC.

Congrats on the progress. Maybe just a question for the retina doctors on the line, Arshad, Darius, Peter and Jeff, wondering what would be your strategy in the real world to start AXPAXLI in a treatment-naive patient? Would you start off with 2 anti-VEGF injections like in SOL-1, then add on AXPAXLI? Or would you use more anti-VEGFs to get going or maybe fewer? Just curious how you would apply this into your practice.

Lisa, thank you for your question. I'm shuffling and laughing because what you said is exactly what everybody else says to me, believe it or not, I'm also still a retina doctor, but nobody remembers that. But that's okay. So let's go to Arshad first with that answer. Arshad, why don't you go ahead? And after that, maybe Darius and then Peter and Jeff, if they want to comment. Go ahead, Arshad.

Thank you for the question. So I think clinical practice, we try to optimize the durability for every patient, and there's a heterogeneous patient set that we see. So there are many patients that come in and you give them one anti-VEGF and they're completely dry and doing well. Those are the patients I'll use AXPAXLI right away after the first injection. And then there are patients who need 2 or 3 loading doses to control their disease.

So I think it's going to vary on the patient type that we are seeing in terms of how we're going to manage those patients. And there are patients who want fixed dosing and there are patients who want treat and extend. And so I think, as I said earlier, I think retina docs will figure out what works best for them and for their patients in terms of optimizing the disease control using the sustained delivery platform and hopefully, we can optimize their outcomes. So you have variable one injection and then AXPAXLI maybe 2 or 3 then AXPAXLI is just going to depend on the patient, how they respond.

Thanks, Arshad. Darius, maybe to you and then Peter after that.

Yes. Thank you, Pravin and Lisa. Everyone is going to treat how the patient rolls into their practice and what their practice pattern is. As I said before, my bias is towards continuous dosing historically. And when I look at this, I view this as a long-term maintainer of both vision and keeping fluid at bay. I would like to get on board and treat immediately with an anti-VEGF agent and then nearly simultaneously add in the AXPAXLI. And the reason for that is I would want to lock in my gains as early as possible.

I don't know if this takes a while to work or if it works immediately from the beginning, and we'll find out more about that as we evaluate the data over time. But my bias would be that if I could do an anti-VEGF and an AXPAXLI early on and then as I don't have to worry about what happens down the road, I could go and say at 24 weeks or at 36 weeks, I'm maintaining this patient on potentially 2 doses per year. That's a fantastic win for my patient population. And they're coming in at that point where I don't have to worry about any sort of variation in either visual acuity or in fluid accumulation. I'll turn it back to Pravin.

Peter, do you want to comment on that, too?

Yes. I agree with everything that's been said so far. And Lisa, it's a good question. How are we going to use this? And are we going to use this in treatment naive? And the idea of putting this on early, as Darius has just mentioned, is very appealing and certainly something we're probably going to do. And this is especially true outside the United States. Outside the United States, a lot of the insurance plans outside the U.S. really limit the number of injections a patient can get in many countries, Italy, in particular. So the ability to put this on board early and to get that coverage is really important. But the other thing is many of my patients in Cleveland have Medicare plans that require Step therapy. So like even if I wanted to put them, for instance, on faricimab or EYLEA HD early on, I can't right? I have to start with Avastin and then I got to switch to a Lucentis biosimilar and then maybe an aflibercept biosimilar.

And finally, 9, 12, 18 months in after I've shown 3 injections of each one of those don't work, I could finally put them on a drug I really wanted to put them on from baseline. And the reason for that is very clear. None of those drugs are actually any better than any of the others. They all were proven in their Phase III clinical studies with non-inferiority studies. In contrast, SOL-1 was a superiority study. So we'd expect that the label would reflect that. And when we've talked to payers, they expect that too. And what that would mean is there wouldn't be Step therapy.

So exactly what you're saying, could you use it in a treatment-naive patient? Well, in traditional Medicare, you could use whatever you want. But most of my patients don't have traditional Medicare. And so because of that, there would be Step therapy. We would expect we wouldn't be required to follow Step therapy, and you could use OTX-TKI in those treatment-naive patients without stepping through other drugs. So in my opinion, I agree with Darius. I would be putting this on very early to keep those patients maintaining that vision gain that we saw early. This is not how we use it in the study. So it's something we'll need to look more closely at.

Thank you, Peter. And thank you for your question, Lisa.

We will move next to Clara Dong with Jefferies.

So just kind of follow-up on the read-through to SOL-R. In SOL-1, patients were dry at baseline, showed a very strong separation for AXPAXLI maintaining the vision. So would you view this dry baseline subgroup in SOL-1 as the closer analog to SOL-R patients given the patient screening in that trial exclude subjects with early persistent fluid. And then also just from the commercial perspective, what data from SOL-R would most meaningfully further expand the adoption beyond what SOL-R already supports today?

Clara, thank you for the question. I can probably answer that. As far as the SOL-R patients are concerned, what I would say is, look, I -- we expect a great deal of stability from the SOL-R patients. We have a ramp that's a 6-month ramp with 2 opportunities to observe. There will be more details that I'm sure we'll share down the road regarding that patient population. But yes, I do expect these patients to be absolutely stable. And you saw from Arshad's talk how well this drug does, particularly when the patients are stable and when there's a fairly dry OCT. As far as the clinical information from SOL-R is concerned, let me be very clear on this. Our expectation is that we will be filing with SOL-1 alone. Our expectation is that this drug will be approved with SOL-1 alone.

And as Jeff Heier said from the podium Macular Society, that process has already begun. We haven't detailed that process to you. That wouldn't be appropriate to detail our interactions with the FDA, but I do want to assure you that, that process has begun. So we believe that there's more than enough information with SOL-1 alone to use this drug very effectively in the community. You've heard that from some of the -- from all of the doctors here. Nonetheless, we are continuing SOL-R. SOL-R is going extremely well. It's being recruited and randomized and executed very, very efficiently. SOL-R will add a great deal of information, but I don't want you to think that we feel that that's a requirement whatsoever. It is still continuing. It adds a great deal of flexibility when the FDA looks at our application, but it will also give us a lot of additional information, but not necessarily essential information, but additional information. Jeff, do you want to comment on that as well?

Yes, I do. And again, thank you for the question. There -- when we looked at SOL-1, and this has been shown, we expect a very high or very low rescue rate based on what we've seen in SOL-1. Keep in mind, SOL-R is going to likely be even less because not only do we have those same guidelines as we've seen in SOL-1, but the idea that patients won't have fluid above a certain level, they'll be followed for not just 4 weeks, but 8 weeks. And over that time, they can't have fluid above a certain level or fluctuations above a certain level. So that gives us even more confidence that the control of disease in SOL-R is going to be stronger than it was in SOL-1.

Thank you, Jeff, and Clara thank you for your question. Next question please, operator?

We will move next to Jon Wolleben with Citizens.

I'm wondering about regulatory strategy here because you're in an interesting situation where SOL-1 was designed for a 9-month primary endpoint, dose at 52 weeks, and you'll have some repeat dosing later on. But what is your initial proposed label duration with FDA? And how does that evolve over time?

John, thank you for the question. Look, our -- obviously, we're not in any labeling discussions with the FDA, but our expectation is that we will have the best label that has ever been issued in our field. This will be a superiority label that we will have. We will -- for obvious reasons. We will have flexibility of dosing of every 6 months to 12 months. Now if the question also, and I think this may be where your question may be going, saying, if we had -- do we have enough experience with cases that are repeated, the answer is we feel that we do and a great deal of flexibility as well. Remember that every patient at week 52 in SOL-1 was redosed.

So in-house, within SOL-1 alone, we have a lot of redosing experience. Now that's under masking, of course, but every patient at week 52 has been redosed. And clearly, with SOL-R, we have a lot of redosing experience as well with that study continuing. So the flexibility comes in as to what the FDA can and wants to do regarding further discussions that we'll be engaged in. They can certainly look at the repeat dosed patients in SOL-1 alone. They can certainly look at SOL-R under masking or SOL-R unmasked as well. That would be really their call. So we have a great deal of flexibility. But our expectation for the label is the only superiority label with a flexibility of dosing encompassing 6 months to 12 months. Thanks for your question, John.

We will move next to Yi Chen with H.C. Wainwright.

My first question is regarding the vitreous floaters, will they eventually be absorbed? Or could they accumulate with the redosing? What is the physicians' experience with vitreous floaters caused by Lucentis?

Thank you for your question. I think Peter start to answer that question regarding the durability of the floaters. But let me pass it on to him first and anybody else that wants to add on after that. Peter, why don't you go ahead? The question was about the expected durability of the floaters and regarding physicians' experience with floaters in general.

Thanks, Yi Chen. I think it's a very interesting question. So as I mentioned before, floaters are something that we've seen in almost every one of our clinical studies, and you specifically mentioned a very high floater rate. in the Lucentis studies. Those floaters, in general, don't disappear. They're different than our floaters and that there's something that's changed in the vitreous. And remember, in the ranibizumab studies, unlike aflibercept, the faricimab numbers, they -- or faricimab in particular, those numbers have way less injections in the MARINA and ANCHOR studies, and Jeff and I were very involved in those studies.

Recall that we gave Lucentis every month, right? And so we're injecting a volume into the eye monthly. So that would explain a very high rate of floaters because you have a very high rate of change of the vitreous. In terms of the floaters that we're seeing here, we believe most of these are related to drug elution, so they're going to resolve. The time point for resolution is probably the time point for bioresorption or actually, in this case, dissolution of the drug itself, the drug will reabsorb into the eye over time. And that should take roughly 1 to 3 months is where we would expect to be.

And the last part of your question, you said, do we expect these to increase over time? And unlike other molecules that are being tested in this space, we don't have any drug remnant at all, right? So once the drug is bioresorbed and a drug is diluted -- or eluded, we would expect there to be essentially no floaters and no buildup of drug remnants in the eye or actually, I would call them more polymer remnants than drug remnants, if that makes sense.

Thank you, Peter. Arshad, did you want to add on to that as well?

Yes, Pravin. So I think I can share my experience as the top site in Phase I. As mentioned earlier, in clinical trials, we report everything and anything. So the hydrogel sits inferiorly far away in the periphery. And once the hydrogel resolves, there's drugs still left. And so if I see that, I call it floaters. So I did not see any patients where actually the drug came in the center or caused any vision issues or symptoms by patients. I was just reporting it because I saw something that we were still learning.

And now we know that this is just a part of bio reabsorption of the hydrogel followed by the drug. So I think it can get confusing for people when they say floaters and they say "Oh my God, it's going to -- what's going to happen when you look at the data," so the one thing I look at is the vision. It has no impact on the vision. That means that it's actually not in the center of the vitreous impacting vision.

And then I was also part of the [indiscernible] trials and those floaters were intense in actually in the center of vitreous impacting vision. So I think I just want to share my experience as an investigator that this is a transient event that in clinical trials we report and none of my patients actually have symptoms. And as Peter mentioned, this is very different than if you have something that stays in the eye for a long time. This is just transient effect, and this is explained by the biology of how this drug works.

Thanks, Arshad. It's a really important question. And what I would say is the first thing to ask is to say what is it because not all floaters are the same, right? It could be blood, it could be vitreous opacities, it could be anything. Silicone oil, could any of those things could all be classified as being floaters. So the first question to ask is what is it? And here, it's very clear. This is drug. And this will go away as we expect it to go away with the drug and it's transient. The second thing to ask is where is it? And Arshad alluded to this. Just remember how these floaters were actually seen. They were not simply seen with what we call a 90-diopter examination which is right at the slit lamp, but they were seen with indirect ophthalmoscopy when looking very far out in the periphery in an area where you may see retinal tears and things like that.

This is something the patient would never see because it's so far out in the periphery that you have to use an indirect ophthalmoscope to be able to see it. So where this occurs is really important. And the last thing, as Arshad said, is does it have any impact on the vision? And we gave you the numbers. It has absolutely no impact on the vision whatsoever. So I think those are really important things to realize. Not all floaters are the same. This is drug. We expect this to go away. It's way out in the periphery. Patients don't see it. This is entirely physician reported. Thank you for the question, Yi. Operator, next question.

I have a follow-up actually. So the -- for the floaters and cataract for the aflibercept 2 milligram in the SOL-1 trial, they appear to be much lower than the aflibercept prescribing information. Which one is more representative of the patient experience in real-world practice?

I'm sorry, could you ask that again? I didn't completely understand.

Pravin. I got it. Basically, you're asking why is the EYLEA rate in SOL-1 different than the EYLEA rate in other clinical studies, like, for instance, V1, V2. Is that correct?

Yes.

Yes. So that's -- there's an easy answer, right? And many people miss this is that -- remember, the aflibercept patients, at least half of them only got one injection of aflibercept versus after loading versus in the V1, V2, they were getting treated either every month or every other month in V1 and then in the other studies, every 8 weeks. So every time you inject into the eye a volume of fluid, you're disrupting the vitreous. These are older patients. And when you do that, you're apt to develop floaters. This is a very common occurrence in an older population of patients. So the rate in the view studies or in the PULSAR and PHOTON for EYLEA HD would be closer to reality than the aflibercept rates in SOL-1.

Peter, thank you. And that would not only just be the floater rates, but I think that would be in everything else as well. So if you're going to do a real-life comparison, in the adverse events table, everything would be -- have to be multiplied by 4 on the EYLEA side as well for a fair comparison. But thank you for that answer, Peter. Thanks for the question, Yi.

We will move next with Lachlan Hanbury-Brown with William Blair.

Congrats on all the data. I guess maybe a question for Dr. Khanani. You talked about how anatomy is where you're really treating most of the time in the clinic. And here, we see good stability, but it does stabilize at maybe 20 or so microns above the sort of lowest point that you get with loading, was wondering just sort of how you view that. Does that kind of increase matter to you? Are there any sort of clinical implications?

And then maybe also somewhat related, but like how would you think about monitoring patients in clinic? You've talked about how you would use it. But obviously, there are a small number of patients that need a rescue. So would you still have to bring every patient in every few months maybe to monitor them?

Lachlan, thank you for the question. Great question. Arshad, why don't you go ahead?

Yes, absolutely. That's a really good question. So clinically, when you look at the amount of fluid that bothers us is usually the fluid in 40 to 50 micron range. And here, you know that 55.9% of subjects maintain CST within 30 microns from baseline at 9 months. So I think you bring a good question that the 20-micron increase is likely driven by those high need patients that were likely not dry after the 2 injections. So the way we do that in clinical practice is we are going to go after the patients that are completely dry after 1 or 2 injections. Those are patients that can be extended quickly. Now it's going to depend on physicians' comfort level initially. They may want to bring those patients maybe 2 or 3 months later just to check for fluid.

They may want to monitor them with home OCT imaging. So I think there are a lot of different scenarios that we can use. But one thing we know that what impacts long-term vision is actually fluctuations in anatomy and those range around 40 to 50 microns or higher. There was a sub-analysis we worked on in terms of quartiles of patients in terms of CST fluctuations in the HAWK and HARRIER studies. And we learned a lot from that data set in terms of fluctuations and impact on vision.

So the bottom line is that we will figure out the high-need patients and then watch them more closely versus majority of the patients who are dry after the first 1 or 2 injections, they can be predictably extended. And as Darius said earlier, I think this comfort level of sustained delivery in the eye gives us confidence that if patient misses a visit or don't come for their follow-up, we will still be able to control their disease and not have impact on their long-term vision.

Arshad, thank you. Jeff, did you want to comment on this, too?

Yes, I'd like to. I think this is a very important question. And when we see -- when we're concerned about fluctuations with conventional anti-VEGF treatments, that's because we know those drugs are no longer present. And so when you see fluctuations in those patients or when you see any fluid, you know that there's nothing on board. This is different with OTX-TKI in that our expectation is we've got drug on board for an extended period. We know that these mild amounts of subretinal fluid are very well tolerated, especially when you have treatment on board. So you're not going to see the fluctuations that you do with the peaks and troughs of intravitreal injections. So these patients are going to tolerate this much better because there's something on board.

I think when we follow patients over time, and we try to learn more about this, we're going to understand what the ranges are for our patients and how we're going to treat. So there will be a number of physicians like Darius, who will just adopt the every 6-month approach and say, I'm very confident that I can maintain disease with 6-month dosing. There will be others that will look for more of an extended approach and they'll follow patients on their own, they'll come up with their own regimen for following these. That will certainly be less frequent visits and figure out what will work for each patient and each physician. But having this drug on board for extended periods of time is what's going to give them the confidence to manage these patients in a whole different manner than what we've been used to.

Thanks, Jeff, and thanks Arshad, Lachlan, thank you for the great question.

We will move next to Serge Belanger with Needham.

First one, can you just comment a little bit on the number of mild, moderate intraocular inflammation events that you reported? Just how common these are in these patients when you're using anti-VEGF? And then secondly, regarding the patient population in SOL-1, I think one thing that stood out in the presentation was how unique this patient population was. So just curious how common are these patients in your practice? Or is it just a function of they're not typically evaluated in the clinical study that makes them unique?

Serge, thank you for the great questions. The first one regarding the IOIs, Darius, maybe I can go to you with that and anyone else that wants to comment after that. Darius, why don't you go ahead?

Thank you, Pravin. And also, Serge, it's a great question. We're always worried about safety, and it's important to recall that we really saw no safety signal whatsoever in this trial. It was an extremely safe file overall, particularly for the AXPAXLI agent. Specifically, the things that we're worried about are things that can cause irreversible visual acuity loss.

So either endophthalmitis or retinal vasculitis, specifically the non-occlusive retinal vasculitis or occlusive vasculitis that have been seen with other medications. We haven't seen any of those. So we did have 9 cases of mild to moderate inflammation, which either spontaneously resolved and that was a vitreous cell one, which may have been drug remnants or responded to topical medications. And this is in line with what we see in both our clinical practice where we're giving frequent injections in our patient population and also within other studies. But really, the take-home here is that there were no vision-threatening events from inflammation in this trial, and I'll return it back to Pravin.

Darius, thank you. I think just as we mentioned floaters in terms of how all floaters aren't the same, I think it's important also to say that not all inflammation is the same. There's inflammation that's mild to moderate as this was perhaps related to some drugs that was classified that way. We'll know more about that later on. But I think what's really important here is what we mentioned in the slide, there was no cases of endophthalmitis and very importantly, no cases of vasculitis, either occlusive or non-occlusive.

The person here, Jeff Heier, who's been in a lot of Boards regarding safety and so on and so forth, has also should be commenting. Jeff, maybe you can make some comments regarding IOIs and how we should think of them in terms of the severity of the IOI, also whether the location, whether it's anterior or posterior vasculitis versus anterior segment inflammation, et cetera. Maybe you can make some comments here, Jeff.

Yes. So I think as you highlighted, Darius and Pravin, it's -- you first of all, have to differentiate how serious is this. And mild to moderate inflammation that resolves readily with topical treatment is of much less concern to us than the more severe types of inflammation that are often associated with vasculitis occlusive disease. We confirmed with all of the uveitis cases that there was none of this present, and that was confirmed on fluorescein angiography and also determined by the reading center not to be present. So that's very reassuring.

You also have to keep in mind that in clinical studies, we actually encourage the investigators to look carefully for this. So even mild amounts of inflammation that would often go unnoticed and often go untreated were detected readily here and treated just as we would want in any clinical trial. But we're not seeing anything that worries us in terms of vision loss associated with these or concerns that this is more of a signal than we would be -- we would normally see with conventional treatment. So the mild to moderate severity, the consistent response, the absence of any significant visual changes gives us confidence that our safety looks good.

Yes. I'd also add that there's one patient who probably was the most severe who in retrospect probably shouldn't have been in the study anyway, and that was a patient with uveitis. It was bilateral, so clearly not due to the drug and recurrence. So a history of uveitis that in retrospect, probably shouldn't have been in the study to begin with. Going to your second part of the question, Serge, which is how representative is the SOL-1 patient population in a community practice, Arshad, maybe I can ask you to answer that question.

Yes. Thanks, Pravin. I think when I look at the patient population, this is a population that require very active anti-VEGF treatment and they respond well to it. So I think the bar here is very high in terms of maintaining vision for these patients over a 9- to 12-month period. So I think this patient population usually doesn't get studied in many trials because they get excluded because the visual acuity is 20, 25 here on average or they gain 10 letters or more. So what we have is we have a unique patient population that was designed to lose vision -- but it's a lot of our patients who actually behave like this in our clinical practice that they will come in and they'll get 1 or 2 injections and they will have vision gains.

But it does not exclude the high need patients, as I said earlier, it does include patients who are frequent need. So I think the bottom line is that if you are studying a patient population that's designed to lose vision and we're able to maintain vision in majority of these patients up to 12 months, I think the bottom line for me is it gives me confidence that I can use AXPAXLI very confidently in my practice to have predictable disease control for 6 to 12 months in majority of the patients.

Thanks, Arshad. I think this is exactly why I said that I expect this drug to be the first one that I've ever seen that actually performs better in the community as opposed to any clinical trials. And what I would also say is people ask me all the time, what is it about the data that's most impressive, which slide? I don't think it's a single slide. I think it's the consistency of all the slides. And most importantly, it really is what matters to doctors the most, which is the OCT, which is the ultimate representative of disease control.

And every single thing that you look at in terms of disease control favors this drug. The OCT is the obvious one. The other one that may not be quite as obvious is retinal hemorrhages. And as you all know, retinal hemorrhages is what we use to sort of -- as a barometer for aggressive disease. And if you look at the baseline characteristics, there are more cases of retinal hemorrhage in the other arm in the AXPAXLI arm.

To begin with, indicating that there were more severe patients who had more aggressive disease than the AXPAXLI arm. And when you look at the end, at the end of the study, it actually reversed. They stayed in the EYLEA arm. However, there are very few in the AXPAXLI arm also. So that's another indicator of better disease control. So I think the consistency of the data that we see over and over again is the most impressive thing as opposed to any particular slide. And I think this is also why this drug will do so much better in the community than even in the clinical trials. Let's go to one question more, operator, one question there.

We'll take our last question from Bill Man with Clear Street.

So my question is on your upcoming meetings with the FDA before submission. What key points do you still need to gain alignment on or confirmation of? And what is your regulatory strategy in Europe?

Yes. So I can dive into that first. And if Jeff wants to comment afterwards, certainly going back to the New England Journal article, et cetera, please feel free to go ahead afterwards, Jeff. The first one, as far as the FDA is concerned, Bill, what we've said very clearly is that the process has already begun. Look, we said this way back in December. We did a lot of work during our quiet time, and it clearly has come full circle with that New England Journal of Medicine article.

And Jeff has very nicely outlined how we fit really all the requirements that the FDA had. Now we typically don't discuss the details of our conversation. So that's not something that I'm prepared to do. But when appropriate, we certainly will guide you and update you. As far as OUS is concerned, look, one of the things in OUS is not just the drug and the trial design, et cetera. It's also the impact that the drug may have on society. That's actually looked at quite carefully. Peter previously already alluded to that saying that the impact that this drug is going to potentially have on society there in terms of patient care is enormous, not just there, but also here. There with the EMA, et cetera, that is considered even more than in the U.S. FDA. So we're in very good stead with them. Our discussions continue with them, and we're very confident that this drug will be approved on a global basis. Jeff, any comments that you want to add in terms of the regulatory pathway, particularly in the U.S. FDA with a single trial?

Yes. So I think that's an excellent question. And we were already looking carefully and planning on submitting under the 505(b)(2) pathway, which, as you know, allows reliance on established safety and efficacy from already approved drugs. And axitinib was approved in 2012 for renal cell carcinoma. Couple that with the recent New England Journal of Medicine article, which talks about the new default being a single study and list certain factors that are important for the strength of that submission, the statistical significance, the science, blinding, alignment with the FDA, supporting secondary data. So all of that really puts us in a remarkably unique situation where we have multiple alignments here, not just with the FDA and these factors, but also the 505(b)(2) pathway that puts us in a very unique position for this submission.

This concludes our question-and-answer session. I will now turn the call back to Dr. Pravin Dugel for closing remarks.

Thank you. Once again, on behalf of Ocular Therapeutix team, I'd like to express our deepest gratitude to the investigators, to study coordinators and the clinical teams whose commitment made SOL-1 possible. Most importantly, I would like to thank the patients and their families who chose to participate in this trial. Your trust, your courage and dedication are what allow innovation to move forward and make advances like this possible. We are incredibly proud of what this team has accomplished, and we remain focused on bringing AXPAXLI to patients as quickly and as responsibly as possible. Thank you all for all your continued support. Thank you all for being here today, and have a great day, everybody.

Thank you. This brings us to the end of today's meeting. We appreciate your time and participation. You may now disconnect.

Good morning, and welcome to the Ocular Therapeutix SOL-1 Topline Data Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded, and a replay will be made available on the Investor Relations section of the Ocular Therapeutix website. This event will conclude at 9:00 a.m. Eastern. I would now like to turn the call over to Ocular's Vice President of Investor Relations, Bill Slattery, Jr. Please go ahead, Mr. Slattery.

Good morning, everyone, and thank you for joining us today. Earlier this morning, we issued a press release outlining the positive topline results from our SOL-1 Phase III clinical trial of AXPAXLI, also referred to as OTX-TKI in wet AMD.

Today's conference call will begin with prepared remarks from Dr. Pravin Dugel, Ocular's Executive Chairman, President and CEO; Dr. Arshad Khanani, Director of Clinical Research at Sierra Eye Associates in Reno, Nevada and Steering Committee Chair for the SOL program; and Dr. Darius Moshfeghi, who was a rescue monitor in the SOL-1 trial and is Chief of the Retina Division, Byers Eye Institute at Stanford University School of Medicine. Following the prepared remarks, Dr. Sanjay Nayak, Ocular's Chief Strategy Officer, will join Dr. Dugel, Dr. Khanani and Dr. Moshfeghi for the question-and-answer session.

We refer everyone to this morning's press release for a comprehensive update of the clinical data released today. During today's call, certain statements we will be making constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995.

Actual results may differ materially as a result of a variety of factors, including risks and uncertainties identified in the Risk Factors section of our annual report on Form 10-K and our other SEC filings. With that, I'd like to hand the call over to Dr. Pravin Dugel to provide an overview of today's announcement. Pravin?

Thank you all for joining us on this historic day for Ocular Therapeutix, for the global retina community, and most importantly, for patients suffering from wet AMD. This morning, we announced positive topline results from SOL-1. The data overwhelmingly show we have a drug, a drug that has the potential to fundamentally change what is possible in wet AMD treatment. Many of us were drawn to ocular by the promise of AXPAXLI to help the millions of patients worldwide burdened by today's standard of care.

Seeing that promise realized in a large, randomized, well-controlled Phase III registrational trial is extremely satisfying. In SOL-1, AXPAXLI demonstrated sustained disease control, robust visual and anatomic outcomes and a well-tolerated safety profile in a randomized population that was specifically selected to lose vision.

We are thrilled to observe that 74.1% of subjects treated with AXPAXLI maintained vision through the week 36 primary endpoint, while 55.9% maintained central subfield thickness or CSFT within 30 microns of baseline in that same period. Maintenance of vision in SOL-1 is defined as a loss of less than 15 ETDRS letters of BCVA from baseline aligned in our FDA-agreed statistical analysis plan. Such a level of consistent activity and long-term durability is remarkable.

These strong results continued to week 52, where 65.9% of the AXPAXLI subjects maintained vision and 44.1% of the AXPAXLI subjects maintained CSFT within 30 microns of baseline. That combination of visual and anatomic stability is rare from a single treatment, and we believe that is exactly what physicians, patients and payers have been waiting for.

Only after establishing that foundation do we arrive at what makes today truly historic. AXPAXLI did not just perform well, but it is now the first and only investigational product in wet AMD with a novel mechanism of action to successfully demonstrate superiority to an approved anti-VEGF. Let me repeat, AXPAXLI is now the first and only investigational product in wet AMD with a novel mechanism of action to successfully demonstrate superiority to an approved anti-VEGF agent since their initial approval in wet AMD more than 20 years ago.

Many programs have tried to reach this bar, all have failed. Today, AXPAXLI succeeded. When I joined Ocular 2 years ago, we set out to orient the organization around a singular bold mission to redefine the retina experience. Our goal was to break the vicious cycle of treatment burden discontinuation and long-term vision loss by developing a therapy that patients can stay on and physicians can rely on. Today's historic milestone represents a monumental step towards that goal.

SOL-1 shows that AXPAXLI can deliver sustained disease control with dramatically reduced treatment burden. And in doing so, it positions AXPAXLI as one of the most consequential advances in retina over the last decade. As a reminder, SOL-1 evaluated a single injection of AXPAXLI 0.45 mg versus a single injection of aflibercept 2 mg administered after an 8-week loading segment with primary superiority endpoint at week 36, defined as the proportion of subjects maintaining vision, meaning less than 15 letter loss from baseline.

The SOL-1 trial design and primary endpoint were explicitly designed to support a potential superiority label and were agreed to under a special protocol assessment agreement with the FDA. That primary endpoint was met convincingly with high statistical significance. The proportion of subjects who maintained vision at week 36 was 74.1% in the AXPAXLI arm compared to 55.8% in the aflibercept 2 mg arm and observed difference of 18.3% and as per the prespecified statistical model, a risk difference of 17.5% with a p-value of 0.0006.

This level of statistical significance gives us compelling evidence that we have a true drug effect with AXPAXLI. As you can see in the data shared today and at the upcoming Macular Society Annual Meeting, the data are incredibly consistent. In addition to the primary endpoint, AXPAXLI shows high statistical significance or numerical superiority compared to aflibercept 2 mg for key secondary and exploratory endpoints.

While the 15-letter superiority endpoint is essential from a regulatory perspective, it is not how retina specialists manage patients in practice. Clinically, we intervene much earlier based on smaller visual changes and most importantly, anatomic control measured by OCT. Fluid accumulation is the earliest and most reliable predictor of future vision loss.

Here, we believe the SOL-1 data are truly exceptional. AXPAXLI delivered likely best-in-disease anatomic control with 55.9% of subjects maintaining CSFT within 30 microns from baseline through week 36, representing a relative risk difference of 17.1% in favor of AXPAXLI with a nominal p-value equal to 0.0013 and sustained consistency beyond that time point with 44.1% of subjects maintaining CSFT within 30 microns through week 52.

That level of fluid stability after a single treatment has simply never been reported before in a clinical trial. Taken together, these data provide very strong evidence that AXPAXLI can provide proactive, predictable and sustainable disease management rather than the reactive, unpredictable and short-acting paradigm that has defined wet AMD care for more than 2 decades.

And it is precisely because AXPAXLI delivered this level of consistent, durable disease control that it was able to do something no other therapy has accomplished, demonstrates superiority to an approved anti-VEGF agent in a Phase III FDA aligned trial. Superiority was not achieved in isolation. We believe it was the result of strong activity, longer durability and consistent control of disease over time. Equally important, AXPAXLI demonstrated a reassuring safety profile in SOL-1.

In retina, safety signals have repeatedly derailed otherwise promising therapies, often signaled early in clinical data sets and ultimately limiting approval or adoption. AXPAXLI was generally well tolerated in SOL-1 with no observed treatment-related ocular or systemic serious adverse events. Durability without compromising safety is what enables real-world adoption. AXPAXLI delivered both in this trial.

These outstanding SOL-1 results further strengthen my confidence in SOL-R, a trial that is prospectively evaluating fixed 6-month dosing and is being conducted in a patient population likely to be much more stable and easier to control. Newly diagnosed wet AMD subjects were only randomized in SOL-1 after showing a peak response to 2 aflibercept 2 mg injections, reaching approximately 20/20 vision or experiencing an improvement of at least 10 ETDRS letters of BCVA.

This population was specifically selected to lose vision. If AXPAXLI can deliver this level of disease control in the SOL-1 population, we should expect even stronger durability signals and higher rescue-free rates with populations such as the one randomized in SOL-R, which incorporates an extensive 6-month screening and loading phase to exclude subjects with early persistent fluid or significant retinal fluid fluctuations.

If approved, I believe AXPAXLI is exceptionally well positioned for immediate and broad adoption given its safety profile, transformative durability and seamless fit into existing retinal practice dynamics, requiring no surgery, no concomitant steroids and no workflow disruptions.

With that backdrop, I am delighted to be joined today by 2 of the world's foremost investigators in retinal therapeutics, Dr. Arshad Khanani, Steering Committee Chair for the SOL-1 program and Director of Clinical Research at Sierra Eye Associates and Dr. Darius Moshfeghi, Chief of the Retina Division at the Byers Eye Institute at Stanford University School of Medicine and a rescue monitor in SOL-1. Their perspectives will be invaluable in helping frame the clinical relevance of today's results.

Before I turn to Arshad, I want to emphasize that today's announcement represents only topline results from SOL-1. We continue to diligently work through all the data received, and we are thrilled with the consistency and strength of the data across the board. We look forward to sharing detailed results at the 49th Macula Society Annual Meeting in just over a week's time. With that in mind, Arshad, please go ahead.

Thank you, Pravin, and a huge congratulations to the Ocular team on what I believe is truly a defining day for wet AMD care. I'll start with a very simple statement. If AXPAXLI were available tomorrow, I believe retinal physicians would use it immediately and broadly in their patients with wet AMD. They would use it because the SOL -1 data showed this is an active, durable and well-tolerated product candidate that delivers a level of predictable disease control we simply don't have today in the clinic.

As a reminder, SOL-1 results were achieved in a population that was specifically selected to lose vision after the loading phase, which suggests the potential for even better disease control in more stable patients. Having served as a steering committee chair for the SOL program, I've had a front row seat to both the rigor of this trial and the quality of the data it produced.

The bar for success in SOL-1 was very high, and the result is a clean, consistent and interpretable data set that allows us to draw confident clinical conclusions and meaningfully reassess what is possible in wet AMD disease management in the near future. For more than 2 decades, anti-VEGF injections have defined wet AMD treatment. Progress has largely come in the form of incremental 1- to 2-week improvements in real-world durability, often without corresponding improvements in long-term outcomes.

Despite these advances, up to 40% of patients still discontinue therapy within the first year alone, largely due to treatment burden, placing them at risk for avoidable vision loss. The opportunity to deliver sustained disease control with dramatically less frequent dosing is not incremental. It represents a logical and long overdue paradigm shift for patients, physicians and payers. Based on the SOL-1 data, that shift now appears attainable with AXPAXLI.

To appreciate the significance of SOL-1, it's important to first understand just how challenging it is to meet this primary endpoint. As a first of its kind study, SOL-1 addressed the question the retina field simply did not have high-quality data to answer. How long does it take newly diagnosed patients with wet AMD to lose 3 lines or 15 letters of visual acuity in the modern treatment era?

What we now know from this landmark study is that a 15-letter decline typically reflects slow progressive anatomic deterioration at the fovea, the portion of the retina responsible for central vision. Put simply, the bar for demonstrating superiority is extremely high. That is precisely why the FDA insists on this endpoint and why no other product with a novel mechanism of action approved or in development has demonstrated superiority to an approved anti-VEGF.

Seeing that AXPAXLI met the superiority primary endpoint with 74.1% of patients maintaining vision at week 36 and 65.9% of patients at week 52 provides clear evidence of the potency and durability of AXPAXLI's VEGF suppression in patients with wet AMD. But as a clinician, what matters most to me is not just that AXPAXLI cleared this hurdle, it's that it did so while delivering the kind of durability, consistent disease control combined with a favorable safety profile that could actually change how I would manage patients.

From a regulatory standpoint, based on the SOL-1 SPA agreement with the FDA, the data suggests that AXPAXLI was clearly successful in showing statistical superiority. But in practice, retina specialists do not wait for patients to lose 3 lines of vision before intervening. We make decisions based on earlier functional changes and anatomic control based on fluid on OCT imaging.

We tend to prioritize anatomic control first and foremost, because it is typically the earliest indicator of disease progression and future vision loss. Our goal is not to just suppress fluid, but also to maintain stable and consistent anatomic control over time, minimizing both the presence of fluid and its fluctuation, which had been associated with irreversible vision loss. This is where the SOL-1 data becomes extremely compelling.

We saw sustained and tighter fluid control with AXPAXLI through the week 36 primary endpoint and clear suppression from the aflibercept arm, which experienced significantly more accumulation of fluid. 55.9% of patients treated with AXPAXLI maintained central subfield thickness within 30 microns from baseline at week 36 compared to 37.8% of patients in the aflibercept arm. This reflects a 17.1% risk difference with a nominal p-value of 0.0013, which is highly significant.

This level of sustained anatomic stability reflects a degree of predictable and durable disease control that extends far beyond what we typically achieve with available therapies today. A therapy that can reliably maintain anatomic outcomes for 6 to 12 months for the majority of patients would represent a major paradigm shift from the current standard of care.

In addition, SOL-1 provides durability insights over an extended horizon of up to 12 months, something we simply do not have for any other pivotal program in wet AMD to date. Importantly, we now have this data in a population where vision loss is inevitable. Newly diagnosed patients randomized after showing strong response to aflibercept 2 mg.

Looking at the results, the week 24 rescue-free rate in SOL-1 stands out. 80.6% of AXPAXLI treated subjects were rescue-free based on the prespecified protocol definition of less than 15 letters loss from baseline or no new vision-threatening hemorrhage, which is not the typical clinical bar for rescues for retinal physicians. To put these findings in the context of real-world clinical practice, we can consider the rescue criteria used in ocular's ongoing non-inferiority trial, SOL-R.

The on protocol rescue criteria in SOL-R is a greater than 5-letter loss of vision combined with a central subfield thickness increase of more than 75 microns, criteria that closely mirror how retina specialists make retreatment decisions in the clinic. When those SOL-R rescue criteria are applied to the SOL-1 data set, the results continue to remain outstanding.

Even within SOL-1's population that was selected to lose vision, approximately 80% of AXPAXLI treated patients would still have remained rescue-free at 6 months under the SOL-R criteria. Looking to SOL-R, which is prospectively evaluating 6-month dosing in a population that is substantially more likely to be stable and easier to control, I expect rescue-free rates in the AXPAXLI arm to be even higher than what we have seen in SOL-1.

Taking these together, these findings provide a clear and clinically relevant bridge from SOL-1 to SOL-R and reinforce the potential for predictable fixed interval dosing with AXPAXLI in real-world practice. To summarize, as retina specialists, we often find ourselves negotiating treatment intervals with patients.

The treatment burden with current standard of care remains high and leads to poor long-term vision outcomes in real-world practice. This data from SOL-1 highlighting the durability, the consistency of anatomic control, the rescue-free rates and the safety profile makes AXPAXLI a potential agent that can offer patients a significant reduction in treatment burden while maintaining tight disease control.

I expect AXPAXLI would be adopted by retina specialists immediately if approved. To further explore what these findings may mean for SOL-R and to share additional perspective on what this means for potential real-world adoption, it is my pleasure to turn the call over to my colleague and a world-renowned retina expert, Dr. Darius Moshfeghi. Darius?

Thanks, Arshad. I echo your congratulations to the Ocular team. It's an honor to be here on a day that I believe has redefined what's possible for our patients with wet AMD. I was an independent rescue monitor for the SOL -1 trial, and the mandate was clear. Every decision was about ensuring patient safety and protocol adherence while building evidence to help many more patients in the future. In retrospect, that responsibility was facilitated by AXPAXLI's strong durability and well-tolerated safety profile.

When you think about it carefully, durability itself is a safety feature, particularly when measured in months. With any other anti-VEGF treatment, one missed visit can result in irreversible vision loss in the time period between 8 and 20 weeks. Due to other health issues, their own family concerns, transportation issues, loss to follow-up, this is a very common occurrence in these elderly patients, especially in a treatment extend paradigm.

AXPAXLI has the potential to provide a meaningful buffer between treatments out to 36 to 52 weeks, maintaining disease control longer and possibly keeping patients safer over time with the potential for better long-term visual outcomes. SOL-1 provides exceptionally strong evidence that AXPAXLI has the potential to stand in a class of its own, combining potent VEGF suppression with a level of visual gain durability that meaningfully resets expectations for disease control.

Because SOL-1 is a first-of-its-kind study, the secondary and exploratory endpoints will be closely analyzed. Importantly, SOL-1 does more than demonstrate superiority, which itself is an incredibly rare achievement in retina and wet AMD in particular. It also validates the underlying durability hypothesis for a fixed 6-month dosing paradigm, precisely what SOL-R is prospectively designed to confirm. Like Arshad, I'm struck by the finding that when SOL-R rescue criteria are applied to SOL -1, approximately 80% of AXPAXLI treated patients would have remained rescue-free through week 24.

This particularly stands out because in order to be randomized in SOL-1, patients needed to gain at least 10 letters of vision during the 8-week loading period or achieve 20/20 vision, meaning these patients have already shown peak response to 2 aflibercept 2 mg injections by the time they are randomized and therefore, are selected precisely because they're expected to lose vision from this point.

By contrast, SOL-R incorporates an extensive 6-month screening and loading phase, specifically designed to remove patients with high fluid fluctuations, resulting in a randomized population that is more stable and easier to control. In that setting, I would reasonably predict AXPAXLI's durability signals, including rescue-free rates to be even stronger. If approved, AXPAXLI is very well positioned for rapid adoption.

This agent delivers exactly what the data-driven retina community is looking for to alter their practice patterns, good safety, durable visual gain maintenance and fluid control, predictable dosing and a seamless integration into clinic workflow. From a clinician's perspective, this is the kind of data set that gives you confidence to rapidly integrate AXPAXLI, if approved into your wet AMD treatment regimen. Let me briefly walk through why. First, safety is king, and there were no safety concerns in this study.

Every single retina specialist will tell you that safety is at the forefront of everything we do. It remains the nonnegotiable foundation for adaptability of new treatments. We've all seen promising therapies fail in development due to serious inflammatory signals or other concerns that eventually complicate real-world adoption. As we can see from the data, the safety profiles between the 2 study arms in SOL-1 are nearly indistinguishable.

AXPAXLI was generally well tolerated in SOL-1 with no observed treatment-related ocular or systemic serious adverse events, SAEs. Importantly, more than 95% of patients reached the week 52 durability assessment, and we've not seen meaningful discontinuations following repeat dosing within that time period. This is unlikely to have been the case if there were any significant safety concerns. Second, AXPAXLI's durability as manifested by stabilization of vision gains observed in SOL-1 is truly transformative.

In the AXPAXLI arm, on protocol rescue-free rates were an incredible 80.6%, 74.7% and 68.8% at weeks 24, 36 and 52, respectively. These levels of visual gain durability at 6, 9 and 12 months with a single treatment immediately offers patients the potential for a more predictable dosing option, which should improve long-term visual improvement gains, reduce the risk of visual loss due to visual attrition and free up valuable clinical capacity.

Crucially, SOL-1 evaluated the durability of a single dose of AXPAXLI in a cadence-matched head-to-head fashion versus a single dose of aflibercept 2 mg, showing highly statistically significant differentiation and leaving little ambiguity about the durability of effect on vision maintenance. This stands in contrast to other recently approved agents and ongoing clinical trials where durability effects were inferred rather than directly tested under identical dosing conditions.

Third, durability alone is not enough. Dosing predictability over time matters. Clinicians adopt therapies based on predictable dosing and disease activity control across months. In SOL-1, approximately 80% of AXPAXLI patients would have maintained vision through 6 months using the SOL-R criteria as well as anatomic stability. And this anatomic stability continued out to week 52, where 44% of AXPAXLI treated patients maintained central subfield thickness within 30 microns of baseline.

That level of consistency is what can drive real and immediate changes to the treatment paradigm. Based on the SOL-1 data set, AXPAXLI has the potential to stand out as a best-in-disease treatment option, not just best-in-class. To my knowledge, AXPAXLI includes the most potent TKI studied in retina to date. It is highly unlikely that an agent with less potency or durability could have been as successful in a trial with the SOL -1 design.

Fourth, AXPAXLI will seamlessly fit into existing workflows. AXPAXLI, which is fully bioresorbable, requires no surgery, no concomitant steroid regimens and no new burdensome monitoring paradigm for remnant accumulation. If approved, it would fit seamlessly into existing practice patterns and over time, may even optimize practices as the field shifts towards fixed interval dosing.

Fifth and finally, superiority claims are scarce because they are difficult to achieve. A superiority claim resets the standard by which other agents will be assessed. It represents a durable point of differentiation and may help mitigate step edits that often constrain uptake of agents approved solely on the basis of non-inferiority.

Taken together, a good safety profile and the remarkable durability of visual maintenance observed with a single dose of AXPAXLI against aflibercept 2 mg in a head-to-head superiority trial demonstrated in SOL-1, combined with the consistent and predictable fluid control and potential for seamless workflow integration, AXPAXLI represents a rare and uniquely compelling combination.

AXPAXLI SOL-1 performance is exactly the type of product profile that I would expect to see rapid day 1 adoption, if approved. In my view, AXPAXLI represents the most consequential advance in wet AMD since the approval of the first anti-VEGF therapy over 20 years ago. Pravin, back to you.

Thank you, Darius and Arshad. Your perspectives carry tremendous weight within the retina community, and we are grateful for your thoughtful contributions today. From a clinical perspective, as you've heard from both Arshad and Darius, what matters most in the day-to-day retinal practice is consistent and sustained anatomic control. In SOL-1, AXPAXLI delivered exactly that, providing evidence of the predictability clinicians need to confidently extend treatment intervals.

From a strategic standpoint, the implications of SOL-1 are profound. Historically, the wet AMD market has rewarded durability, even incremental improvements of 1 or 2 weeks. In SOL-1, AXPAXLI demonstrated durability that extended out to week 52 with an unprecedented two-thirds of subjects maintaining vision. Just as importantly, AXPAXLI is designed to fit seamlessly into current retinal practice dynamics, as Darius highlighted.

If approved with a superiority label, AXPAXLI could also bypass payer step edits, which have historically been a limitation on novel therapies in wet AMD. Taken together, these attributes support a likely therapy that is: one, immediately adaptable; two, potentially practice expanding at a time when the number of patients needing retinal care continues to expand. Retinal specialists could potentially see more patients less often, and three, highly aligned with payer incentives.

For patients and caregivers, this can mean improved quality of life with reduced treatment burden. For physicians, it means simplified logistics and fewer capacity constraints. For payers, it means potentially improved long-term outcomes and lower total cost of care driven by fewer patients going blind. Looking ahead, we believe the strength and statistical integrity of SOL-1 data provide a clear path toward regulatory submission.

Consistent with recent FDA commentary, we believe SOL-1 represents exactly the type of single, well-controlled FDA-aligned registrational trial that can support an NDA filing. Accordingly, we plan to hold formal discussions with the FDA and pursue approval through the accelerated 505(b)(2) pathway thereafter. If approved, AXPAXLI could become the first TKI to reach the retinal market and the only therapy in wet AMD with a superiority label compared to an anti-VEGF agent.

This possible accelerated NDA strategy does not alter our ongoing SOL-R non-inferiority trial, which completed randomization in December 2025 and is expected to have topline data in the first quarter of 2027. SOL-R remains an important component of our global regulatory and commercial strategy. And today's SOL-1 results only strengthen our confidence in its outcome.

In closing, let me briefly recap today's significance. SOL-1 provides robust evidence that AXPAXLI is an active, durable and well-tolerated product candidate, delivering consistent visual and anatomic disease control in a population that is inherently difficult to manage. AXPAXLI is the first and only novel agent to demonstrate statistical superiority to an anti-VEGF in a Phase III FDA-aligned trial in wet AMD, clearing a bar that has alluded the field for more than 2 decades.

The clinical relevance of these data is underscored by robust secondary outcomes, including sustained anatomic control with 55.9% of AXPAXLI subjects maintaining CSFT within 30 microns at week 36 and 44.1% at week 52. AXPAXLI demonstrated exceptional durability in SOL-1 with 74.1% of AXPAXLI patients maintaining vision through week 36 and 65.9% through week 52, supporting the potential for extended dosing intervals of up to 12 months.

AXPAXLI was generally well tolerated with no observed treatment-related ocular or systemic serious adverse events providing high confidence for real-world adoption. SOL -1 should provide a clear and clinically intuitive read-through to SOL-R, which is designed to confirm non-inferiority in a fixed 6-month dosing interval in a population that is likely to be more stable and easier to control.

Applying the SOL-R rescue criteria to SOL-1, 77.1% of AXPAXLI patients would have remained rescue-free at week 24, and we expect this number will be even higher in SOL-R. Based on the strength and integrity of the SOL -1 data set, we intend to submit an NDA subject to planned formal discussions with the FDA, positioning AXPAXLI to potentially become the first TKI in retina and the only therapy in wet AMD with a superiority label compared to an anti-VEGF agent.

Together, these elements define how we intend to redefine the retina experience, anchored by a robust patent estate extending into 2044 and providing the foundation for disciplined life cycle investment, long-term differentiation and sustained value creation. We look forward to our first clinical data presentation of the SOL -1 data set at the upcoming Macula Society meeting.

Before we move to the Q&A portion of the call, I want to sincerely thank the investigators, the patients and their families who made this study possible and the Ocular team whose relentless commitment carried us to this moment. I'd also like to take a moment to provide an update on Donald Notman, our CFO and COO. As I know several of you reached out after we announced his temporary medical leave of absence.

Donald is doing very well. He does not yet have a specific timetable to return, but we expect he will be back at some point soon. I think you'll all join me in wishing Donald the very best. Today's results mark a defining moment for Ocular and for the retina field. And we're energized by the opportunity to build the future of retinal care from here. Operator, can you now open the call for questions?

[Operator Instructions] So our first question comes from Biren Amin at Piper Sandler.

Congrats on the data. I wanted to ask regarding read-throughs to SOL-R given the data set that you presented today, what do you think the data set tells you regarding achieving non-inferiority on BCVA versus EYLEA 2 mg every 8 weeks?

And then second question relates to the aflibercept arm and SOL arm. Just your thoughts on the outperformance of the rescue-free rate and also lack of significant letter changes in the control arm? And what do you think led to those results given aflibercept PK level should be minimal at week 36.

Thank you for the thoughtful questions. We're really fortunate to have both Arshad and Darius here. So we'll take advantage of them and let them do most of the talking instead of me. Arshad, why don't you go ahead and take that first?

Thank you, Pravin, and good morning, everybody. So Biren, the first question was about translation from SOL-1 to SOL-R. As you're aware, SOL-R has a long-running phase and patients who have any fluctuations or fluid accumulation are excluded. So we are looking forward to -- we've enrolled the patients who actually have very controlled disease. And in SOL-1, obviously, we had a population that was much higher need than SOL-R.

So looking at, obviously, the rescue free criteria that we applied to SOL-1 data set, approximately 80% of patients were rescue-free would be in the SOL-R study using the SOL-R criteria based on SOL-1 data. So I'm highly confident that because the patient population is less high need, I think we'll be able to show non-inferiority potentially in SOL-R.

Remember, when you're looking at a large heterogeneous patient population, patients who drive vision down are the high, high need patients, and we don't have those patients in SOL-R. In terms of the control arm in SOL -1 and when you look at the rescue-free subjects at 9 months with vision and anatomy, I think we need to keep in mind that a lot more patients in the aflibercept 2 mg group got rescued. The rescue-free rate in AXPAXLI was 74.7% and aflibercept was 56.4%.

So when you look at these patients, what happens is that the patients who are moderate or high need were already rescued. So as I said, it's a heterogeneous disease. And in this disease, patients will need treatments if they have fluid accumulation. So I think the control arm is a subset where we have never studied this before. But I'm not surprised that there are some patients in the aflibercept group that went a long time without needing any treatment from my perspective. Pravin?

Thank you. Thank you, Arshad. Darius, let me give it over to you, and maybe you can answer those questions as well from your perspective.

Yes. Thank you, both Pravin and Biren. These are 2 different trials. SOL-1 really focused on strong responders to visual acuity -- to anti-VEGF with good visual acuity and a proven fluid response. Whereas in SOL-R, it's a highly selective population with less vision and greater CSFT variability. When we look at it, we see from the SOL-1 subset that about 77% of the patients would have maintained a treatment-free interval at 6 months.

And when you go into that more refined population of SOL-R, I actually think we're going to actually have much better results in that population. Going to your second question, why did the control arm do so well? I mean it's really remarkable that the control arm did that well, much better than anyone expected. And yet AXPAXLI still beat a superiority outcome.

This is pretty much the hardest thing to do in retina is hit superiority in wet AMD, particularly when your comparator brings their A game and AXPAXLI did it. You brought up the PK values. We know that fluid substantially leads visual acuity loss. And so we have not ever had a data or any other trial that has showed this sort of approach where you give a single dose and see how long it lasts.

What we're learning here is that impact can last a while. These were treatment-naive patients. They could only get in if they got up to 20/20 or gain 10 letters. Frankly, this is the first data that we have on patients who had 3 injections and then were followed for either vision loss or vision-threatening macular hemorrhages.

So while we may have anticipated that the aflibercept arm would have done worse, it shows how long it actually takes to lose 15 letters after a loading regimen, and it's a testament to the strength and durability of AXPAXLI that it was still able to maintain a superiority outcome against aflibercept when it's doing much better than anticipated.

Darius, thank you. And Biren, just my two cents on the control arm. So let me just give that to you because it's a very -- it's a question that I'm sure is on everybody's mind. There are a couple of things that I've learned from this. The first thing that has taught me, and again, I realize that this has never been looked at before in any other study.

The first thing that it taught me is how long it takes from a loss of the drug effect to OCT fluid accumulation to vision loss and not just any vision loss, vision loss of 15 letters or 3 lines. That's a lot of vision loss. It takes a very long time. This is consistent with the fact that in all the earlier clinically relevant parameters, most importantly, the OCT, AXPAXLI clearly beat EYLEA in every single one of them consistently.

So what's the relevance of this? Well, as Darius mentioned, the bar for superiority is extraordinarily high, and we managed to hit it. Nobody else has for almost a quarter century. What that means also is that if we're fortunate enough to be approved with a superiority label, we will not only be in a different orbit but we'll be completely protected. I think it's very unlikely that anybody will dare do a superiority trial seeing what they saw today.

So again, we'll be in a great position if we're fortunate enough to be approved with a superiority label. Again, a different orbit and completely protected. The other part that I have to add is, look, this discussion regarding the control arm is a purely academic exercise. It has absolutely no practical or clinical relevance whatsoever. I don't think there's any clinician that's going to look at the SOL-1 data and say, now after 2 decades, I'm going to completely change the way I use EYLEA.

I don't think anybody is going to go out there and say, starting tomorrow, I'm going to give 3 shots of EYLEA and wait for the patient to lose 15 letters of vision. So it is an academic exercise. It really has absolutely no clinical relevance whatsoever. And as Darius said, despite all of this, the bottom line is that AXPAXLI beat the EYLEA arm in every single clinically relevant parameter. And that's really the most important point.

The data are incredibly convincing. They're absolutely, absolutely consistent. And AXPAXLI achieved what no other drug has ever achieved in a quarter century. It's superior to an anti-VEGF. The reason that this is a historic day is not only do we have a drug, but we have a drug that's potentially better than the anti-VEGFs, and that really -- that's the bottom line. Back to you. Thank you, Biren.

Great. Thank you for the questions, Biren. So our next question comes from Tara Bancroft at TD Cowen.

Congrats on the success of the trial. It's certainly no small feat. And I also -- I really want to extend my well wishes to Donald. We miss him. So I guess my question is, I'm wondering if you could give us some more context for how the vision and the CST curves compared in the overall ITT population, including those who are rescued and if those ITT curves will be shown at Macula or other future conference.

Tara, thank you for the question. And again, I'm very, very happy to tell you that Donald is doing very well, and we also miss him a lot. As far as the Macula Society presentation goes, what I would tell you is, look, we're still putting all the data together. We certainly will have more data at the Macula Society presentation. We look forward to showing all the data as soon as we can, but it does take a little bit of time, and the team is working diligently on that.

But your questions regarding what we see, particularly in patients who are rescue-free in both arms are very relevant, and thank you for that. So let me pass it on to Arshad first. Arshad, what are your impressions of the question that Tara had in regard to what you've seen so far with the visual acuity results as well as the OCT results?

Thanks, Pravin. I think that's a very clinically relevant question because patients in clinical practice, we are not allowing them to lose 15 letters. We want to control fluid, as I said. So I think when you look at vision, vision appears to be maintained in majority of the patients and majority of the patients, 74.7% at 9 months are rescue-free. But I think clinicians treat patients based on anatomy. And when you look at the anatomy, you see very large separation between AXPAXLI and aflibercept.

And again, as I said earlier, 74.7% of patients treated with AXPAXLI are rescue-free and only 56.4% of patients with aflibercept. So when we look at patients, I can predictably say that majority of the patients will have good anatomic control that's sustained and durable. And this is a drug that can easily go 9 months, if not 12 months. And I think looking at the CST fluctuation or CSFT change within 30 microns is super crucial for the retina community. 55.9% of patients in the AXPAXLI arm at week 36 maintain CSFT within 30 microns.

And we know that CSFT fluctuations 50 microns or more lead to irreversible vision loss over time. So we have a drug here that can actually have sustained disease control over a period of 9 to 12 months. And that number for week 52 was 44.1%. So as a clinician, the most important data set, obviously, from today in terms of efficacy is the sustained anatomic control that we are seeing from AXPAXLI, which obviously is going to be very meaningful for our patients in clinical practice.

And Darius to you with Tara's question or maybe a slight modification of that, which is really -- maybe I can ask more directly, which is given everything that you've seen, given the data that we've managed to put together so far, maybe you can talk a little bit about the adaptability of this drug in your practice?

Thank you. I'll try to address all of that, Pravin and Tara. We view these results from the perspective of maintenance of visual acuity, the less than 15 letters lost from baseline. However, our subjects are viewing it differently. They gained 10 letters and then held on to 7 letters at week 36. From their perspective, our subjects in this trial gained vision. It's like I gave you $10 and sent you off for 9 months, and you came back with $7. Are you ahead or you're behind?

From our subjects' perspective and your perspective, you're ahead. And based on that, I think this is going to lead to rapid adoption in our clinics because why wouldn't you give your patients all the opportunity to be ahead regardless of when it kicks in. When I look at those curves on visual preservation over time, I see that we really see it going kind of plateauing for the AXPAXLI arm at around 12 weeks.

We don't really see the plateau on the aflibercept until around 24 weeks. I want to get and lock in my patient's visual acuity as fast as possible, and that's why I would convert my patients to AXPAXLI if this was adopted. Since it's doing something we're already doing, which is an intravitreal injection, it would be seamlessly integrated into my clinic.

And as both Arshad and Pravin have pointed out, we're really locking in our CSFT control with 55% within 30 microns of their baseline CSFT out at 36 weeks. So overall, visual preservation and CSFT control is giving us a very predictable option and driving more and more of us towards a fixed dosing sort of world where we could be looking at 6, 9 and potentially 12 months dosing.

Thank you, Darius. And I agree with you. I think from my perspective, to show evidence of disease control, that stability of CST within 30 microns at 36 weeks is really the most objective and the most impressive. Operator, maybe one last final question. I know we're up against the clock, but maybe one more question, and then I will cut it off. But please go ahead.

Great. Sounds good. And our final question comes from Tazeen Ahmad at Bank of America.

Thanks for all the details that you provided on the study. I wanted to ask just in general, a couple of questions. For a physician, just based on the data that's been presented so far from SOL-1, what additional color do you think at all they would need from SOL-R in order to make this a meaningful part of their practice in terms of prescriptions to patients?

And then just in general on safety, it was good to see no serious side effects. I wanted to maybe follow up on, I guess, numerically slightly higher incident of cataract seen in the study and get your opinion on if that's clinically meaningful.

Thank you for your question. Arshad, maybe I'll start with you in terms of the questions that Tazeen asked.

So I think the question about what are we looking for SOL-R is we are dosing patients every 6 months. So I think establishing efficacy as well as safety of every 6 months dosing, obviously, will be the goal. Efficacy, we have obviously seen that this drug can go 6, 9 or 12 months in majority of the patients. So I think it will be for the label mainly to get that 6 months dosing. As you know, in the first year, patients only received 1 AXPAXLI injection in SOL-1.

When I look at adverse event profile, it's important for me to point out a few things. Things I'm looking for is intraocular inflammation, #1, which is the reason many potent drugs have failed to be commercially utilized significantly. And that rate is less than 2%. I'm looking at any cases of retinal vasculitis or occlusive retinal vasculitis or endophthalmitis.

And none of those cases are reported in this trial in the data set. In terms of cataracts, this is an elderly patient population, and the numbers actually are very low. So I'm not surprised that there's a few patients here and there in terms of the difference, but I don't think that's meaningfully different. But obviously, we'll look at the data in more detail as it's available.

So bottom line, at this point, I'm not concerned about anything in the safety. The safety looks clean. And I think this is the biggest reason that physicians will adopt this product quickly and broadly because it appears to be comparable in safety while bringing superiority tight fluid control and protection of our patients in terms of vision by having sustained disease control over time.

Thanks, Arshad. And Darius, a final word to you. You emphasized in the opening the importance of safety and maybe your impressions on the safety profile for AXPAXLI.

Pravin, you're stealing my thunder once again. Tazeen, thank you for your questions. As I noted in my first comment, safety is king. And I was along with Barry and Kal, the rescue monitors for this. And so we saw most things that came across regarding visual acuity change and/or vision-threatening macular hemorrhage, and we had no safety concerns whatsoever in this trial.

From a visual acuity maintenance perspective and then from the durability perspective, I need no other data to rapidly offer this if it's approved to all of my wet AMD patients. The first thing it does for me is it introduces dosing predictability. As a fixed dosing adherent for the last 20 years, the ability to predictably dose now between 9 and 12 months is transformative for both my patients and my clinic.

And second, it introduces peace of mind. If my patient misses a visit, becomes ill or incapacitated or they have to take care of their family members or simply want to travel more, they don't have to worry about the trade-off of missing a visit versus dealing with life's complexities. AXPAXLI is a smoothing function for visual acuity maintenance.

Again, regarding the cataracts, I agree with what's been said already, which is this. It's an elderly patient population. Nothing was deemed treatment-related or procedure related. And so overall, this is a very transformative drug for our patient population. And if it gets approved, I believe it will be rapidly adopted.

Thank you, Darius. Operator, back to you, and thank you, Tazeen, for the question.

Great. Yes. Thank you, Tazeen. So this concludes our Q&A session today. Pravin, I'll turn it back over to you for closing remarks. Thank you.

Thank you. Before we conclude, I want to reiterate how excited and encouraged we are at the SOL-1 results discussed today. This was a landmark study, and the success is a direct reflection of the extraordinary commitment of the patients who participated, the investigators who executed the trial with rigor and care and the entire Ocular Therapeutix team who brought this program to life, I am deeply, deeply grateful to all of them.

We look forward to sharing more exciting details from the SOL-1 data set at the upcoming 49th Macular Society Annual Meeting next week. Thank you all for your time today, your thoughtful questions and for joining us in what is a defining day for Ocular and the future of wet AMD care. Have a great day, everyone, and thank you.

Good morning, and welcome to the Ocular Therapeutix Third Quarter 2025 Earnings Conference Call. [Operator Instructions] As a reminder, this conference is being recorded and will be available for replay on the Investor Relations section of the Ocular Therapeutix website.

I would now like to turn the call over to Ocular's Vice President of Investor Relations, Bill Slattery, Jr. Please go ahead, Mr. Slattery.

Good morning, everyone, and thank you for joining us today. Earlier this morning, we issued a press release and filed our quarterly report on Form 10-Q, outlining our financial results and business updates for the third quarter of 2025, along with several updates to our registrational programs for AXPAXLI, also referred to as OTX-TKI in wet AMD and non-proliferative diabetic retinopathy.

Ocular's Executive Chairman, President and CEO, Dr. Pravin Dugel, will summarize recent business highlights before we move to our question-and-answer session. Joining Dr. Dugle for the Q&A portion of the call will be Donald Notman, Chief Financial Officer and Chief Operating Officer; Sanjay Nayak, Chief Strategy Officer; and Steve Meyers, Chief Commercial Officer.

We refer everyone to this morning's press release and our Form 10-Q for a comprehensive update of third quarter 2025 financial and business results.

During today's call, certain statements we will be making constitute forward-looking statements under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially as a result of a variety of factors, including risks and uncertainties identified in the Risk Factors section of our annual report on Form 10-K and our other SEC filings.

With that, I'd like to hand the call over to Dr. Pravin Dugel to review our recent updates. Pravin?

Good morning, everyone, and thank you for joining us today. At Ocular Therapeutix, we are courageous, bold and opportunistic. We make decisions from a position of confidence. We refuse to accept the status quo, not in how we develop drugs, not in how we design trials, and not in how we think about the retina market. Our purpose is clear: To redefine the retina experience for patients, physicians and payers around the world.

2025 has been a transformative year for Ocular Therapeutix. We've advanced 2 registrational studies in wet AMD, SOL-1 and SOL-R, each designed to answer distinct clinically relevant questions. As our momentum continues, we are thrilled to announce today that SOL-R has reached its target randomization of 555 subjects, an important milestone that reflects exceptional execution and strong investigator enthusiasm for AXPAXLI. In addition to SOL-1 and SOL-R, we designed a long-term extension trial, SOL-X, which goes well beyond simply providing long-term safety data and may provide further evidence that AXPAXLI treatment should be started early to obtain the greatest visual benefits.

Equally important, we've unveiled our registrational HELIOS program in diabetic retinopathy, which we believe represents the next frontier in our mission to deliver long-lasting, clinically impactful and genuinely sustainable therapies for retinal diseases. This is a bold initiative to pursue a single broad superiority label that captures the entire spectrum of diabetic retinal disease, including non-proliferative diabetic retinopathy, NPDR and diabetic macular edema, DME. With 2 complementary strategically designed studies, HELIOS-2 and HELIOS-3, we intend to address both populations within a one unified program. If the HELIOS trials are successful, we expect that we would not need any additional studies to market AXPAXLI for use across the spectrum of diabetic retinal disease.

At our recent Investor Day, I described how Ocular is now positioned to redefine this field through a strategic triad: #1, the potential for a superiority label that may set AXPAXLI apart from all other anti-VEGFs in both wet AMD and diabetic retinal disease; #2, expanding the market to potentially capture the vast untapped opportunity across wet AMD and diabetic retinal disease; and #3, potential for immediate adoptability made possible by a product profile that seamlessly integrates into today's retina practice. Today, I'd like to elaborate on each of these pillars, how they define our strategy, guide our execution, and position Ocular to lead a potential generational shift in retinal therapy.

Let's start with superiority. To date, no approved therapy in wet AMD has demonstrated superiority to an anti-VEGF. Each successive entry has only been incrementally longer lasting. This has led to an increasingly commoditized landscape, a market where differentiation has eroded and pricing pressures have intensified. More recently, biosimilars have turned what was once a breakthrough in the field into one defined by step therapy restrictions and rapid discounting that encourages a pricing race to the bottom. We believe AXPAXLI has the potential to break this cycle.

SOL-1, our Phase III superiority trial in wet AMD was designed under a SPA agreement with the FDA and remains on track for top line data in the first quarter of 2026. If successful, we expect AXPAXLI could be the first and only therapy with a superiority label compared to a single dose of anti-VEGF. This superiority label extends beyond wet AMD and now includes diabetic retinopathy, where we will initiate two superiority trials, HELIOS-2 and HELIOS-3.

Achieving a superiority label would put us in a category of one. Why does this matter? Because a superiority label not only defines a clinically differentiated asset but it also fundamentally changes market dynamics. It can potentially insulate us from the pricing compression and formulary step therapy that plague ME-2 agents. When a product demonstrates superiority and is approved by the FDA, it can become a premium drug chosen first by the physician, not forced to be a later line option by the payer. We believe this is the holy grail of retina, superior outcomes, improved durability and a pricing model that rewards innovation. We are proud that both SOL-1 and HELIOS-2 in wet AMD and NPDR, respectively, are designed under formal FDA agreements and anchored in superiority endpoints. These are not marketing terms. They have substantive statistical meaning, as agreed by a regulatory body, giving us a path to pursuing claims that no other company currently possesses.

The second pillar of our triad is market expansion. Today, the global annual anti-VEGF market is estimated at roughly $15 billion. That figure tells only a fraction of the story. It reflects patients who are currently treated, not those who should be. In wet AMD, up to 40% of patients discontinue therapy within just the first year, often due to the burden of monthly or bimonthly injections. In diabetic retinopathy, the situation is even more staggering. Fewer than 1% of the 6.4 million NPDR patients in the U.S. received treatment, even though anti-VEGF drugs have been shown to work in this indication. The gap between what's possible and what's practiced represents what we believe is the largest expansion opportunity in retinal medicine.

Our goal with AXPAXLI is not simply to compete for share within today's treated population but also to expand that population by reducing burden, increasing adherence and improving long-term outcomes. We believe we can achieve this through three key drivers. First, durability. AXPAXLI is designed to deliver sustained suppression of VEGF for up to 12 months following a single injection. This could allow physicians to see their patients less often while maintaining disease control. Second, flexibility. The ability to tailor dosing intervals between 6 and 12 months, providing real-world adaptability across diverse heterogeneous patient needs. Third, confidence. Data from both SOL and HELIOS programs, combined with FDA-aligned trial designs and our planned long-term open-label extension in wet AMD may provide the evidence base physicians and the payers need to support early consistent use. Even modest improvements in adherence could translate into hundreds of thousands of additional patients retaining vision, and a market opportunity significantly larger than what is measured today.

At our Investor Day, we showed analysis demonstrating how we plan to move the current treatment discontinuation spiral towards a treatment retention cycle with AXPAXLI in wet AMD. Expanding treatment into diabetic retinal disease accelerates that market expansion even further. This includes NPDR, a disease 3x as prevalent as wet AMD with no standard of care in use today and DME. This is not hypothetical incremental growth; this is redefining the market.

The third pillar of our triad is the potential for immediate adaptability. When we talk to retina specialists, one theme is clear, workflow matters. They want innovations that improve outcomes without requiring alterations to practice dynamics. AXPAXLI was designed precisely with that in mind. It requires no surgery. There is no need for concomitant steroids, and we believe no additional monitoring is needed. AXPAXLI will be administered by retina specialists who are familiar with intravitreal injections and perform these tasks every day with EYLEA, VABYSMO, or Lucentis. The experience itself will also be familiar. We are conducting all our registrational trials and expect to launch with a prefilled injector, just like the prefilled syringes used with most commercial anti-VEGF injections today. Moreover, the single hydrogel is designed to be fully bioresorbable, intended to leave no remnants behind without active drug. The procedure and the post-injection experience are similar to current anti-VEGF injections, except that AXPAXLI could last up to 12 months. This makes AXPAXLI not just innovative but also easily adaptable. Patients may benefit from fewer visits and longer durability. Physicians benefit from a potentially better drug with the same workflow and payers benefit from reduced utilization, predictability, fewer patient dropouts, and potentially better long-term outcomes.

AXPAXLI can allow retina specialists to see more patients less frequently. It can enable a more predictable schedule for patients. And even if patients need to reschedule a visit, there should be enough drug on board to cover them until they can get in to see their physician. Ultimately, AXPAXLI may help alleviate the burden that often leads to treatment discontinuations or problems with adherence. The bottom line is that we believe AXPAXLI can simplify, optimize and even scale modern retinal practices. And importantly, this view isn't just ours. It is shared by the stakeholders who matter most when it comes to patient access and value.

Over the past several months, we've spent significant time engaging with payers representing more than 75% of U.S. commercial lives and over 25% of Medicare Advantage lives to walk them through our clinical strategy, study designs and endpoints. We have been extraordinarily pleased with the feedback we have gotten from these conversations.

On superiority, one payer described the potential of a product with AXPAXLI's expected durability as game-changing while another noted that it could be clinically preferred ahead of the entire anti-VEGF class. On market expansion, one comment captured it best; avoiding blindness is invaluable and less costly. And on adaptability, another payer noted, there is value in consistent, sustained and uninterrupted therapy. These conversations affirm what we already believe. Payers can see the potential of a product with AXPAXLI's target profile to deliver meaningful clinical differentiation, expand access, and redefine value in retina by improving outcomes while potentially reducing the overall burden of care.

Turning to our SOL registrational program for AXPAXLI in wet AMD. Our success to date is built on outstanding execution. In SOL-1, I could not be more pleased with how the study is running, including retention, trial conduct, and safety monitoring. As it relates to retention to date, more than 95% of patients remain on study. That's almost every participant staying engaged over the course of the study, which is unheard of for retina trials.

As it relates to rescues, to date, per our mask review, over 95% of rescue events have met the prespecified protocol-defined criteria. Let me repeat that. Over 95% of all rescue events have occurred exactly as designed. That level of compliance under masking is exceptional. Simply put, patients are staying in the trial and physicians are waiting until patients meet the predefined thresholds before administering rescue treatment in the vast majority of cases. This speaks to the discipline of our sites and the clarity of our protocol, which is likely to yield a robust data set when we receive top line data in the first quarter of 2026. These details matter. Protocol adherence ensures that when we unmask data, we will be looking at a clean, reliable data set that can withstand the highest level of regulatory scrutiny. Just as importantly, the SOL-1 trial is washed over by an independent data safety monitoring committee, and there have been no safety signals to date. This is also worth repeating clearly, there have been no safety signals to date as observed by an independent data safety monitoring committee.

SOL-R continues to progress in parallel with its 6-month screening and loading phase, serving as an innovative patient enrichment strategy designed to derisk the study population. SOL-R is the first trial of its kind to include an extensive 6-month screening and loading phase, specifically designed to exclude patients with early persistent fluid or significant retinal fluid fluctuations, which can otherwise introduce variability and disrupt non-inferiority trials. I am thrilled to share this morning that SOL-R has now reached its target randomization of 555 subjects. This marks yet another significant milestone for Ocular and reflects the remarkable speed and execution of our clinical team, along with the overwhelming enthusiasm and engagement from investigators across the world. The exceptional pace and scale of recruitment across the SOL program underscore the strong demand among retina specialists and patients for more durable therapies like AXPAXLI that can potentially deliver better long-term outcomes while reducing the treatment burden. To maintain our commitment to both patients and investigators, we will continue to allow randomization of previously enrolled subjects currently in the loading phase of the trial. We continue to expect top line data for SOL-R in the first half of 2027, and we will refine our guidance at the appropriate time.

Taken together, the SOL program has been designed to generate a comprehensive efficacy and safety package that addresses the most important questions retina specialists will have, giving them the confidence to use AXPAXLI immediately upon launch if approved. After subjects have completed 2-year follow-up in either SOL-1 or SOL-R, they will have an opportunity to enroll in our SOL-X study for additional 3 years. In this open-label extension, all enrolled subjects will transition to every 6-month treatment with AXPAXLI. To be clear, this study is a strategic initiative, not a regulatory requirement. We believe SOL-X could generate valuable insights into the potential long-term benefits of using a non-pulsatile treatment like AXPAXLI, in addition to providing long-term safety data. The study is designed to assess key outcomes, such as vision preservation, antifibrotic activity and most importantly, the potential consequences of delaying AXPAXLI treatment in the control arm patients. SOL-X outcomes may further expand AXPAXLI's potential by highlighting the need to start AXPAXLI treatment early or risk worse long-term visual outcomes. By reducing the treatment burden and potentially improving long-term outcomes, we believe the data from SOL-X could increase both short-term and long-term patient retention significantly.

Let's now turn to diabetic retinal disease, which we define as both diabetic retinopathy and DME or diabetic macular edema, where our innovation extends to how we think about trial design, endpoints and label strategy. Our HELIOS program represents a bold differentiated approach to this disease. We are pursuing a broad diabetic retinopathy label that also encompasses DME, a complication within the diabetic retinopathy continuum. We believe this strategy allows us to capture the full spectrum of diabetic eye disease with a single registrational program. The unmet need here is staggering. Diabetic eye disease affects more than 100 million people globally, yet the majority remain undertreated. Even among NPDR patients without DME, disease progression leads to irreversible vision loss if left unmanaged. Current treatment paradigms are largely reactive, waiting until vision-threatening complications occur prior to intervention. We believe that must change. Our HELIOS-2 and HELIOS-3 Phase III trials are designed as superiority studies to demonstrate that early infrequent treatment with AXPAXLI can meaningfully alter the course of disease. HELIOS-2 is being conducted under a SPA agreement with the FDA, underscoring our continued commitment to regulatory alignment and scientific rigor. Together, these 2 trials will evaluate 6 and 12-month dosing intervals, providing flexibility to address diverse patient needs.

A key innovation in these studies is our primary endpoint, an ordinal 2-step DRSS endpoint at week 52. Historically, Phase III DR trials have relied on binary diabetic retinopathy severity score or DRSS endpoints, counting only the percentage of patients who achieve a greater than or equal to 2-step improvement, or those who achieve a greater than or equal to 2-step worsening, not both. While straightforward, this method discards valuable clinically relevant data. Our ordinal analysis by contrast captures the entire spectrum of patient responses: improvement, stability, and worsening, allowing every participant to contribute data to the statistical analysis. This approach offers several distinct advantages. It reflects real-world treatment goals to both improve disease and prevent worsening. It increases statistical powering, allowing more efficient studies with a smaller sample size. It potentially provides a higher probability of success compared to other endpoints considered, and it aligns fully with FDA guidance as confirmed in our SPA for HELIOS-2. We evaluated other endpoints such as vision-threatening complications or VTCs, but those present major limitations. VTCs are binary and event-driven, which require much larger sample sizes and longer durations to reach statistical power. They also reflect late-stage disease progression rather than early therapeutic benefit.

In short, ordinal DRSS is not only more clinically relevant with a potentially higher probability of success but it is also agreed to with the FDA from a regulatory standpoint. It's the right endpoint to demonstrate AXPAXLI's disease-modifying potential in DR. Since announcing this endpoint at our Investor Day, the feedback from both investigators and the broader retina community has been outstanding. We believe this approach represents the future of diabetic retinopathy trial design, and we expect this ordinal endpoint will become the new gold standard for the field moving forward.

Unlike our wet AMD program, the HELIOS-3 trial employs sham injections and there are important regulatory reasons for that distinction. DR trials have very different regulatory requirements compared to the 2023 FDA draft guidance for wet AMD. Sham should not be used in wet AMD or even in center involving DME studies because they require subjective visual acuity primary endpoints where sham injections may not provide adequate masking and could influence outcomes. In DR, however, outcomes are based on objective retinal photographs, not subjective patient responses. Moreover, since there is no universal standard of care for NPDR, sham control is not only acceptable but necessary to ensure global regulatory alignment, particularly in countries without approved therapies for this population.

Finally, our design strategy enables us to pursue a single unified DR label that encompasses both NPDR and DME. Because DME is a complication affecting a subset of DR patients, all patients with DME inherently have underlying retinopathy. In HELIOS-2 and HELIOS-3, we plan to include patients with non-center involved DME. Subjects with non-center involved DME demonstrated improvement with AXPAXLI in our HELIOS Phase I study. We believe this approach eliminates the need for separate DME trials and may position us to address the full diabetic eye disease spectrum with a single registrational program. By focusing on a superiority-driven DR label that captures the entire continuum of disease, we believe AXPAXLI can unlock a market opportunity that is not just incremental but transformative for patients, physicians, and payers worldwide.

We ended the third quarter of 2025, with approximately $345 million in cash, which does not reflect approximately $445 million in net proceeds from our October equity financing. We were thrilled to see the enthusiasm for participation in our recent financing, validating the bold opportunistic decisions we have made to date. Every decision that is made in this company is made from a position of confidence in our drug, AXPAXLI, and in our clinical strategy, and in our market potential. Our confidence is compounded by consistently positive feedback we are hearing externally, including from payers who represent the vast majority of covered lives in the U.S. These discussions have reinforced the excitement we have seen from investors and further validated our triad-based strategy. These perspectives underscore that the market is already preparing for a future potentially defined by AXPAXLI, one where potentially better outcomes, lower burden and cost efficiency converge.

Following our recent financing, we are now in an enviable position with an expected cash runway into 2028, and the financial flexibility for top line data from both SOL and HELIOS registrational programs, advance SOL-X, our long-term extension trial, invest in manufacturing capacity and infrastructure, and prepare for commercial launch and global expansion in anticipation of a potential AXPAXLI approval. We are operating from a position of increased strength. Every capital decision we make is proactive, not reactive, made from conviction, not constraint.

When you put it all together, our science, our trial design, our execution and our strategic vision, the path forward is clear. We are building Ocular Therapeutix around the triad that defines how we intend to redefine the retina experience: potential superiority label, setting a new standard of durability that transcends incremental improvements, creating lasting competitive differentiation and potential insulation from pricing and step therapy pressures; market expansion, transforming a $15 billion treated market into a much larger addressable opportunity by reducing burden, improving adherence and reaching millions of untreated patients with wet AMD and DR; immediate adaptability, delivering a product that fits seamlessly into existing practice; no surgery, no concomitant steroids, no change in workflow, simply a better, longer-lasting treatment that aligns with how retina specialists already work. This Triad isn't a marketing pitch. It's the blueprint of how we intend to redefine retina, period.

To summarize today's key points: #1, SOL-1 remains on track for top line data in the first quarter of 2026, with exceptional retention and trial integrity, reaching statistical significance and SOL-1 has the potential to enable a superiority claim on the AXPAXLI label in wet AMD; #2, SOL-R has now reached its target randomization of 555 subjects and is rapidly progressing toward top line data in the first half of 2027, built on a real-world design with a derisking patient enrichment strategy; #3, our HELIOS program will initiate imminently, leveraging a novel ordinal endpoint established per the SPA agreement for HELIOS-2 with the FDA -- we believe this is the optimal endpoint that increases statistical power and provides us a greater probability of success compared to other endpoints; #4, we continue to pursue a broad diabetic retinal disease label, including DME that could significantly expand AXPAXLI's reach; #5, our financial strength gives us the flexibility to obtain top line data from each of our SOL-1, SOL-R and HELIOS programs, pursue our SOL-X open-label extension study and prepare for commercialization with confidence; #6, and finally, through the triad of superiority, market expansion and immediate adaptability, we're building a company positioned not just to participate in the retina market but to redefine it. At Ocular Therapeutix, we are bold in our science, courageous in our strategy, and relentless in our pursuit of excellence.

Thank you for your time and your continued support. Operator, we are now ready to take questions.

[Operator Instructions] Our first question comes from Tazeen Ahmed with Bank of America.

Thanks for the very detailed update. I maybe wanted to get a sense of how you're thinking the initial label for wet AMD could look like? Because you're doing a lot of work among SOL-1, SOL-R and SOL-X. So what would the initial label look like and what do you think would be attributes of the label that you would think would be competitive that may need to be added on later as more data comes in?

Thank you, Tazeen. Thanks for the question, a very appropriate great question. And I'll start out by saying, of course, we're not in labeling discussions with the FDA as yet. But you can see that this company has strategically placed the clinical trials in such a way as we get, we believe, the best label in the history of our field. We expect our label to be a superiority label based on SOL-1. We believe that we'll have the flexibility of dosing every 6 months to every 12 months based on SOL-R and SOL-1. And we'll also have flexibility, obviously, of repeat dosing. That's what we expect from the initial label. Again, we're not in discussions with the FDA, as you can imagine. However, the other thing also that I'd like to note is that although this will not be in the label, remember that in the masking arm of SOL-R, we are going up against high-dose EYLEA. So although the randomization is 2:2:1, and although this is not for statistical analysis, we certainly will have the numeric data. So we believe that we'll have a great competitive advantage versus the second generation of anti-VEGFs with high-dose EYLEA as well. Tazeen, thank you again for the question.

Our next question comes from Tara Bancroft with TD Cowen.

So my question is on NPDR. So one really quickly, for the expected patient populations in the HELIOS trials. Can you tell us what percentage of the enrolled that you would expect to have that are non-center involved DME? And then the real question is, if you could maybe describe in a little more detail for us, what is it that underlies your confidence in having a very broad DME inclusive label beyond only the non-center involved, especially compared to a different approach of running separate DME trials altogether? Because in that, I think it would be helpful if you could also discuss whether the inverse could be true that successful DME trials could be inclusive of NPDR at all or not?

Tara, thank you for the question. Great question again. So as far as the first question is concerned, really a quick answer. The fact of it is that we don't know. And when the time is appropriate, we certainly will guide you as to the stratification of our baseline patients that we have enrolled. In regards to the second question, the first thing to look at is the data from the HELIOS-1 study. Recall that with a single injection of AXPAXLI, a single injection at week 48, every single patient with non-center involving diabetic macular edema improved. Again, every single patient with diabetic macular edema improved with a single injection. We've looked at these patients in every which way that was presented in our Investor Day, including in terms of total volume, et cetera, et cetera. And Peter Kaiser showed you every single patient and every single patient with a single injection improved. On the other hand, every single patient who was not treated in the control group got worse. So we have great confidence based on the HELIOS-1 data that patients with non-center involving diabetic macular edema will improve.

Now again, we're not in labeling discussions, obviously, with the FDA. But what I can tell you is that historically, the FDA has given label based on the disease itself. If you recall in my last company with IVERIC Bio, we studied only patients with extrafoveal geographic atrophy. There wasn't a single patient that we studied with center-involving geographic atrophy. And yet, when you see the label of that drug you will see that it's a broad label encompassing all of geographic atrophy. The same can be said of previous studies for diabetic retinopathy such as PANORAMA. The same thing could be said for visual limitations in clinical trials that have not extended to the label, such as going all the way going back to ANCHOR and MARINA. So we have great confidence that we will have a broad label that will encompass all of diabetic eye disease and that we will not need to do another study for diabetic macular edema. Recall also that it doesn't work the other way around, because every single patient with diabetic macular edema will have diabetic retinopathy, but not every single patient with diabetic retinopathy will have diabetic macular edema.

So again, we have great confidence that we will never need to do another diabetic eye disease trial again for retina. We believe that we will obtain a broad label that will encompass not only diabetic retinopathy but all of diabetic macular edema. Thank you, Tara, for that question.

That's fantastic proxy to IVERIC.

Biren, are you there?

Can you guys hear me?

Yes, please go ahead with your question.

Maybe, Pravin, on the SOL-R study, could you just talk about what percentage of patients were randomized from the screening phase? And for SOL-X, I understand on the open-label extension, you're going to enroll patients from SOL-1. But are SOL-R patients also going to be eligible to participate in SOL-X?

Biren, thank you again and thanks for the question. So as far as SOL-R is concerned, recall that what we have is a very thoughtful and long ramp. Recall also that if you look at every single study that's ever been done with an anti-VEGF, whether it'd be Lucentis, EYLEA, Avastin, Beovu, anything. But what you see is a curve when you plot the visual acuity with a number of injection that looks identical, which is that after 2 injections, the visual acuity improves and then it stabilizes. Now what we could have done is simply to say after 2 or 3 injections, we'll go ahead and randomize patients in SOL-R, because we'll have a certain degree of confidence in regards to the stability. We didn't do that. We went way above and beyond. What we did was to say, okay, we will do 3 loading doses and we'll have a unique period, 2 observation periods, not 1 but 2, in order to weed out any patient who would be unstable with any fluctuations in the OCT of 35 microns or greater. And after that, we went ahead and give 2 more loading doses and only then do we randomize. So it's a very long ramp.

As far as the screen failures are concerned, Biren, that was your question, we haven't guided you to that as yet. We will when the time is appropriate in terms of giving you the baseline details. But as of yet, I'm just absolutely thrilled to report as we did this morning that we reached our target randomization of 555 patients. This is a credit not only to our clinical team, which has been just absolutely outstanding in terms of execution throughout this entire process with SOL-1 with SOL-R, and you'll see very soon with the HELIOS studies, but it's also a credit to the patients and to the PIs. And we're incredibly grateful to both that we've reached this point of target randomization.

In regards to the open-label study, both studies, SOL-1 and SOL-R will funnel patients into the open-label extension. Again, we will have a lot of data that we will have in that open-label extension. I think one of the most important things that we will have is what the crossover patients will do. Now remember, the crossover patients will cross over after 2 years of pulsatile therapy. We don't believe that those patients will ever catch up. And the reason for that is that we know that fibrosis can be detected as early as 90 days after pulsatile therapy. And we believe that with 2 years of pulsatile therapy that will limit the patient's vision improvement. And we will have data showing that for the best long-term outcomes, it is necessary to start AXPAXLI from the very beginning. We believe that data will be very important.

The other part related to this also is that in all studies, starting with the 7 UP study, for instance, long-term outcome has shown a gradual decline in visual acuity based on fibrosis and atrophy. And we believe that with constant suppression that AXPAXLI will provide, we will see continued visual acuity improvement and stabilization, which will also add to the long-term outcomes that will benefit from immediate treatment with AXPAXLI and continuation of AXPAXLI with long-term constant suppression of VEGF.

Thank you, Biren, for your question.

Our next question comes from Colleen Kusy with Baird.

Congrats on all the progress. Just as we're getting a little bit closer now to the SOL-1 data, just what details would you expect to share in the SOL-1 top line? Specifically, would you include 6-month BCVA? And what do you think will be the most important data points from SOL-1 that will help give us confidence in the read-through to SOL-R?

Colleen, thank you for your question. A great question, which I'm sure is on everybody's mind. Here's what I would say. Look, what we have done and what we have said is that we are very strategic in terms of planning these studies and our expectations of what the goal of these studies are. The sole purpose of SOL-1 is a superiority label, that's what we're pursuing. The purpose of SOL-R is clinical relevance. And the purpose of SOL-X is to provide long-term data to support both of these things.

We also recognize what the challenge of SOL-1 is. We've recognized the challenge there is to go ahead and show you data in our secondary and exploratory analyses that will give you even more confidence in the success of SOL-R. We understand that challenge. We will absolutely meet that challenge. We have not guided you as to what we will show you as yet, but we certainly understand what we need to do with the card turn in terms of the narrative of a positive SOL-1 study. But let me also say that while we will provide you even more confidence in the success of SOL-R there should already be a great deal of confidence that SOL-R will succeed based on several factors. First is the derisked patient randomization that I've already spoken to, which has really the longest ramp, the most thoughtful derisking that I've ever seen of any study. And the second one is pertaining to the trial design is the endpoint. It's a 56-week endpoint. It's a singular endpoint that we believe is absolutely optimal for us.

Again, it's a singular 56-week endpoint. But to summarize, Colleen, what I would say is we understand the challenge. We will absolutely meet the challenge. We will provide you even more confidence based on the SOL-1 card turn that there will be a positive SOL-R study. Thank you for the question.

Our next question comes from Sean McCutcheon with Raymond James.

Maybe a quick one for me. Can you speak to the progress of getting the NPDR studies up and running? I know you're using a similar site footprint to the wet AMD program? And how do you anticipate that accelerating those studies?

Sean, thank you for the question. Look, the process started immediately after the race for NPDR, and we are very fortunate that we have fantastic sites all over the world. You've seen the results of that based on the execution of SOL-1 and SOL-R. And yes, many of the same sites are being used. There're additional sites as well that we are very, very fortunate that we have people in this company, as you know, with an enormous amount of expertise. Many of the folks here have trained many of the people that run these sites and certainly know pretty much everybody around the world. So we're in an envious position of being able to strategically pick the very best sites. And you've seen that.

Again, look, it's easy to forget where we were, Sean, not long ago. We had a trial that everybody said was not recruitable. We recruited way ahead of schedule in record time. And then people said, well, even if you did recruit that trial, there's no way that, that -- the execution is going to be good. Doctors are going to do whatever they want, patients aren't going to stay. We've provided you data in our Investor Day and today, real numbers to show you how well the execution is taking place that 95 -- we have a 95% on protocol rate, over 95% on protocol rate and over a 95% retention rate. Those things are absolutely unheard of for any trial in retina, let alone a trial that supposedly was impossible to recruit. And oftentimes, we forget that. We forget the level of execution that this team has provided. And that's not only thanks to the clinical team but that's also thanks to the sites that they've selected and the personal relationship that all of the team has with not only the PI but the entire site. So the answer to your question is we will give you guidance to the HELIOS progression. We're very pleased with the way that it's going, and you'll hear more details to follow. Thank you, Sean, for the question.

Our next question comes from Jon Wolleben with Citizens JMP.

This is Catherine on for Jon. I just have another quick one for the DR program. I'm just wondering if there's any risks associated with using the ordinate 2-step DRSS endpoint, especially since you're considering using a smaller patient population. Is there any concerns regarding a higher placebo effect given kind of patient variability? I wonder if you could speak to that? And how do these risks compare to traditional endpoint?

Catherine, thank you for the question. It's a very appropriate and fair question, and it's something that we've looked into quite a bit. And what I can tell you without hesitation whatsoever is that we have great, great, great confidence with the ordinal endpoint. Now if you look at the talk that was given by Peter Kaiser in our Investor Day, you'll see that there're all kinds of scenarios that were put in, including the data that we have with the HELIOS-1 study. And as you can see, the level of success achieved by the data on the HELIOS study was overwhelming. So in this particular case, given the drug that we have and given the data that we have, we are very confident that with the ordinal endpoint that we will succeed.

Again, if you look back at the HELIOS-1 study, what I would say as a clinician who's practiced for over 30 years and also with all the other clinicians that we have in this company, is that we've really never seen a situation where a single injection of a drug, again, a single injection of a drug after week 48 has results where every single parameter is in favor of the drug. And remember, this was just the drug. This was not a combination of agent. EYLEA wasn't combined with this. This was simply AXPAXLI and nothing else, completely transparent. And what you will see there is not only in terms of the diabetic retinopathy score but also in terms of diabetic macular edema. And then we've looked at it in every single which way possible, including the total fluid volume, including perfusion and every single parameter favored the drug with a single injection after week 48. So we have great confidence in the endpoint, and we have great confidence in the success of both HELIOS-2 and HELIOS-3. And remember also that HELIOS-2 has an FDA-approved SPA going with it as well to validate that study and validate the study design. Again, I also want to repeat that both HELIOS-2 and HELIOS-3 are superiority studies. Catherine, again, thank you for the question.

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

For the HELIOS-2 trial, once started, how long do you think it will take to complete enrollment of 432 patients? Do you think NPDR patients would be relatively difficult to enroll because they are reluctant to get treatment in the first place?

Yi, thank you for your question. So we have already seen a great deal of inertia to enroll these patients. In fact, we saw that before we even announced the trials. As I was asked earlier on by Jon, whether we're using the same sites or not, I said, yes, there was a great deal of overlap, including other sites. The sites have already been demanding for this -- demanding the study. There is such a need out there for these patients. And remember, what we're enrolling is we're enrolling advanced severe -- moderate to severe -- advanced non-proliferative diabetic retinopathy. So a lot of these patients are symptomatic. They may not have lost vision but they certainly have blurry vision, et cetera. They certainly are knowledgeable that there are -- there's a threat to their vision. So there's a great deal of need out there and a great deal of enthusiasm to have something that is absolutely sustainable, both by both patients as well as the PIs. And this is completely sustainable. As you know, it's a single injection if it does what we expect it to do, that will last for a year. This is -- we know that this is a target that's derisked, that's validated in other studies. So we believe that this is a relatively derisked study. And especially given what I just said about HELIOS-1, we're very, very confident in the results. So to answer your question, we don't think that there's going to be any issue whatsoever in completing these trials in a very efficient manner. This is already underway and we will guide you when appropriate. Again, thank you, Yi, for the question.

We've reached the end of our question-and-answer session. There are no further questions at this time. I would now like to turn the floor back over to Dr. Dugel for closing comments.

Thank you very much. I'd like to thank all of you for your time today. I'd like to thank all of you for your diligence and for joining us. We look forward to updating you on our progress. If you have any follow-up questions whatsoever, please reach out to Bill Slattery, our Vice President of Investor Relations, and have a great day, everybody, and thank you again for your time.

This concludes today's teleconference. You may disconnect your lines at this time. Thank you for your participation.

All right. We're going to go ahead and get started. Thank you all for joining us today. We appreciate your interest in ocular and look forward to sharing the story with you. Before I pass the mic to Pravin, please note that during today's presentation, we will be making forward-looking statements under the Private Securities Litigation Reform Act of 1995.

These statements are subject to a number of risks and uncertainties that could cause actual results to differ materially. Such risks and uncertainties are detailed in the Risk Factors section of our annual report on Form 10-K and other filings with the SEC.

With that, it is my pleasure to introduce Dr. Pravin Dugel, Ocular's Executive Chairman, President and CEO.

Thanks, Bill, and welcome. Welcome to all of you. It's an exciting day for us. You'll have -- you'll see that we have a very robust and informative Investor Day, and we've got great speakers, panelists, et cetera. The last time we had one of these, it was right here in this room, and it was -- I think it was June 14 of last year. And if you think about where we were then, and think about where we are now, it's pretty incredible.

There are not a lot of companies that I think change as much as they have, as much as we have in that short period of time. I think of this company as having gone through 3 different kind of phases. When we last met here last year, we were sort of in the culture building phase. We had recruited the best of the best of the best in every single department. And the question was, could we build a culture, first and foremost, to make them happy, so that they can go out there and say, you know what, this is the happiest place I've ever worked in, right? That was essential.

And the second thing was, could we build a culture to make them productive? And I think we've checked that box and proven to you that, yes, we can and yes, we did. And then after we left, we left saying, now we have to execute. Now we have to show you that we've got great people. We've built a fantastic culture, and we can produce something. And remember, we had a study that everybody said was simply not recruitable, right? And you'll hear the results today. So we check that box, which is we absolutely can execute.

And now we're back together again in the same room in the same hotel and we're checking a third box, and that's of positioning. You'll hear today about how we plan to position this company. And it's not just positioning for success. It's not just positioning for domination really of this field, but it's to actually redefine the entire field. And that positioning is going to be based on a triad. And today, you'll hear this triad resonate over and over again through the talks.

And let me go through that with you. And that Triad really consists of superiority, which is the superiority label, which I consider really the holy grail of retina, and we'll go over that in a bit. The second part of that is the market size. As big as the opportunity is that you know of, we actually think is much bigger. That's just in wet AMD that doesn't even include nonproliferative diabetic retinopathy and diabetic macular edema, and we'll go over that.

And the third part of the Triad is the seamless adaptability why this drug will be used the day that it's marketed. So -- let's look at each individually. First of all, superiority. As you know, AXPAXLI is on track to be the first and only drug with a superiority label versus an anti-VEGF, the first and only. As you also know, we have a superiority study in both wet macular generation; and two, in nonproliferative diabetic retinopathy, DME.

Very importantly, it's not just that we have superiority studies, but we have a spa in each of those fields. We have a SPA for the SOL-1 study and we have a SPA for the HELIOS 2 study. So we've got FDA validation that we are on track for superiority. So you might wonder why is that so important? Well, there's a morass already that's going to get bigger and bigger of non-inferiority drugs. These are all met non-inferiority drugs, and that's going to be complicated by biosimilars and generics, et cetera, that are already there.

So you know what happens when something like that happens, there's a race to the bottom in terms of pricing, step therapy comes in, et cetera. When you have a superiority label, the first and only you have the potential to be completely immune from all of those pricing pressures. It puts you an entirely different orbit.

Now I know that some of you will call your KOLs and say, hey, does a superiority label matter to you. And they'll say, I never look at a label before I inject, doesn't mean a darn thing to me. And I get that. And famously, one of your colleagues noted that I said the same thing about 10 years ago, too, so I get that. but that's the wrong question to ask.

The right question to ask your KOLs is to say, does it matter to you that you get to decide what drug your patient is going to be on. Does it matter to you that you don't have to be forced to use a cheaper, lesser drug and watch your patients fail and then petition for the drug that you wanted in the first place. Does it matter to you that now you have a premium drug with the highest ASP possible and every one of them will say yes. That's the right question to ask.

And that's why the superiority label absolutely matters. And the triad of that superior label is not just the label but the supporting data that we will have from our open-label extension as well as our superb IP.

The second part of the triad, the market size. You know that wet AMD is a very large market. And the number that's been floated around is $15 billion. We actually think that, that's an underestimation. And you'll see a great presentation today by Jay that will outline that. The 1 thing that's irrefutable is that the market absolutely rewards sustainability increases, even if it's tiny and even if it's incremental. We have proof of that and history has just repeated itself.

You can go way back to the time that Lucentis was out there. And I'm old enough to have lived through it, a miracle drug that came out with phenomenal studies by a company that's one of the greatest scientific companies on earth, Genentech. Right? Lucentis had a 7-year head start. And you know in this field, a 7-year head start as an Infinity, a 7-year head start, then came EYLEA from a company that nobody at that time had ever heard of. Regeneron, right? Now ELA is not safer, it's not stronger. It may arguably last a week longer. And after a 7-year head start, guess what this unknown company did, it dominated the market. And now history has repeated itself again with VABYSMO.

VABYSMO is not safer, it's not stronger, it may arguably last 2 weeks longer, an incremental increase in sustainability and on track to dominate the market. Now we are in a different orbit altogether. We'll have a superiority label and we have durability up to 12 months. We're not incrementally more we're in a different or 12 months with data also as Nomurada will show you what we're designed for in the open-label extension to show that the chronic long-term outcome will actually be better, and we believe it will be.

Now what about the market size? Again, the market size is said to be about $15 billion, but that is despite the fact that in this country alone, there's a 40% dropout rate within the first year and let that sink in. We have a known treatment that we've had for almost 4 decades. That works. Despite that, in this country, a 40% dropout rate in those patients are going blind. All of them at some point will go blind. So if we reduce that dropout rate by even 10%, we certainly will with AXPAXLI being more sustainable, that means that 0.25 million fewer patients are going to go blind. They're going to be treated. That's a huge, huge impact. What do we do for this? And Jay will go over this.

We need to bend the attrition curve, and we're more about that. What does that mean? That means that the actual decrease of usage, not just mortality, not just drop out -- but when you actually look at the unit use, it's actually much more than that. And there in lies the opportunity as well, which is to bend that attrition curve, and that's what AXPAXLI will do.

And if you can bend that attrition curve, now the market size is huge, and you'll hear about that today, much bigger than even the $15 billion. And that's just wet macular degeneration. That doesn't include what we announced today, which is nonproliferative diabetic retinopathy, which is 3x as large and for which, right now, there is no treatment at all. So we will define the ultimate treatment in nonproliferative diabetic retinopathy and diabetic macular edema. So the last part of this triad adaptability.

This is pay is designed for an absolutely seamless and immediate adoption. It's an ideal target product profile. It's a monotherapy drug, best in durability for up to 12 months that we will prove with SOL-1 and an extremely good safety profile. It's a single bioresorbable hydrogel -- there are no remnants. There's nothing floating around. There are no mandated steroids. There's no surgery.

In fact, the workflow doesn't change at all. The doctors don't have to buy a single piece of new equipment. The workflow is exactly the same. They simply reach out and get a better drug with hopefully a higher ASP. It's a small needle. It's a 25-gauge needle that is going to be also self-sealing. So the experience is going to be no different whatsoever. We believe it will be immediately adopted. This will also allow ultimately, the retina specialists to actually see more patients, but less frequently for each patient. It's the ultimate of making the payers happy, the doctor is happy as well as the patient's happy.

So you'll hear about this triad over and over again today, that as superiority, that of market size and that adaptability, that's how we're positioning this company in this phase. That's how this company is going to be positioned.

So before I finish, let me just also address the elephant in the room, which is that you probably heard there was some news this morning. and some of you may have heard that. Let me just address this very, very directly. If I could look at all of you eye to eye, I would at this point. Every single decision that is made in this company. And I mean every single decision that is made in this company is made from a position of confidence. Let me just repeat that. Every every single decision that is made in this company, every single decision is made from a position of confidence.

If you're confident in your drug, if you're confident in your clinical trials, the decisions that were made this morning is exactly the decisions you'd make. This company is courageous. This company is bold. This company is opportunistic, and this company is going to redefine retina. It's not just going to succeed. It's not just going to dominate, but it's going to absolutely redefine retina. And everything we do is based on the confidence we have in this drug, and I just want to make that very, very clear.

So you didn't come to hear me. You came to hear the rest of the agenda. At this time, someone like me gets to turn around and say, let me introduce you the KOLs. That's not what I get to do, I get to do better. It's not even let me introduce you to my colleagues. I get to do better. I get to say let me introduce you to my dear friends.

These are folks that are the global leaders in retina that I've had the pleasure and the honor of knowing for 3 decades or longer. So it's extremely humbling to me that I get to invite them to this meeting when 4 years and years, they've invited me to many of their meetings. I think you know all of them, Dr. Arshad Khanani from Reno; Dr. Eleonora Lad from Duke University; Adnan Tufail from Moorfields and Patricia Schlottmann from Buenos Aires. We're absolutely honored to have them here and thrilled that they are here to talk about our program.

Again, you came not for me, but you came for the rest of the company, and I'll start by introducing -- not that she needs an introduction, but Nadia Waheed, who is -- and this is not an opinion, this is just a fact who is just the greatest Chief Medical Officer in the history of this planet.

Thank you Pravin. So welcome, everyone, and it is an absolute pleasure to have all of you here today. So I am thrilled today to talk to you about our robust SOL program. And just to give you a quick overview, our SOL Program consists SOL 1 clinical trial, which I'm going to be talking about, it's a superiority trial. There is Solar, which is focused on adaptability that my friend, Jeff Hire will be speaking about. And then we look at OE that again, my friend of rates Rod will be speaking about, which looks at long-term outcomes for patients. So I will kick off with an introduction to the SOL-1 study. And jumping into X1. You've already heard about the of superiority and what it means to our clinical program.

Essentially, the SOL program is designed as the only current registrational program in wet AMD that enables us to apply for a severity label. This enables us to potentially bypass step therapy and places us in the best possible position for maximizing reimbursement for our physicians and increasing access for our patients. So I'll walk you through our thoughtful trial design, the significance of a severity label; and finally, we'll dig into our strong trial execution for SOL-1. And let's start with the clinical trial design. So the SOM, as you're all familiar, is a severity study comparing a single dose of AXPAXLI to a single dose of aflibercept.

Currently, it's the only superiority study ongoing for wet age-related macular degeneration. It's a 2-arm trial, with 344 total subjects randomized 1:1 to receive either Xpax or aflibercept after loading period. The primary endpoint is at week 36 -- but of note, the trial is masked to week 42, at which time point we have several secondary and exploratory endpoints. And then we follow all these patients up to the 2-year time point.

The week 36 superiority endpoint, as you're all familiar, is the proportion of patients who maintain visual acuity, which is defined as less than 15 letters of BCVA loss from baseline. So top line data is expected in Q1 of 2026. But as I had mentioned, we've chosen week 36 as our primary endpoint because we hope to show superiority of 9 months of durability. However, keep in mind that the trial is masked all the way to 12 months, giving us the data to demonstrate 12-month durability of AXPAXLI as well.

In year 2 of the study, patients in both arms of the study will be redosed every 6 months. And what that does for us is this -- this enables us to use these patients to contribute to the FDA's requirements for a safety database.

So our team at Ocular therapeutics thoughtfully created a study design that is derisked from a clinical regulatory and a commercial standpoint. And I want to start with how we derisk the trial from a clinical perspective. So at screening, we choose patients that are treatment naive for wet AMD and unlike other trials to qualify to be randomized within the study, patients are required to show a strong response to live either gaining at least 10 letters of vision or attaining 2020 visual acuity.

This allows us to use the loading phase to carefully select patients that are very strong anti-VEGF responders for randomization. What that does is we then treat them with either AXPAXLI or EYLEA at baseline and follow them to failure. And this design leverages the strength of AXPAXLI, which is its durability, its 1 -- in a cohort of patients who are extremely responsive to anti-VEGF and therefore, are vulnerable to anti-VEGF treatment withdrawal, which is what we expect to see in the Eylea or the [ siveceptarm. ]

In addition to derisking the study clinically, we've also -- by randomizing these strong anti-VEGF responders as I mentioned, we've also derisked from a regulatory perspective via a SPA or a special protocol agreement with the FDA. We've aligned with the FDA to secure the SPA by not using sham injections for masking, by having a control arm and an active arm that had the exact same dosage schedule as per FDA guidelines. And because of our close adherence to both the FDA requirements as well as the FDA recommendations, we're the only ongoing Phase III wet-AMD trial with a SPA.

So now that we've discussed the trial design, including the specifics around the dosing schedule, the week 36 and 52 end points. and how the team has derisked the trial from a clinical perspective and a regulatory perspective, let's talk about the importance of a superiority label and how we further derisk the study from a commercial perspective as well.

So the SOL-1 study was designed with a severe RD label in mind. All existing and pipeline wet AMD treatments are noninferior to other anti-VEGF treatments. And this leaves a huge market opportunity for AXPAXLI to be the only wet AMD treatment on the market with the superiority claim on label. Why does the severity claim matter? And I think Pravin went over this a little bit, and Jay will probably also go over this a little bit. But with AXPAXLI, retina specialists will have the opportunity to potentially bypass the need for step therapy to select the best treatment for their patients to get their patients the drug that they need and to be reimbursed for it.

So next, let's talk about trial execution. When we started this study, in fact, when I joined last year right before our Investor Day last year, we were told that this was an unrecruitable study. And that even if regroupment happened that we would -- patients will drop out, investigators would never stick to the stringent rescue criteria and would rescue whoever they wanted, whenever they wanted without any heed to the predetermined protocol rescue criteria.

The team at Ocular Therapeutics has a laser focused on strong execution. And not only have we recruited with exceptional speed, as you all know, -- we're also seeing the results in terms of protocol compliance and extraordinary retention. Rescues in the study are reviewed on a mass basis, like external mask rescue monitors. They're monitored regularly to ensure strong protocol compliance and I'm delighted to report that greater than 95% of rescue events have met protocol-defined criteria.

Additionally, because of the team's diligent efforts, SOL-1 has over 95% redemption rate to date with strong physician and patient engagement and overall minimal attrition throughout the study. Also keep in mind, that this study was designed with a 90% or greater than 90% statistical power and making sure that patients are retained within the study helps us maintain our statistical power.

Strong steady execution, of course, is always based on the foundation of safety. And with that in mind, our studies have a targeted safety profile consistent with standard of care therapies. They're conducted under an independent DSMC monitoring committee, and we've had no new or unexpected safety signals seen within our clinical trial under the DSMC. So SOL-1 data will be hugely impactful to the market. We sought to derisk the trial clinically, commercially and from a regulatory perspective. We've done this by seeking FDA alignment conducting SOL-1 under SPA, meeting the requirements for the FDA study database with every 6 months repeat dosing in the second year.

We're also focused on establishing the durability of AXPAXLI and achieving a superiority label with strong trial execution, all geared towards providing the best treatment option for patients and for retina specialists. And as you know, the goal of SOL 1 is to provide evidence that AXPAXLI is safe, it's effective, and it's durable for patients.

We're confident that we're going to be able to execute on this. And I'm going to end here and hand over to Jeff to take us through SOL-R. Thank you so much.

Thank you, Nadia. It's very exciting for me to be here and think that it was just a year ago when we all sat here. And those of us on the team who have stepped back to prepare for this and recognize and appreciate the progress, the remarkable progress that's occurred in the past year, it's incredible. And thank you for sharing your afternoon with us to review that progress with us. So consistent with our commitment to redefine the retina experience the design and execution of solar will enable the retina community to immediately incorporate AXPAXLI into the treatment regimen for wet AMD, reducing the treatment burden that we so desperately need to improve outcomes.

Over the next few minutes, I will share our unique study design and emphasis on patient selection has derisked study outcomes, resulting in increased confidence in study success. The SOL program answers questions that would often impede rapid adoption in the clinical practice. And we hope and believe that the data from this complementary set of trials will allow immediate incorporation of AXPAXLI into treatment regimens.

Let's start with patient selection. SOL-R compares AXPAXLI dosed every 6 months to standard of care EYLEA dosed every 8 weeks. With the third HD EYLEA arm dosed every 6 months for masking purposes only. Please note that the primary endpoint is a singular unblended endpoint at 56 weeks, 8 weeks following an injection in both the AXPAXLI and 2 meg EYLEA arms.

As we've presented previously, enrollment was completed ahead of schedule, and we are in the remaining stages of patient running continuing to focus on patient selection, as I will describe in detail. Previous work in Phase III studies has shown us that patients with early persistent fluid can disrupt noninferiority trials.

In the VIEW study, the afilbercept Phase III program patients with early persistent fluid, meaning fluid in the first 3 months required monthly EYLEA injections. Even Q8 week EYLEA performed worse. Patients who did not have persistent fluid demonstrated stable, consistent responses across all treatment arms, as you see on the graph on the right.

Therefore, the methodical extended screening process in SOL-R will exclude patients with persistent fluctuating fluid, a process that we believe could be critical to study success. Why did we spend so much time and effort on this component of the SOL-R study design? because 4 of us on the ocular team played an instrumental role in the view analysis that highlighted the differential response of patients with and without persistent fluid.

And we understand the impact of inclusion of such patients could have on study outcomes.

With this understanding, let's look at how we design SOL-R to address these patients. During the conventional component of the screening phase, where patients are excluded for reasons such as non-AMD CNV and lesion size, we begin the careful process of derisking our trial population. Focusing on the pre-randomization phase, patients received 3 doses of any anti-VEGF agent with the exception of BV. We then do something unique in retina trials we have 2 evaluation visits after the first 3 anti-VEGF doses, where patients are evaluated for both retinal thickness. They need to be less than 350 microns and increase fluid. They can't increase more than 35 microns from any point.

Having met this criteria, these patients then receive 2 more doses of EYLEA. The end result of this careful patient selection is that we will have excluded subjects with early persistent fluid and meaningful fluid fluctuations. An understanding of how and why we designed the run-in phase of SOL-R, coupled with a positive SOL-1, explains why we are confident of the success of the SOL-R study.

Let's review additional aspects of the SOL-R study design that lead to a high likelihood of success. As I already said, our primary endpoint is at week 56. Unlike many noninferiority trials, this is a singular unblended end point. And this is another way of reducing the risk of solar. In fact, AXPAXLI patients will have received 3 doses prior to the primary end point.

With the last dose being just 8 weeks before the primary readout, AXPAXLI will be at its peak, while EYLEA is at its 2-month trough. A single unblended endpoint, 8 weeks following both an AXPAXLI and a 2-meg EYLEA injection treats each arm identically. But favors AXPAXLI in that there will still be axitinib left at 6 months from the previous injection and the effect of the new hydrogel injection will result in an increased amount of active axitinib at the 56-week time point.

Remember, the positive SOL-1 will demonstrate that AXPAXLI lasts for 9 months, highlighting the point that there will be more AXPAXLI than a single dose at the primary readout. So we've reviewed in detail the methodical approach to randomization to enroll patients that are reliable anti-VEGF responders without fluid fluctuations.

Beyond clinical derisking, we have also reduced our risk from a regulatory standpoint. Per the repeated FDA guidance, we have not utilized sham injections in our protocol for masking and have instead incorporated an arm with the exact same dosing regimen as AXPAXLI.

To the best of our knowledge, this is the only noninferiority trial designed entirely in line with the FDA draft guidance on wet AMD. This all brings us to commercial derisking. The unique design of the SOL program with complementary, not identical Phase III studies, will help to satisfy clinical, regulatory and commercial questions. While SOL-1 will show maximum durability of expaxle, SOL-R will show efficacy at Q6 month dosing that is comparable to standard of care. We are also unique in being the only wet AMD trial with some built-in comparison to EYLEA HD, though, again, that's an arm only for masking purpose.

We hope and expect this complementary data set will answer questions not typically addressed by identical pivotal trials and will drive strong and immediate adoption. While Solar is already clinically derisked, we do believe that a positive SOL-1 will increase the chances of a positive SOL-R even more. Why? SOL-1 randomizes patients who have demonstrated a strong response to anti-VEGF treatment, but only received a maximum of 3 injections. -- they will have a much higher need for supplemental injections.

As Nadia said, these are patients who are likely to fail without treatment on board, which they won't receive for 12 months. So our patients, as we have shown, are less likely to have variability in visual acuity and anatomical outcomes, hence, less likely to need supplemental injections and less likely to demonstrate either anatomic or visual fluctuations. So 1 success will show that AXPAXLI is a safe, effective and durable anti-VEGF agent.

SOL-1 success will show that expat as 9-month durability in strong responders, patients who are vulnerable to treatment withdrawal. AXPAXLI should provide longer durability with less supplemental injections in well-controlled patients. and exactly 6-month durability is likely to be achieved in solar given the enriched patient population. Each of these increases the probability of SOL-R success.

So everything we've discussed to this point focuses on study success and regulatory approval. How will clinicians extrapolate these elements into clinical practice. As we've discussed, we believe a positive SOL-R will give us a potential label showing safety and efficacy comparable to standard of care with dosing every 6 months. simplifying the decision-making tree for most patients with wet AMD.

From a regulatory viewpoint, we have very low risk being completely aligned with FDA guidance. With approval, we are confident we will be in a strong position to redefine retina treatment. Our submission to the FDA will consist of the following: 36-week superiority and 52-week durability outcomes from SOL-1 coupled with 56-week noninferiority from SOL-R.

The Q-6-month redosing safety will be from both studies. AXPAXLI is ideally set up for seamless immediate adoption in the clinical practice with demonstrated monotherapy activity, likely best-in-class durability and a potentially clean safety record across 2 pivotal programs.

A single fully bioresorbable hydrogel is injected. And upon bioresorption no remnants are left behind. This means there are no remnants remaining for any length of time without active drug. There's no need for concomitant steroids to control side effects related to treatment and no need for a surgical procedure.

Finally, and this is most important, axle is designed to optimize practice dynamics. It's a familiar intravitreal injection. It will give a predictable schedule for patients and even if patients visit is delayed, there will be enough drug to cover them until they can make the visit.

All of this will lead to improved treatment adherence. AXPAXLI will allow retina specialists to see more patients, not less, and they will see them less frequently which will help to alleviate the treatment burden that leads to treatment discontinuation or problems with adherence.

At the end of the day, that's not only what we clinicians strive for, but it's also what patients and caregivers desperately want and need.

Thank you. I'd now like to introduce my friend and colleague, Namrata Saroj.

Thank you, Jeff, and thank you all for being here this afternoon. As Pravin mentioned, I think the 2 themes that the team executed is thoughtfulness and confidence. So as I introduced to you the SOLEX trial, our open-label extension trial, you're going to see both of those remenant through there. So as we all know, AMD is a chronic disease that requires long-term management. Hence, it's important to understand the impact of this treatment over a long time. Recognizing this, we're initiating an extension study.

It's called the SOL-X study to further follow patients from SOL-1 and Solar to understand the long-term effect of space. So today, we're going to highlight 3 aspects here: the objectives, the trial design and the potential impact. So let's first look at the objectives. As mentioned, the overall objective of SOL-X is to understand the long-term impact of pax, which most importantly, safety, but beyond safety, we also need to explore the disease-modifying potential of continuous VEGF suppression, which we expect from AXPAXLI.

So focusing on the disease-modifying aspect. The first objective would be to evaluate the reduction in fibrosis. -- associated with chronic exidation.

Secondly, we will explore the long-term maintenance of visual benefit, especially in context of the expected anatomic stability that we expect from AXPAXLI.

And finally, this is really a really important part of the SOL-X trial design is going to be looking at patients who will actually be receiving a delayed AXPAXLI treatment because for about 2 years, they would have been receiving EYLEA, so by highlighting these potential effects of delaying AXPAXLI treatment, we will be providing physicians a clear reason to initiate expect early and the potential of that super claim that was brought up with Sol and Solar is going to allow physicians to do so.

So now that we've outlined our objectives, let's now move on to the trial design. All patients from SOLO1 and SOLAR will be eligible to continue into SOL-X.

As a reminder, with constant VEGF suppression, patients in the AXPAXLI arm are likely to have lower CSFT fluctuations. On the other hand, however, as we've routinely observed in prior studies we expect the afilbercept arms to have prominent scale effect due to the pulsatile nature of treatment. So -- the other thing that's been brought up here is the thoughtfulness that team's experience. And so using our collective knowledge, very thoughtfully, we've defined an extension study that unlike other extension studies, patients will continue to have the same dosing schedule of every 6 months, similar to the second year of the pivotal SOL 1 and SOL-R trials.

This is really important because we want to maintain a steady-state suppression with consistent and a practical dosing schedule. Through this schedule, we will be able to demonstrate benefits of the sustained VEGF inhibition for up to 5 years. Patients in the aflibercept control arms now in both studies will be crossed over to space every 6 months. This patient cohort will be -- will enable us to understand the suboptimal effect of the delayed treatment with AXPAXLI. What's our hypothesis here? It's that patients with lack of consistent disease suppression and fluid fluctuations over 2 years, even when switched to AXPAXLI may not have the same visual benefit as compared to patients who were originally started on AXPAXLI.

And that vision gap that we will see potentially will last up to the 5 years. So ultimately, data from SOL-X will provide us robust evidence supporting the use of AXPAXLI early and continuously as we seek to define the future of retinal disease treatment.

So in conclusion, let's look at the potential impact of this trial in synergy with our pivotal SOL 1 and SOL-R trials. As stated before, the pivotal SOL studies will potentially support a superiority claim to enable AXPAXLI as first-line therapy. Well, with further support by the cohort of the crossover patients in SOL-X, AXPAXLI fully could be initiated without delays of step therapy.

Similarly, with SO1 and SOL-R, we will show that AXPAXLI will have safety and efficacy that's comparable to current standard of care. Now combined with the SOL-X data showing the importance of consistent VEGF suppression in the reduction of fluid fluctuations and fibrosis, we hope to convince physicians of the sustained benefits of AXPAXLI.

Now finally, with a 6- to 12-month dosing schedule, which is a very practical dosing schedule, we hope to show improved patient adherence in the long term, which will significantly expand the market opportunity. So in conclusion, the collective data from the SOL program with SOL-1, SOL-R and SOL-X will establish AXPAXLI as a preferred drug of choice.

And with that, I'm going to turn it back to Jeff to moderate our panel.

Thank you,. And first of all, I want to thank our esteemed colleagues for taking time out of your busy schedules to join us today and helping to provide insight and perspective on today's presentations. So our shot -- let's start with you. Over the last few years, we've seen the introduction of multiple new therapies for retinal diseases. We all have busy clinical practices. How have the new agents impacted your prescribing patterns. And with these, are there still major unmet needs today.

Yes, Jeff, it's great to have options for our patients and with [indiscernible] if I have a choice, I'll pick one of those drugs because they have incremental benefit. I use mostly VABYSMO because of the flexibility of dosing and then extension of treatment interval. But we run a real-world study, and we're still continuing to generate data on the truck study. We're 3.5 years into it now. And it's not pharma supported.

And our goal was to see how we are making a difference for our patients. And if you look at the data, what we have seen is, on average, we are adding 2 weeks or aflibercept 2 milligrams in the truck study in previously experienced patients. And in naive patients, our average is 10 weeks. So we are making a difference for a few weeks, which from a patient perspective and clinic perspective is good, that's why it's being adopted. But we still have nonadherence. We still have fluid fluctuations. We still have high treatment burden for our patients.

Many of my patients come from 3 or 4 hours away, and they can come in every 6, 8 or 10 weeks. So I think as a field, we really need to have agents that actually can make a meaningful improvement in durability. And that's what the path survey shows every year. What is the biggest unmet need. So Here, we have an opportunity as a clinician as a trialist to go months instead of a week. So I think it's good to have options, but we can do better. And my hope is that we will deliver that to our patients in the future.

Thanks, Arshad. And for those of you who don't know the path survey as a survey that's always administered to retina specialists, and it usually has about 1,500 to 2,000 responses. So it truly reflects what you said our shot. Nora, you've done a lot of important work looking at Medicare databases. And in particular, you've done work on treatment adherence. How can the various longer-duration therapies in development impact adherence?

Thanks, Jeff. It's a pleasure to be here with all of you. So when I started off at Duke, 1 of the main problems I saw in our clinics was a request for durability and caregivers are really frustrated with the treatment burden. I mean it's just such a difficult thing to have to inject so frequently. So we did have access to the 100% Medicare database with a lot of data. And we found that in 500,000-plus Medicare beneficiaries the risk of discontinuation of these injections was very high. You heard the 40% number for Pravin.

We saw that really patients were receiving half of the treatments they needed. Over time, that led to poor visual outcomes, drops in vision over time. And that's been shown by numerous studies that we can all site and they've been done in both outside U.S. and U.S. So really what we need is durability, durable treatments. And the options available to us, we all know TKI inhibitors, gene therapy, they all have different considerations. But a few of these treatments, in my mind, have the combination of adaptability, how easy we can implement these treatments in clinic. -- flexibility, 6 to 12 months would be game changing for us. and durability, again, major or major need in the retina clinics.

Thanks, Nora. I want to follow that up, Nora, with -- we talked about the importance of a superiority label from our standpoint. Pravin mentioned that he thought it would have value to clinicians. Can you give us your thoughts on that?

Yes, I'd love to. So I think the presentations are pretty comprehensive of that. But obviously, a superiority label would be game changing, and it would make this drug the full package, and there's a reason for that. as clinicians, we are bound by step therapy. So this is over -- this will overcome and circumvent that problem. I mean, we have to use step therapy.

Now our clinical practices will change with the induction of biosimilars. We're already starting to see them in our clinics. I think this would make for really a compelling case for using this drug versus the other.

Thank you, Nora. Adnan, Nora mentioned biosimilars. And we know these are increasing in practice and are likely to increase more over the next several years. How would a treatment like this impact the use of biosimilars. So I guess the flip side is with biosimilars impact the use of this treatment.

So I'm based in the U.K. So I think there's no doubt that biosimilars already are making a significant impact due to the cost pressures on the NHS. But the biosimilars aren't addressing the big issue that we have is being able to deliver the care, the increasing number of patients need anti-VEGF beyond just the AMD diabetes indications, and that's a significant capacity issue.

So I think having a proper robust durable drug will really address that. And I don't think the biosimilars will be able to complete. By definition, we'll have superiority data to address that. And I think it really would be very attractive for the NHS to take that on board.

And we've seen from Pravin's initial presentation that a longer-acting drug will tend to dominate, and we've seen that on the NHS as well. that the longer-acting drugs have dominated over the previous generation of drugs.

Thanks, Adnan. Patricia, you're 1 of the preeminent investigators in Argentina. I would argue the preeminent investigator in Argentina. And Argentina as a country enrolled very well in these studies. What's been your experience with the SOL program?

Thank you, Jeff. Yes, there was a lot of enthusiasm from patients and doctors to be part in this study. It was mentioned before that somebody thought it would be a difficult to recruit study, but it was very easy for us because the moment you put the concept of getting less injections, that was a driver for most of the patients. And let me bring up a story from a patient. This is the typical patient that will fail big guy middle aged. He's the one that is the most fearful of injections.

He's the one that would say, I don't want any injections. And to add to that, he would leave far away from the clinic. He would be like a 2-, 3-hour drive to come to the clinic. So I was a little bit unsure whether to invite him to be part of the study. But the moment we started discussing, this is a study that aims at having less injections. He was like, "I don't mind coming as much as you want. " This is a monthly visit study, so we need to check them regularly, and he was happy to come, provided we don't give them injections.

We don't know that beforehand, but he was very successful. He's being a very successful study -- a very successful patient, sorry. So he comes -- he drives 3 hours. He comes with a wife. He's thought the sun in law, even the granddaughter they come to the clinic. And basically, it's just for a coffee and a -- they get the OCT, the vision checked and he's very happy no injections. And he said, "No, no, you're doing well, no injection for them. And it's not only patients living far away. It's patients that may leave very near the clinic, they come and they're happy to come to be checked but not receive an injection.

And that changed my perception of what is the reason for failure. Most of the time, we think that coming very often to the clinic it's a reason for failure, but coming very often to the clinic for a coffee and a chat is not the same as coming from an injection. So they're very happy to come check, be part of the study provided we don't give them the injection. So the clear incentive there is not having regular injections, and that is a major driver from patients. The study was also a success because of the way it was organized. The company works really well.

We have very good contact with the CRO and with the company so that helps. We have run some held of studies in the past. So this one is marvelous is being run. And durability is a topic that we bring into the discussion with patients these days. In the past, it was just about efficacy. So now the question of how often I'm going to be treated, it becomes a major discussion there. So patients are happy, retention is being really good because why not come to the clinic, why would they miss the appointment if they're just coming for OCT vision, coffee, chat, cookie and then back home for the absolute majority of the patients.

Sounds great. Cookies sounds nice. So Arshad when the SOL 1 trial started, many felt that investigators would not wait for a 15 letter loss that protocols would be off rescue or off that rescues would be off protocol and retention would be a big issue. As the Steering Committee Chair, can you speak to those issues?

Yes, absolutely. I think the initial skepticism was fair, right? We have never done this in a clinical trial setting, and it was a unique study. But I think as I spoke to investigators, and we realized that as presented by Nadia, that we have to gain tan letters to get to 2020. So there was a net loss of 5 letters. It was not 15 net loss, but 5. So that gave some comfort to the investigators.

The other thing was understanding that there's a spa that actually this is a regulatory vetted and STEM trial that we're actually looking at true durability head-to-head of 2 different treatment options. So that gave comfort. And I think talking to the patients, just like Patricio, I talked to many of the colleagues here before we launched the study, and I wasn't sure myself if my patients are going to sign up for it. And we start talking to the patients that you will come in, we will watch you really carefully. And if you need an injection, you will need it, either arm you're in, that was the protocol.

So what I realize is that actually pretty much all patients were okay with that as long as we were following them closely. And making sure that if they need treatment, we gave treatment. And you saw the numbers greater than 95% of the rescues are per protocol. So actually, all of us are following the protocol. And I think all that together kind of give me a new insight in retina clinical trials that -- the landscape is changing. And I think if we understand why we are doing this, right, we haven't had studies where we have actually looked at true durability. This is a true durability study. So I think as [ steering committed share,] I'm very, very happy with what we have seen. And of course, working with you, Jeff, and Nadia, Peter and all the team has been great.

So I think as Patricia said, it's a team effort from all of us to kind of change how we're going to treat patients in the future. burden and hopefully optimize the outcomes for my patients because that patient could be my family member or my mother or my mother law. So we need to make sure that we do our best, and this is what we are doing. We're doing our best.

And we appreciate that you're treating both of them similarly.

It's very nice, as what I mentioned.

So Adnan, we have -- we know that SOL-1 will have top line data in the first quarter of 2026. And a lot of people are trying to say how to interpret that, how will you define success in SOL 1?

So it's such a smart trial design that I think just simply getting a positive outcome will be success. So I'm a bit of a data tourist. And so it's nice to have a trial design that robustly says if drug X is more durable and superior to the drug Y. What we've had to date in recent clinical trials is both for the newer anti-VEGF, both treatment arms were not managed the same way. So the comparator arm was given in a fixed dosing and the novel drug that we're testing out was dichotomized depending on how it responded on fluid drying. So only a small subgroup of those patients showed some longer duration of action, so it didn't label, but there are marketing claims suggesting that.

What I want for my patients is having robust data to say that drug X is superior than drug Y, and it will last robustly for 6-plus months. And this allow me to plan my clinics, which have capacity issues robustly and to get -- and hence get better outcomes for my patients.

Thank you. Patricia, in retina, we are clearly well behind other fields in how we understand the variability of our disease. Can you speak to the variability you see in your daily practice and comment on the patient selection in the SOL program to address this variability.

Excellent. So yes, we see patients being treated on a daily basis in our clinic, some of them responding really well going through a loading phase and then needing few injections after that. And then we see others that look exactly the same that those at the beginning, but they need injections every single month. And we're lacking the biomarkers with for some subpopulations we may, but for the majority, we lack the biomarkers to see who is going to behave in which way.

So put it in a trial and going back to the image that you showed in which this was described, we don't know what is the baseline characteristics of these patients that are going to be fluctuating more and, therefore, needing more injections. We're lacking these biomarkers, and we cannot identify them at baseline. So therefore, these patients that are the high needs regular injections one after the other, that they don't respond to treatment A,B,C,D or or whatever treatment you may have. These are the patients that you want out of your study.

Otherwise, they will contaminate the whole series and you'd rather do that, and this is part of the great design that you have in the study by which in the loading phase, you get a sense of the response of these patients this very small population, you get them away, so you avoid the noise, and you just keep the best population to prove whether the drug works better than the comparator in this case. So it's -- it's a great, great design, and it's going to give us the best result from the best type of patients.

Arshad. If SOL-1 is successful, how do you think about the probability of success of SOL-R?

So Jeff, obviously, there are 2 different studies, but when you look at the design of SOL-1, it will give us data on efficacy, safety and durability of a single vacate injection over 9 months. So translate that into SOL-R, where we are actually have a screening period, as Patricio was saying that we screen out patients who have fluid variability. So we want stable patients who respond well to anti-VEGF.

And as you skip a visit like you showed the design, they don't get fluid accumulation, which was defined as 35 microns or more. So you're actually getting optimal patients in there, and you're treating them every 6 months so, SOL-1, 9 months primary endpoint here, you are treating them every 6 months. And then your primary endpoint, which is brilliant, is 8 weeks before the primary endpoint, you're getting another injection of AXPAXLI.

So as a clinical trialist, I have to say that it's a very robust creative design that's very derisked in terms of success. So I think, of course, at the end of the day, we have to see the data from both studies. But if I had to predict, if SOL-1 is positive, there's a very high chance that SOL-R will be positive.

Thanks, Arshad. Adnan, today, we shared more details about SOL-X our long-term extension study. When you think about unmet needs in wet AMD, what do you expect to learn from the extension in this.

So obviously, your pivotal trials will address the kind of short-term effectiveness and superiority of space. What I'm really interested in -- for my patients is that durability and benefits sustained long term? So our group ran a study where we data-mined EMRs across the U.K. and look to the outcomes over more than a decade of anti-VEGF as new anti-VEGF came online, and we altered the way we treat our patients. And over that more than a decade, we have not improved our outcomes. So our vision tails off after that initial period in parallel over the last decade from ranibizumab in 2018 in the U.K. all the way through.

We are not getting better real-world outcomes. So what we really need is a drug that is genuinely durable have a clinical extension trial that will be translatable into real-world care, which SOL-X, I believe, does -- and the NHS is very health economic driven, and we model out data for the lifetime of the patient. And so this sort of data is going to be very, very important in the value proposition of the drug.

So that's helpful from a European perspective then with a drug with the characteristics that we've described for AXPAXLI have a big impact.

I think, yes, I think it will be a huge impact, incredibly attractive on multiple levels. And we've talked about it, it's attractive, as Patricio said, from the patient perspective, from our capacity in an incredibly busy hospital and obviously, from the payer's perspective as well because we do have sustained benefits for the lifetime of the patient.

That's great. So Arshad, we've been involved in the design of many studies. Can you speak to the uniqueness and the potential benefits of complementary pivotal studies as opposed to identical pivotal studies.

Yes, absolutely. I think -- and you and I have designed so many of them. And the first question always is that you do exact same thing in 2 trials and you don't learn different things. And I think here, we have an opportunity to look at adverse patient population and ask different questions, right? So you are asking a question about true durability, as Adnan said and possible superiority in SOL-1.

And then in SOL-R, you're asking the question about repeated dosing, noninferiority to standard of care, right? So when gets approved, we have multiple different questions that are already answered. So I think that actually helps us adopt the drug much quicker. We started the truck study because we had no information on previously treated patients from the VABYSMO study. They were all naive patients. We didn't know the safety, we didn't know durability. We didn't know efficacy anatomic improvement.

So I think here, it's -- again, there's an opportunity to change things in a meaningful way how future trials are done and how we can get the data. So I think the complementary studies are going to be very important for the field and how we design trials in the future. So again, it's a very exciting time in retina. We are actually answering multiple questions in the Phase III instead of waiting to answer those later, which kind of halls adoption so here, we will have an opportunity to really implement the treatment as soon as we can.

Great. Thank you, Arshad. And I want to thank the panel for their insightful thoughts in these first questions. And now I'm going to pass the microphone over to Jay Robbins from our finance team.

Thanks, Jeff. Thanks, Jeff. Good afternoon, everyone. Before we talk about the opportunity for AXPAXLI, I want to delve a bit deeper into the current treatment dynamics and market dynamics for anti-VEGF therapies. Today, what we see is an anti-VEGF market that's growing quite robustly.

As Pravin mentioned, it's roughly $15 billion in 2024. But when we look at underlying unit growth, it's relatively flat. And I mean that's surprising because we're seeing a transition to second-generation premium-priced anti-VEGF therapies. What we're seeing, and this aligns with a lot of what our panel has discussed today, is that the second-generation therapies aren't doing a lot to really move the needle in terms of units or getting more patients on therapy. That's why we view the opportunity here for a next-generation product to come to market is significant because of the adherence challenges because of the durability challenges that our panel has discussed.

Now when we look at the market here today, 1 of the things we noticed the high injection burden is creating a treatment discontinuation spiral. And the combination of the unsustainable long-term burden of frequent injections monthly by monthly places a tremendous burden on both patients and caregivers, getting to the office, getting dosed represents a significant time commitment. As a result, patients are delaying therapy. And when they delay therapy, what happens is we see inconsistent pulsatile dosing, over time, that inconsistent puls-ive-tile dosing leads to decline in BCVA scores. It leads to vision loss over the long term and those poor outcomes and declining vision each year cause more patients to drop off therapy, which creates a recurring spiral such that over time, we see attrition increasing year-over-year-over-year in this market.

Yes. That's why, as Pravin had mentioned, there's the opportunity for a second-generation therapy to come to market here that can help solve for the adherence challenge and that can help really recatalyze unit growth in the market. Consequently, we look at other markets where we've sort of seen this adherence dynamic play out. If you look at what's happened in RA recently over the last 15 years, the migration from steroids to anti-TNFs, now to third, fourth generation therapies has driven an increase in adherence and has driven a significant increase in the number of patients on therapy.

Same dynamic is also playing out with Eliquis in the anticoagulant market. That's why we view the opportunity here for longer duration of luting therapies, LDETs, the next generation of products for retinal vascular disease coming to market have the real potential to change the treatment paradigm. With simplified dosing, they're going to offer a much more consistable continuous therapy over time, right? It's going to be a much lower treatment burden for patients and their caregivers.

Over time, you're going to have a consistent, reliable dosing. We have the ability to actually extend a bit if needed. If patients skip a few weeks, it's not going to materially alter outcomes. And I think what we have here is, okay, if we're able to solve for the continuous dosing issue, we're able to keep patients on optimal therapy over the long term, it's going to lead to improved vision outcomes.

And that's why we're going to sort of flip the script here and we're going to migrate it from a treatment discontinuation spiral to a long-term treatment retention cycle. We'll have something that's easy for patients to use, easy for the clinicians to administer and it's the type of therapy that can begin to generate improved long-term outcomes.

So we look at the commercial opportunity for AXPAXLI. As Pravin had mentioned, we're excited for 3 reasons. One, this will be the first therapy to market with a superiority label for both wet AMD as well as diabetic retinopathy. This is an adaptable therapy. It's largely in line with current practice. And we have the opportunity to really drive market expansion here across multiple fronts.

I think you all are relatively familiar with these markets and these sort of disease states. They're all significant -- so that's why we view a product combination or product profile such as AXPAXLI, it's poised for rapid adoption. We've seen this already with the movement from first to second generation anti-VEGFs. Now with long duration eluting therapies coming to market. So you've heard from our clinicians, we're poised to see a similar trend towards rapid adoption.

Out of the gate, this would mean significant share gains as we launch over time with AMD? There's a large number of patients on therapy already. You look at that, there's roughly 900,000 patients treated today. As we progress into there's limited use today, but this is a largely greenfield opportunity in the long term. There's a few effective therapies for diabetic retinopathy. And we feel AXPAXLI again, its ease of use, low administration burden is well positioned for adoption.

Over time, we'll look at pursuing into other areas such as no vein occlusion as well. But I think the key piece to take away here is the adherence piece. We've talked a lot about adherence today and improving adherence is really the key to growing the market over time. So when we started investigating adherence, the literature was all over the place.

There was a lot of work that looked at adherence among patients who were on a VEGF therapy for 18 months to 2 years. there wasn't a good population base look at what's happening overall. So we had done a couple of analysis of some major databases totaling over 6,000 patients. And we were shocked to find that at 1 year, only 56% of patients are dosed to maximum label. So again, that's about half the patients are still dosed to maximum label at 1 year. 14% of are suboptimally dosed. And those are the patients most at risk for dropping off in the subsequent year.

At year 1, we've already seen roughly 17% of patients drop off and 13% are lost to follow-up for a multitude of reasons. That's why if we have the opportunity to start addressing the adherence challenge sooner, we reduce the injection burden. It's the key to really bending that adherence curve over time. and increasing the amount of patients on therapy. So let's talk about the other important piece here. adherence and BCVA scores.

There have been several studies in the literature YTO study as well as some of the studies on port delivery that have looked at patients who've been on VEGF therapy, multiple years, 7, 10 years. Patients who are able to make a consistent commitment to monthly dosing for 10 years, actually have BCVA scores that do well. But there's an incredibly small percentage of patients that are actually able to do that.

Consequently, that's why there's the need for sort of next-generation therapies for retinal vascular disease. If we look at BCVA outcome sort of in a normal population, they decline significantly over time. That's why AXPAXLI with the reduced dosing cycle the potential to sort of improve adherence, we feel can sort of have the ability to generate this sustained improvement in BCVA scores over time. So what does that mean? I think as Pravin has mentioned in the past and his introduction in our panel had also discussed, we have the ability to start modulating that adherence curve upward.

You modulate the curve, you grow the number of patients on therapy each period. And we think out of the gate, the durability advantage will provide us a significant uptick in that curve. The next piece to consider is what happens when we have the long-term outcome study.

Our long-term outcome study, SOLX, if it is able to show a significant benefit over time, we'll further expand that curve, right? Again, this is sort of the advantage. This has been the missing piece in the market. if you're able to show long-term durability, if you're able to show that you can maintain BCVA scores, we have the ability to unlock substantial long-term value in the wood AMD market.

Lastly, moving towards diabetic retinopathy. This is a largely greenfield opportunity for us. We're kicking off the first NPDR studies. But if you look at NPDR treatment today, it's negligible. There are a few options. If you're a largely working age population, having to go in for monthly or 6-week injections, it's an incredible burden.

If you can take the diabetic retinopathy patients, who, again, largely working age and give them an option that's similar to going to the dentist each year, we're poised to see a significant transformation in this market. We think we can basically start unlocking the NPDAR market relatively quickly. DME and PDR, most patients are currently treated right now with laser and there's very limited sort of use of VEGF.

But again, treatment rates relatively low. I think you have the opportunity to unlock a significant potential here over time as we sort of release the data and we start penetrating the DME and DR market. The big question is, okay, what is this going to look like and what can we do for adherence over time. The great unknown and we'll explore this more in our later clinical studies is what does that actually mean in terms of how long we can keep patients on therapy? So I think in conclusion, as we look at sort of the markets today, we're very excited about having the combination of a superiority label, a product that's highly adaptable, really start driving market expansion for retinal vascular disease.

AXPAXLI is really poised to become the new standard of care. We'll pioneer the expansion into this untapped diabetic retinopathy opportunity. There's no current viable treatments today. This is a significant low-hanging fruit as we march towards commercialization. And with AMD, we're going to lead the conversion to long-duration eluting therapies with a superior label right? We're going to overcome a lot of the adherence challenges that have really limited volume growth in the wet AMD market.

Much like other markets like RA, you start solving for the adherence issues, you're going to kick off significant volume and unit growth.

Right. Lastly, as we look at the company today, we're well positioned. We're executing on our clinical trials. We have a world-class team that's driving us towards registration. We're now well capitalized to prosecute those development plans and march towards building our commercial infrastructure.

Over the next couple of years, we'll work to sort of really build out that commercial organization to prepare for what is in a once-in-a-generation product launch that will be the first paradigm shift for treating wet AMD that we've seen in a number of years.

And with that, I'll turn it over to Peter Kaiser to talk more about the diabetic retinopathy opportunity.

Thanks, Jay. I've been excited to give this talk for over a year. So we'll see how I do. So it's really my pleasure to talk to you about ocular therapeutics expansion into diabetic retinopathy. And we're going to look at both our strategy, which is obvious, end points, which is not so obvious as well as our Phase III registration program. Now we've always planned to enter the diabetic retinopathy market because it's a massive unmet medical need and certainly a large commercial opportunity.

Globally, there are more than 100 million people that have diabetic retinopathy and this prevalence is expected to actually increase because there's a massive epidemic of diabetes. When you look at diabetic retinopathy, it's the leading cause of blindness in working-age population. Most patients have nonproliferative diabetic retinopathy. And for those of you who don't know, that's defined as not having any neovascularization. And most of these patients are actually asymptomatic. They're completely unaware that they have a need for treatment to prevent this permanent blindness.

We have FDA-approved products. But despite having them less than 1% of patients are actually treated with anti-VEGF agents. So the question you should ask yourself or why are so few patients treated despite that risk of blindness. Clinical trials tells us as physicians 40% of patients with nonproliferative disease will develop a vision-threatening complication within 1 year. And we know that anti-VEGF agents significantly reduce this risk. However, the problem is that current anti-VEGF regimens are unrealistic.

They require frequent visits, frequent injections, and this is an unsustainable model for working age population of adults, who also have the burden of diabetes. So patients and physicians want a durable, long-term solution. And it's this disconnect that really underscores the major unmet need, and it's a significant opportunity for innovation with AXPAXLI.

So I want to go back and look at our HELIOS 1 study. We've presented this many times, but I'm going to go a little more detail of this study. We enrolled patients with moderately severe to severe nonproliferative diabetic retinopathy in noncenter involved diabetic macular edema. And they were randomized 2:1 to either a single AXPAXLI injection or to sham injection. There's no loading doses in this study because it's not required in this patient population. They were then followed for a full year looking at them monthly. Now at baseline, all the AXPAXLI patients had severe nonproliferative disease, Level 53.

And I'll tell you what that means in a moment. So in other words, they were just 1 step away from developing proliferative diabetic retinopathy. That's the worst form of diabetic retinopathy where neovascularization is seen, at 1 year, after just 1 injection, 100% of those AXPAXLI treated patients were either stable or improved with 23% achieving a 2-step or more improvement in the DRSS scale.

In contrast, none of the sham patients improved. They were all either unchanged or worsened. Now that's data you've all seen, but I'm going to go through a little bit deeper dive of the HELIOS 1 study. Here are all the AXPAXLI patients who entered the study with noncenter involved DME. These images that are shown here are what we call retinal thickness maps. And on slide right is what a normal scan should look like. The retina with no leakage is yellow and green.

You can think of those maps, those maps that you saw when you were in kindergarten, our mountains are white, oceans are blue. In contrast, the patients who have diabetic macular edema, that appears as those red areas in the heat map. And at baseline, all of these patients had diabetic macular edema, after a single injection, every single 1 of these patients improved.

In contrast, which I'm not showing, none of the sham patients improved. This is another way to look at this. This is looking at total retinal volume. What that captures is the total amount of retinal fluid in the macula and this now includes all the patients in the HELIOS-1 study. This is a much better way to look at a patient's diabetic macular edema.

At baseline, the AXPAXLI patients shown in blue, had a slightly worse diabetic macular edema at baseline compared to sham. And after a single injection, they had a progressive improvement in a diabetic macular edema such that by 40 weeks and onward, they had near total near-normal total retinal volume 40 weeks onward. We had normalized their retinas. Thus in HELIOS, all the patients who received AXPAXLI, they had improvement in their diabetic macular edema, none of the sham-treated patients did. And if we could replicate this in Phase III, this would certainly be a very strong case for the use of AXPAXLI both in the prevention as well as treatment of DME in patients with diabetic retinopathy.

But I really want to show you this. This is the most compelling data from the HELIOS study for most physicians. What I'm showing you here are what are called fluorescein angiograms, and the way we obtain a fluorescein angiograms, you inject a fluorescent die in a peripheral vein and you take pictures of the eye. The die goes to the blood vessels in the eye and in normal blood vessels does not leak out of the blood vessels and it appears white.

Normal vessels don't leak. Diabetic vessels, which are shown in blue and green do leak. So the images here, blue and green represents leakage of the die outside of the normal blood vessels. And we know that higher levels of total retinal vascular leakage is associated with more advanced diabetic retinopathy, greater risk of disease progression and worse visual outcomes. So when we showed the before and after to retina specialists, these images were incredibly impactful in all the patients who received a single AXPAXLI injection, there was a dramatic reduction in our total retinal vascular leakage at both 6 months as well as 1 year.

And you can see that at the end of the study in the AXPAXLI treated patient there, those blue and orange areas are disappearing going back to being normal blood vessels.

In contrast, all the sham patients worsened. So in HELIOS, with a single injection of AXPAXLI, we demonstrated a disease-modifying effect across multiple structural and functional outcomes at 1 year. These are effects that are not seen with current regimens.

For retina specialists, and I'll let them speak to it in the panel, these results were unprecedented. So looking at the global diabetic retinopathy market, we seek to unlock this market with a broad diabetic retinopathy label. This would allow us to treat the full spectrum of diabetic eye disease, all patients with diabetic retinopathy. So this would include patients with/without diabetic macular edema. Since by definition, all patients with diabetic macular edema have underlying diabetic retinopathy.

So a diabetic renopathy label actually expands our market by about 80 million patients compared to a DME only label. So a very important aspect of our expansion into diabetic retinopathy was deciding potential endpoints. And this is an area where we put our 30 years of experience together most of us have been steering committee members or study chairs of diabetic retinopathy studies, and we wanted to come up with a better way to evaluate a diabetic retinopathy study.

But let's go back in time and look at the diabetic retinopathy severity score. So normally, diabetic retinopathy is categorized by analyzing color photograph images. And then each eye is assigned a score called a diabetic retinopathy severity scale, DRSS. And you can think of this like a ladder with many rungs. Each rung represents a different stage of disease, all the way from level 0 or no diabetic retinopathy up to level 85, which is at the top of the ladder and a treatment, whether it be a systemic treatment GLP-1, for instance, or a local treatment like an anti-VEGF injection can change a patient's position on its ladder either up or down.

What's important to know the number to keep in the back of your head is that if you had severe NPDR, Level 53, all our patients in HELIOS-1 were at level 53, 80% of those patients will progress that one step to Level 61 or proliferative disease. So if you think about it in diabetic retinopathy, our goal then is to both improve the disease as well as prevent worsening.

So the primary endpoint that the FDA has used in all approvals to date, has been this idea of a 2-step improvement in the DRSS. However, this FDA validated endpoint collapses that scale into a binary change in only one direction. There have been 4 approvals to date. That have used this 2-step improvement binary endpoint. Although many recent studies have actually done the easier endpoint, which is prevention of worsening, but that's also just a binary outcome.

So here are the results of a theoretical Phase III study based on statistical simulations using our HELIOS 1 data. If we look at 2-step improvement, the statistical simulation show that we would easily hit statistical significance in terms of a 2-step improvement in the DRSS versus sham.

If we look at 2-step worst thing preventing it, we would also hit statistical significance. The problem though, when we knew this is that if you use a binary endpoint, it simplifies the DRSS into a simple yes, no question. You either gain 2 steps or you prevent a 2-step worsening. And this makes it easy to interpret, but it throws away vital DRSS information. So this reduces the statistical power of the study and requires a substantially more patients to reach statistical significance.

So our HELIOS data were exceptional. We reached statistical significance irrespective of the binary endpoint chosen improvement or prevention of worsening. But what happens if a hypothetical drug or the sham control responded differently. So here's another simulation with Phase III data showing a hypothetical drug that has almost doubled the improvement in the DRSS and almost double the prevention of worsening over sham injections. So this is certainly a clinically meaningful result.

They're numerically superior outcomes. However, if you look at 2-step improvement in this simulated study, it would fail the primary outcome and looking at 2-step worsening, even again, numerically better, it also would be a failed clinical study. So at Ocular Therapeutics, we have been redefining development in the SOL programs and now in the HELIOS program.

When we looked at the historical diabetic retinopathy primary endpoints, we knew that if we use the binary outcomes, we will be excluding relevant data. And we needed to choose either improvement or worsening before we started the study, making this a higher-risk trial.

And as I mentioned, our teams have been designing and running clinical studies for over 30 years. From our experience, we knew we could do better. We could find a better clinical endpoint that would leverage data from every patient in the clinical study, account for both disease improvement as well as preventing worsening. And this is what clinicians want.

If you ask a clinician, they want to have a treatment that is true disease-modifying with a long-term durable solution that's a treatment they would actually use in diabetic retinopathy, and that became our goal. And to achieve this, we chose ordinal DRSS as our primary end point.

Now prior to this morning, many of you probably have never heard of an ordinal endpoint and probably up to this point, you still don't know what an ordinal endpoint is, so I'm going to attempt to explain to you why this is a more powerful endpoint for a diabetic retinopathy study. An ordinal endpoint uses all the patient information, so it allows -- it looks at 2-step improvement that counts. Prevention of 2-step worsening, that counts.

And finally, if you have no change, that also counts because those patients go into the denominator. So every patient counts in normal analysis. It allows us to capture the full DRSS scale not just one direction like we would have had to do with the binary outcome. And this maximizes the study value of each and every patient. This also increases the statistical power to study, making it smaller, shorter and lower risk.

By increasing the power of the study, we can detect a treatment effect with fewer patients or if we have the same number of patients, you get a clear stronger signal from less patients. For regulators, payers and physician preventing worsening as well as making the disease better strengthens the case that this therapy is disease-modifying, not just hitting a regulatory check box.

So let's look back at the data I just showed you a hypothetical drug in a hypothetical sham that had failed both binary outcomes. -- despite having clinically meaningful results. When we use an ordinal endpoint, we capture both the improvement prevention of worsening as well as those patients who didn't change in the statistical analysis. So this exact same data achieved statistical significance using the oral approach. And this is why it's a much more powerful outcome.

What about prevention of vision-threatening complications as a primary outcome. First of all, it's never been used in any diabetic retinopathy study. And I'll explain to you why in a moment. In the HELIOS-1 study, 38%, [Audio Gap].

Vision-related primary endpoint to show at least a 15-letter delta up or preventing down. So the FDA's definition of a vision-threatening complication requires both the appearance of PDR or center-involved DME. -- combined with a 15 letter loss before they would count it as a vision threatening complication. So this is very different than a clinician's definition. There is no vision requirement in our definition.

The other thing is each vision-threatening complication would be counted separately by the FDA. We bunched it together in the clinical studies -- but for the FDA, they're going to look at the vision-threatening complications of PDR or the vision threatening complications of center-involved DME, not the combination. So if you look at these FDA rules, to use vision-threatening complication as a primary endpoint would lead to a very low event rate.

And this then requires a very large study and much longer follow-up to allow for that loss of vision. Most importantly and the biggest reason there is no physician on the planet that would withhold treatment for a patient who develops PDR and waiting for a 15 letter loss of vision before rescuing that patient. This is very different from macular degeneration. If you let that PDR patient lose 15 letters, that patient may have permanent loss of vision. And when I say loss of vision, I mean totally blind, black nothing forever. That's why no physician would allow you to wait for a 15 letter loss.

In contrast, this oral outcome uses both DRSS improvement as well as worsening like we've used in the past. So it's in familiar to investigators as well as to the regulators. Every patient in the study contributes data which gives us greater statistical sensitivity and a positive study shows a disease-modifying effect in that we get both improvement in the disease as well as prevention of worsening, which is important for physicians and patients to use the product. So an ordinal endpoint allows us to have a smaller, shorter, more relevant less risky and less costly trial than any other endpoint we could have chosen.

Let's look at it a different way. When we look at efficient trial design, if you were to use vision-threatening complications using the FDA's definition with a 15 letter loss -- this require a trial of at least 3 years duration and a study size of almost 1,600 patients. In contrast, a binary change will be a much shorter study, 1-year outcome -- and if you look at vision -- I mean, DRSS improvement, it would be 650 patients. If you looked at prevention of worsening that would be 450 patients. So again, much smaller study. But if we look at an ornal outcome, this has that similar 1-year outcome but requires significantly less patients to achieve 90% power.

So we believe that the ordinal DRSS end point will be a preferred primary endpoint, and I guarantee you every company going forward is going to use this outcome in their clinical studies because it gives you the smallest trial size, the smallest -- the shortest trial length, it's the least expensive because of that -- it also has the least clinical risk. But if you think about it, there are really 2 reasons clinicians treat patients with diabetic retinopathy, to make them better and to prevent them from getting worse. -- and this endpoint captures both.

So the entire team is excited to present our diabetic retinopathy study. It consists of 2 complementary studies using this novel or not 2-step primary endpoint in both studies. Now this is the first time this is being used in any study. And as I said, I think it's going to be the gold standard going forward.

We feel that this is the most clinically relevant endpoint with the highest probability of success. We are targeting a broad diabetic retinopathy label, which would include by definition, the ability to treat diabetic macular edema, meaning we only need these 2 studies to treat any diabetic patient.

And most importantly, we have received FDA alignment on our primary endpoint with a special protocol agreement. So like our macular degeneration program, our team likes to think outside the box when we design registrational programs. We want them to have the lowest regulatory risk, but also the greatest commercial impact.

Our regulatory team has worked very closely with the FDA to get an endpoint that we think is the goal standard going forward. And instead of identical trials, we have 2 different, but complementary studies.

The first is the HELIOS 2 study. And this study will randomize patients with moderately severe to severe nonproliferative disease without center-involved DME. So levels 47 and 53. This is an identical patient population to the HELIOS 1 study. And it was purposely chosen like all the patients in all our programs. The reason you chose 47 and 53 because that gives you room to both improve as well as prevent worsening. So you don't have a ceiling or a floor effect.

Recall that level 53 patients, 80% of them will worsen that 1 step, Level 61, which is proliferative diabetic retinopathy. Patients will be randomized to receive either an injection of AXPAXLI for masking purposes low-dose ranibizumab, 0.3, which is the approved dose for diabetic retinopathy.

Now unlike macular degeneration, no loading doses are required in this patient population because the standard of care is watchful waiting. Patients aren't normally treated in this population. They'll be followed monthly up to the primary endpoint, which will be at 52 weeks using the ordinal endpoint that we've discussed and that has been agreed to with the FDA. After the primary endpoint is being evaluated and additional injection of AXPAXLI and ranibizumab will be given and all patients will be followed for 2 years for safety.

The HELIOS 3 will randomize an identical patient population as HELIOS 1 and HELIOS 2 to -- in a ratio of 1:1:1 of AXPAXLI dosed every 6 months or at 12-month intervals versus sham injections. Now I know you're sitting there saying, none of your other programs you sham. Why are you able to use sham in this study? And there's many important reasons. First, Diabetic retinopathy is very different regulatory rules compared to the 2023 FDA draft guidance that covers macular degeneration.

In that draft guidance, Sham should not be used in wet AMD or even DME studies because it doesn't provide adequate masking and sham injection could influence the visual acuity endpoints of those studies. In contrast, the use of a sham in our study will not affect the primary outcome because a diabetic retinopathy study's outcome is based on pictures of the eye, it's not based on patient effort, like a visual acuity outcome.

And finally, there's no standard of care for diabetic retinopathy. So sham control is acceptable. It's actually necessary for a global study where there are oftentimes no approved drugs for nonproliferative diabetic retinopathy in many countries outside the United States.

The primary point is at the same time point, 52 weeks and again, using the same FDA aligned ordinal DRSS end point. So looking at our HELIOS program in diabetic retinopathy, we have 2 complementary trials designed to unlock a very broad diabetic retinopathy label.

Both trials will use the same ordinal primary endpoint, which is aligned with the FDA. The HELIOS-2 is a superiority study that will be conducted under a special protocol agreement with the FDA. It allows us to have a 12-month durability label, superiority claims to ranibizumab and repeat dosing flexibility.

HELIOS-3 is a superiority study compared to sham, looking at both 6 and 12-month dosing of AXPAXLI, this allows us to have on label 6-month repeat dosing in those patients who will have higher anti-VEGF needs. So in conclusion, we're very excited Diabetes represents 1 of the largest and fastest-growing segments in retinal diseases with minimal current penetration.

With AXPAXLI Ocular Therapeutics is positioned to unlock this opportunity with only 2 studies to achieve a broad diabetic retinopathy label, which would also include the ability to treat diabetic macular edema patients who all have by definition, diabetic retinopathy HELIOS 1 showed us disease modification across DRSS scoring DME improvement in all patients and most impressively reducing total retinal vascular leakage in all patients who received AXPAXLI.

Our registrational program is designed for regulatory success, commercial impact and most importantly, it's for our patients. We have derisked this program with an FDA special protocol agreement using this novel powerful or no primary endpoint. And we really believe that AXPAXLI has the potential to redefine the treatment of diabetic retinopathy, expanding our leadership in retinal diseases. -- with a broad label, differentiated durable dosing and FDA aligned endpoints, our Helios program is designed for regulatory success, commercial impact and significant long-term value creation. Thank you.

So now I'm going to move on and we're going to do a panel and discuss some of these things. So I'm going to start with you had. I've sat with you on many, many steering committees, chaired programs or your investigator. We're using a unique ordinal DRSS end point. This has never been used before, but it's validated by the FDA, they agreed with us, gave us a spa. Can you speak to the advantages of using this endpoint compared to a binary endpoint that's been used in the past.

Peter, excellent overview, by the way. So I think the frustration as a clinical trial list, as you said, has been the fact that we always had to have a binary endpoint and many programs wanted to do something different, but nobody had capabilities to come up with an endpoint that's going to redefine how we plan future trials. So kudos to you and the team because I think this is a huge step forward for the field. every trial will use this. And the reason I think it's important that you said it well, that as a clinician, a young diabetic comes to my clinic, I'm scared that they're going to go blind 5, 10, 15 years from now.

And I feel kind of use less in a sense that I have a treatment, but I'm not using it because I know that their 2020, the treatment burden is too high. The cost is too high. they have to miss work, they have to drive themselves. So I have this fear, right, that they're going to go blind. And I can't do anything about it. And I think we need to treat diabetic retinopathy, but we can't treat it with the current standard of care.

And then the 2-step binary does not give us information on the spectrum of the disease. Michael is a physician, somebody walks in, if I can keep them the way they are, that's a huge success. If I can improve them that a huge success. So improvement of retinopathy or slowing down or worsening, those are very meaningful for us. So I think this is the first time, Peter, as you said, that you have -- the team has done that. And that's really important for everybody else that's going to follow in the future because, first super important that the spa kind of validates that.

So I think as a clinical trialist, I am really excited for this program, but I'm excited for all the patients with diabetic retinopathy and the programs coming because this is going to change how we do clinical trials. Fewer patients, more derisked trial, more real-world kind of situation where we are actually getting the full spectrum. So -- so really, really important advancement for the field.

Nora, the classification system that we've used for diabetic renopathy was actually first designed in the 1960s before Pravin was born at the Harley House, and then it was refined for the ETDRS study. Can you elaborate on what this scale is to DRSS? And why in your mind, is this clinically relevant?

So first of all, a wonderful comprehensive presentation. You showed it really nicely. I thought the DRSS, it's a photographic standardized grading scale. It's but easily understandable. You can tell how a patient goes in the journey of disease from mild disease to severe PDR or vision-threatening complications because they can bleed or get a traction of retinal detection, a really bad diabetic macular edema that really undermines their vision quickly. So -- but the DRSS, importantly, it's reproducible its objective. It has been used for regulatory approval. It has a long track history of success. You showed the 4 programs in which it was used. I work with Degrading Center pretty closely, 1 of the major reading centers that is behind these FDA approvals and use we grade these photographs all the time. I was one of the greatest at some point in my career.

So they're familiar it's very useful, and it does show the clinical journey, I think, from beginning to end, and the end is not pretty. As Arshad mentioned, we want to be ahead of that. We want to be proactive in our treatment approach. -- very useful. The 2 programs out of the 4 that are most commonly known are the Lucentis and EYLEA approval. So -- and importantly, the DRSS scale shows us over time, what happens to patients that develop vision treating complications, as I mentioned, the hemorrhage, the bad DME, the traction of repondetachments.

So for those of you who don't know Adnan, he's truly 1 of the foremost clinical trialists from Europe, good friend. We've served on numerous committees together. So I wanted to throw this out to you. Can you discuss the risks of using either a 2-step improvement or a 2-step worsening in other words, a binary endpoint in a DR study.

So although they are attractive endpoints and being used to date in other clinical trials that you showed, they dichotomized and they're validated surrogate biomarkers, they kind of dichotomize the patient's data and don't really summarize the totality of it. So for example, if you can have a patient that improves 2 more stages of of TRS staging. You can have another patient that just improves 1 level or a patient that has a catastrophic worsening of levels of ETRS. And if we have a dichotomous endpoint which is improving 2 or more levels of ETS grade it handles the other patients who may improve and those that have catastrophic visual loss exactly the same. So you're really handling patients that can improve and worsen in that sort of dichotomous endpoint.

So having an ordinal approach really makes a lot more sense because it handles the totality of the data, those that improve those that worsen and those that are stable and look at all of that. And so apart from looking at the totality of the data, has the added advantage of improving the power of the clinical trial. -- to make a more elegant and efficient clinical trial to get the same results.

So Nora for our patients, obviously, they want to prevent vision-threatening complications. The most important treatment goal in nonproliferative diabetic retinopathy patients. Do you think this would have been a better endpoint over our ordinal 2-step approach.

I do not, and I'll go over the practical implications of why. So vision trending complications are bad, as I mentioned. But clinically, our goal is twofold in managing our patients these vision-threatening complications and also preventing disease progression, keeping the patients stable and well, I think, is key. In addition, VTCs imply a 15-letter loss of vision, and that's a really high bar for us clinically.

I think, honestly, it's unethical for most of us to be waiting for that. You could have -- I'll give you an example. So in those nice diagrams that you've shown at the end is PDR and high-risk proliferative disease can present a 2020 vision. -- but the patient has all these vessels that can leak and bleed, as you saw in the fluoroscein over time, it can lead to attractional retinal detachment and literally can't happen overnight. They're still 2020 and suddenly, they're gone. -- loss of vision entirely. So we cannot wait for that. We have to be proactive in our treatment approach. So looking at DTC as an endpoint is not practical or ethical, I don't think clinically.

In addition, the other practical issue is the FDA, as part of the regulatory process would make you choose 1 or the other in clinical design, either diabetic macular edema or prevention of VTC with a 15 letter on PDR. And so you have to choose 1 or the other, so you don't capture the whole patient experience, where the owner scaled us so very nicely.

So Adnan, a statistical unbelievable person. From a probability of success. No, he truly is -- if you don't know Adnan, look them up. Google. He's amazing. But do you think that we would have been better off using VTC as a prime endpoint?

So obviously, what's most important to the patient is function and VTC predicts function. However, VTC or vision fattening complications is a structural endpoint that is relatively rare in your population that predicts eventual visual loss sometime down the line, which is an even longer time. And the reason we have validated surrogate endpoints is to make trials more efficient. So a 2-step visual change predicts vision-threatening complications further down the line that predict visual loss.

So it makes far more sense to look at the much more efficient trial design, which is the 2-step change. And now you've actually raised the bar. We just have with the ordinal change that's even better than a 2-step change. So it's really a far more efficient trial design. Apart from the efficiency of the trial design, it's remarkably unethical to do what the FDA are suggesting as a breadth for the vision-threatening trial complications with visual drop.

So in the U.K., we have diabetic screening. On all 4.5 million diabetics for 20 years where every single diabetic gets images. And we have a national standard that once a patient gets proliferative disease, nothing to do with visual drop. We have to see and treat them within 2 weeks. So there is no way this kind of vision-threatening complication trial design with visual acuity loss would be acceptable, I think, from an ethics committee as well.

So Patricio, we're not leaving you out. We showed a bunch of statistical simulations with hypothetical data. looking at that, looking at the ordinal masses, what are your thoughts on what you saw with the simulations?

Well, clearly, as you presented, the ordinal endpoint captures what we want to see clinically, how many patients improve how many patients get worse, how many patients stay the same. So you don't get a picture of extremes or you have to choose what you want to look at. When you show your simulations, it's very interesting because that was -- clinically, there will be a very good drug. It's a drug that has good improvements, keeps majority of patients the same, very little complications and is tested in front of a population that was very lucky because you had a sham population that had improvements out of the blue.

So -- if you look at that, clinically, that would be very relevant for us, but when you test it with a binary end point, that would be a fair study if you apply the ordinal endpoint that will be an approved drug. So when we look at the HELIOS 1 data, that's data that is very compelling. It's very strong data that will probably be approved under any sort of analysis that you would do, binary or ordinal, but if you move into a Phase III trial with a larger amount of patients, bigger and that means possibility of getting more noise in the evaluation. Why not go for the ordinal the best and not only the most I would say, honest and clinically significant one. This is a study that where we're not only looking for getting an approved new treatment, but learning how to use it on our patients.

So Nora, we've talked about this novel ordinal endpoint, which people are going to be saying in their sleep all night. How do you think results of that oral endpoint will affect you when you talk about treating patients with non-proliferative disease.

Yes. So I mentioned in some cases of patients who really cannot wait for that 15-liter drop that will be required for DTC. But I'd like to congratulate the team on this endpoint. It's novel. I think it's pioneering work, and I think it will be adopted a lot of other companies because it is so useful and it does reflect how we want to practice clinically. So again, we want the patients to not lose vision, to maintain their vision, and we want them to prevent vision loss and improve their vision.

And I think this ordinal scale captures all the range of how we practice clinically. So really, it is the most useful. And again, congrats on kudos. I think you will lead to a paradigm shift in the better way.

We aim to redefine treatment. Adnan, I mean, Arshad a steering committee member chair for the SOL programs, First off, what are your thoughts on the trial design, HELIOS 2 and 3? And number two, would these DR programs allow you to treat patients with DME?

So first, I like the trial design a lot, right? I mean you're looking at the real-world outcome of stabilizing, improving or slowing down the worsening. So that's number one.

Number 2 is I love and there's flexibility there are drugs out there, we don't have flexibility and we cannot use them more often than what the label says. So here you have flexibility. If a patient needs it every 6 months, you'll be able to do that if they need it every 12 months. Great. So you have that.

The other thing, obviously, is no loading doses, right? Some of the trials, we have seen loading doses and then they go into the treatment. So having no loading doses makes it very, very easy to recruit.

And then lastly, you're going for a broad diabetic retinopathy label, right? So I love and the label is broad because when you look at DME, all patients with DME have diabetic retinopathy. But not all diabetic retinopathy patients have DME. So you're actually going for a much bigger market, so any patients with DR, even if they have central or noncentral DME, we will be able to give them this option because DME, it's even worse than AMD, right?

The vision outcomes are even worse because the undertreatment is even more rapid because they're younger and working. So I think looking at as a clinician, as a clinical trialist, I think this is really going to give us an option and the trial design is, I think, is brilliant because we will be able to get treatments to those diabetic patients that go blind in front of our eyes because we just can't treat them with the current options.

So Adnan, historically, companies have done their DME studies and then later, they follow up with a DR study or they use the DME study to get a DR label. Do you think we need to run a separate trial in center involved DME alone?

So I think it's unlikely. So Arshad really set the background. So in your current trials, you have -- you're treating but patients in that trial, as you've shown in the HELIOS 1 trial, will either have DME that's not involving the center at baseline or have incident diabetic macular edema afterwards. We know from research work from my colleague and many others, that the DME, the pathobiology is the same, whether it's in the center or just away from the center.

And we know from previous trials, the response is the same. So within the DR trial, you will have robust measures of response to DME and preventing incident DME. So I'm pretty confident that you will get a broad label for DR, including DME, which would be very exciting because Arshad mentioned the burden of treatment, not just for AMD patients, in some ways, it's more problematic for diabetic patients because they're in the working age population. They have multimobility, they have to go and see multiple different doctors that have to take time off work that impacts on the national economy in the U.K., and I've said we're very healthy economic centered in the U.K. So there's real value in having a durable therapy there.

So Nora in my practice, I rarely, if ever, treat NPDR without DME. I rely on watchful waiting. How do you currently treat your DR patients. Do you use anti-VEGF agents, which are approved for this?

Yes. We share your experience at Duke, also a large-volume retinal practice, not dissimilar to yours. And so we are challenged by the volume of injections An additional challenge is this patient population. Diabetics are working adults, they're very busy, and they cannot present for frequent preventative visits and even less so for frequent injections. So I like the greenfield terminology that Jay used because I now understand how this opportunity will be even greater in this population, how will open up treatment possibilities for this unmet patient population.

So yes, I think the value proposition for a higher and diabetic renopathy than in what AMD?

So Patricia, Argentina, South America, we'll let you speak for all of South America, how about that? How do you treat NPDR today? And what do you see as the unmet need in your patients?

Well, we treat the patients unfortunately, unlike many other specialties in medicine, we only show up with a treatment when the patients are already complicated. They cross the line from nonproliferative to proliferative -- so the question is why do we do that? And I guess it's the same situation worldwide. Maybe our system is a little bit more slow in delivering, but the strategy and the idea is the same. Why don't we treat with the treatments we have now? Because the risk ratio, the risk-benefit ratio that we get from treatment is only valid when the patient is at high risk -- that is a proliferative diabetic retinopathy. It's very near getting into blinded, so we need to do something as extreme as to put laser treatment to the retina.

So we don't put that before because the retina, it's okay so far it's not at high risk, although the risk is pretty high. We wait until the patient has crossed this line. This will be the equivalent of your cardiologist telling you that it's only going to lower your cholesterol when you have a heart attack. So once you have a heart attack, we're going to put medication to prevent that. And that's something that medicine does this preventative measures. We don't do it because it's too burdensome for the patients. I'm not going to say to a patient, it's going to be very difficult to have a patient agreeing into coming on a bimonthly basis to get an injection to prevent something that may happen in the future. But if we look at the HELIOS 1 data, we could replicate that or similar to that in a Phase II study that would -- that would allow me to tell the patients sort of putting them in the anticholesterol medication saying, come once a year, I will do a little injection in your eye and that will prevent you getting near that red line that once you cross it, you get into more aggressive treatment.

We cannot do that now with medications that are approved because it means inviting failure has come over, they're going to get 3 injections never come back again. But if we have something that we can deliver on a yearly basis on this patient, that's going to be taken by every patient and probably by every retina decision as well.

So in conclusion, let's have each 1 of you answer this question. Let's just assume our trials are successful. -- the product profile that we've outlined is how the approved label is, how likely are you to use AXPAXLI in your patients -- and how quickly would you start using it. I'll start with you Adnan in the U.K.

So we are fortunate in the U.K. that all my patients on the NHS get access to all the different anti-VEGFs. But I mentioned repeatedly that there's a capacity issue to deliver all this treatment. So I think AXPAXLI because of the durability that we will be shown in the SOL trial, we'll address the capacity issue. And the other thing that also is related to durability is making sure our patients not just for a short-term duration, the duration of a clinical trial, but for the lifetime that the patient has the sustained visual benefit. And our current treatments don't address the capacity and don't address long-term benefits, which, as I mentioned, are -- and when I look back at large data tools, we are not improving our long-term outcomes. So that addressing capacity and long-term outcomes, I think will make it a really perfect fit for the NHS system.

Nora, what about you in Duke?

I share Adnan's perspective on patients' request durability and their caregivers. And I think a durable delivery of every 6 to 12 months will be game-changing in both neovascularMD and diabetic retinopathy. So short term, it would lead to decrease rates of discontinuation and long term to improve vision outcomes. I think, again, game changing.

c

Patricio?

So we will be able to treat more patients with less injections. But the driver for the change of paradigm are going to be the patients. Once the word is out, they're going to say, "I want that one. I don't want the 1 that needs an injection every 3, 4 months, if you're lucky.

And I'll leave the last statement to you, Arshad.

So I think when you look at a new product that is widely adopted, you have to look at 3 things. Number one, it has to have the ease of use. So physicians don't want to change what they're doing. So easy intravitreal injection, not surgery, not anything else. I'm talking about wide adoption. Number two, -- it has to have similar efficacy, but better durability. We saw that with VABYSMO. Vision outcomes were noninferior to standard of care, but we have better durability. But the third is the most important one, I think, in addition. It's intraocular inflammation, cataracts, remnants and optomitis. So those 3 things are super important for checking the box for a product. If you have 2 of those and now the third one, if you have first, second and third, but not the first one, you're not going to be widely adopted.

So when I look at the data to date, obviously, we have to run the trial and get the data. But if the profile looks how it is, especially actually checks all the boxes. So I think it's going to be widely adopted and very quickly adopted if we are able to see the similar efficacy, safety and durability profile that we have seen.

Well, thank you to the panel for your great comments, and I'll turn it over now to my boss, Dr. Dugel.

I hardly a trust me the other way around. What I learned from that panel was that obviously, Peter must either want or owe something from Adnan 3/4 of the way into the program, 2 superlative introductions. I don't know where, which is pretty amazing. So I think what we do now is to have the analyst move here, and I think we have the speakers move there. and let's see who all the speakers there. Sanjay, if you could also come up here in case there are questions I can't answer. Why don't you -- if you can't sit there just at where I was the cannot ask you stuff as well once you sit over there anywhere you can. Come on up. Sanjay?

No, come on up that way you can -- there may be some questions that you could answer that I can't. Okay. So what we'll do is we'll go ahead and ask -- this is the Q&A for all of you.

The only thing that I ask is that you please take the mic stand up and identify yourself and your affiliation, not so much for me. I know everybody here, but for the physicians here. Go ahead. Tara?

I'm Tara Bancroft at TD Cowen. So my question is a simple one. Seeing have Dr. Kaiser asked a lot of KOL questions, which were great. But I'm curious then for the Helio series of trials, if you could tell us more about your powering to and also potential time lines to get through each or both of them to get to an eventual approval.

Yes. So I can answer that. All of the -- both the clinical trials have empowered to a 95% in level. As far as time lines are concerned, look, we haven't disclosed our time lines as yet. We will when appropriate. If you want a context, you can look at the PANORAMA study, and that took about 15 months, we believe that it will be a lot more efficient. All of us having been involved in Panorama I think we realized that, that was not going to be sustainable. It was more of a proof-of-concept study than everything else. And you saw the amazing enthusiasm here for this study, which obviously, the drug is going to be sustainable and widely used more than that. Remember that we already have the sites already here, right? It's the same sites that recruited so efficiently for SOL-1 and SOL-R and it's a matter of just -- they're already greased and write drug to go. So it's just a matter of reactivating those sites. So I'll give you the context of Panorama, but we believe we'll be a lot more efficient here. Yes, Biren?

Biren from Piper Sandler. Maybe starting with SO1 for the physicians. You talked about superiority claim being important for your prescribing patterns potentially. Can you talk a little bit about the margin that you'd like to see in terms of rescue free rate pay versus injection EYLEA from the trial?

The rescue free rate -- can you specify that Biren.

So specifically, so one is designed for 15% delta on superiority. So 35% with a and 20% with control. So I want to kind of understand from the physicians in the KOL panel if they view that as a clinically relevant outcome or whether they believe that that the treatment delta should be something different?

So just to be clear, the rescue is the very first time that the patient is rescued, which is 15 letters or less, right? I mean, after that, the PI decides what -- how to additionally inject based on whatever the patient shows, that's not mandated. Just to be very, very clear. So in SOL-1 as opposed to solar, it's only the first rescue that counts, although we're following the patients from that point on, it's whatever the PI wants to do as a standard of care. But why don't you go ahead, Arshad and any other panelists can answer that as well.

I think, Biren, I think the main thing I'm looking for is so 1 is to meet the primary end point. because remember, the rescue here is very different than what we do in clinical practice. So I think we just want a positive study, as Adnan said, and and we want a product that we can use to extend durability for patients. And we know that it's a heterogeneous patient population in drill world. So I don't think that number from the trial makes a difference on the usage for us. We just want to make sure that it's a drug that is efficacious, safe and is durable.

I agree. I like to design. There is a lot of heeteroginate in wet AMD patients. We've learned to tolerate some types of fluid versus others depending on visual comes from clinical data like the CAD study, et cetera. what I'm looking for is the ability to treat my patients with a drug that I think works best and the superiority label would help a lot because otherwise I'm forced to use step therapy drives me crazy that the payers tell me how to practice, to be honest. And then biosimilars are coming.

So as I agree, I think the superiority is essential, but the SOLAR study will show pragmatically that the 6 monthly dosing is a translatable therapeutic into clinical practice. So it's in combination.

So yes, just what Adnan said, these are complementary studies and probably the best conclusion will come when we have the results from the 2 of them. But having the approval of the first 1 is going to bring a lot of good messages to the second study.

Thank you. Anybody with the speakers, if you guys want to answer just chime in.

Yes. I think as the KOLs have said and they're all very busy clinicians as we are or have been. These are -- what we've designed this for is the superiority, but this isn't how we treat in real practice. And solar is going to give much more insight into the standard of care noninferiority that don't really help guide us.

So Biren, to your -- go ahead. Why don't you go ahead with a microphone over there, but here's what I'll tell you from my perspective. Look, there's a purpose to each of these studies. The purpose of SOLO-1 is to get a superiority label. The purpose of SOL-R is to be clinically relevant. Neither of these trials are ever going to be looked at by itself. -- by definition, right? For approval, we need both. So the thing that I tell everybody is these are fair questions to ask and you should ask them but please understand that when this drug goes to market, both trials will be there.

And the physicians, the payers and the patients we'll have all the information they possibly need, more than in any other drug that has ever been out there when physicians got it in their hands. So always remember to look at both of these trials together, the purpose of SOL-1 is a superiority label their purpose of SOL-R is clinical relevance.

Now having said that, I think this is where you're also going, and this is a fair question. What we have in SOL-1 is a fantastic endpoint from a regulatory point of view. And again, the reason for that is it's a path to a superiority label. However, from a clinical point of view, it may not be quite as relevant. That's why we have SOL-R.

Having -- but the challenge that we have and we understand this, and I want to make sure that I address this as transparently as I can. The challenge that we have with a positive SOLO-1 study is to extract information from that study and make sure that you understand how that's relevant to the success of SOL-R.

In other words, it's not going to be enough, and I get it to simply say, look, we've got a successful SOL-1 study. What we've got to do for all of you is to say and look at the other information we're showing you from SOLO-1 and now you can be more confident than ever that SOL-R is going to succeed. We understand that, and we will do that.

Colleen Kusy with Baird. Thanks for all the information today. Question on the longer-term outcomes for what patients, Dr. Tufail, really interesting work that you've done. Curious if you have any hypothesis as to what's driving those consistent outcomes? Is it under treatment or potentially macular atrophy.

So it's really hard. So what happens in real world? You have big -- we had big EMR data tolls from I think that 30 hospitals in the U.K. that you're very structured the EMRs, as opposed to kind of free text you have in the U.S. So we have quite robust data. We -- what happens is it's difficult. We don't have all the images, so we can't exclude progressive atrophy as a cause. But the number of treatments is increasing. So in the last decade, the number of treatments we've had per unit time has actually increased as we've gone from PRN dosing to fixed EYLEA in first year and then treat and extend.

However, we have parallel curves that the vision tails off in parallel with each 3-year cohort over the last decade. I don't know why the more aggressive treatment is not doing as well, but it's still not as aggressive as a clinical trial of fixed dosing all the way through. And we have a very old paradigm in ophthalmology, whereas in hypertension, we don't check the blood pressure and very antihypertensive dosing, we stick to fixed dosing, which is actually how the clinical trials originally timed to deliver the therapy.

But because injections are not the most pleasant thing in the universe and they're not inexpensive on health care systems, we as ophthalmologists have evolved these trade-off dosing regimes in the real world, which are treatment extend or PRN dosing rather than fixed dosing forever. So I think that is a major contributor and we, as the ophthalmology community plus the patients have kind of gone that way.

To some extent, going towards a fixed 6 monthly dosing kind of addresses that issue but in a much more digestible way, both for us capacity issues and for the patient. So I think that will help. Now obviously, we're not addressing the underlying dry AMD, but that's a different challenge. But I think having fixed dosing will make a huge difference into itself.

Pravin, I was just asking Colleen if he wasn't able to understand that through -- he's got a very thick. He's got a very thick book and [indiscernible]. So you read [indiscernible] Adnan was chairing this session. I presented the 7-year results from the later Phase II port delivery trial where patients then went into 5-year extension in portal. So 7-year data on patients who want sustained delivery. So here, I'm describing pulsatile injection sustained delivery. So in that data set, on average, we lost over 7 years, 2 to 7 letters over 7 years. we put that curve and you can still see the on-demand, it's on retina website.

We put that curve over this real-world outcome curves that Adnan was describing, Cat 5 year, 7 UP study, in those studies, you lose 15 to 22 letters. Board delivery system refill every 6 months. right? But it's a surgical procedure, hardware in the eye, complications, not widely adopted very small market.

I think that's the best proof of concept for the benefit of sustained delivery in patients with neovascular MD. So that's why I'm excited about the SOLEX study that will generate 5-year data on that. So I think macular atrophy probably will happen, we can't stop it. But you know that, that delta is actually from undertreatment and from pulsatile peak and trough CSD fluctuations. So I'm really excited about the SOLEX actually because it will show us in a prospective fashion. If we can simulate what we did with bol delivery system with an in-clinic, every 6-month easy injection, I think that will really change the trajectory of it.

If I can maybe just add something to that on a very practical level, you have an elderly population. -- you have to come back quite frequently for these injections. And they just need to miss 1 or 2 injections when they can have quite a marked visual drop. And the chance of you getting the vision back with a major visual dropper in macular bleed is only about 1 in 3. And at that age group they're going to have the flu. -- other intercurrent disease, their CAGR may not be able to bring them. And those events are cumulative over time. And so having this much more sustained delivery that the proof of print being shown in a trial, but I think that is going to be translatable into much more translatable into the real world. For me is what's missing in our current therapies. And it's slightly frustrating that we haven't really improved over the last decade in the long term.

Super helpful. A quick 1 for the company, if I could. Just on -- did you get any specific feedback from the FDA that you'd need to trials in PDR rather than just one?

So Peter, why don't you -- I know you wanted to say something about the last question, but why don't you also answer Colin's question regarding why we need trials for diabetic retinopathy.

Sure. So the other thing I wanted to add because Colleen question is great. So obviously, if you don't treat a patient their vision is going to go down. But even with pretty good treatment. So for instance, in NHS in the U.K., they have good treatment because they're it's paid for. They have nurses who give injections. And they still have loss of vision. And a lot of that comes from fluid fluctuation. We saw that in Cat. We saw it in Ivan.We wrote about it in VIEW. Wrote about it in Hawken Harry. It doesn't matter the drug, the more fluid fluctuations you have the more atrophy, the more fibrosis the patient developed. And that's the whole idea of SOLEX. Can we prevent that over time and actually have better outcomes like they showed with the port delivery system.

In terms of your second question, most companies only have to do one DR study because they've already got DME and AMD approved. And so the rules of the FDA say, you need 2 different studies for each indication after 2 studies then you can do 1 study thereafter. So on RVO, 1, 2 indications, sorry, after that, you can go down to 1. So because this will be our second indication, we need to do 2 studies.

Sean McCutcheon, Raymond James. So obviously, there is some skepticism here for good reason on the market in NPD. -- maybe can the docks on the panel speak to what your minimal treatment frequency needs to be in order to -- in order for you to think that this is a viable therapy within NPDR and what patients are amenable to in this population?

Yes, Sean, thank you. So the question to anybody in the panel is, look, -- and I understand the skepticism is because you've got an approval -- we got 2 approved drugs that are not used, thus the skepticism. So Arshad, why don't you go ahead and then anybody else in the panel after that.

Yes, Sean, great question. So on average, with moderate to severe NPDR, I'm seeing those patients every 4 to 6 months. So if I have a minimum 6-month treatment, I think they'll be very well received. It's not that they -- we don't believe as a field that anti-VEGFs don't do what they're supposed to do. Patients love improving and patients love not having vision-threatening complications because they know somebody who went blind from it or there are other in blind from it. It's just a treatment burden. So yes, 6 months plus, it's going to be very widely adopted.

I agree. So the issue we have with NPDR is not that we don't want to treat. We just cannot. We have capacity issues. And they're in the U.S. or outside the U.S., Europe, South America -- so we just cannot. And this is again a younger population, very busy like all of us in this room. It's hard to come in, the approved agents have the implications for frequent injections every 1 to 2 months. So this is what happens. My frequent patients in NPDRs what happened. Even with DME, they come in, they get 2 shots and then they get lost to follow-up. And then they come back when they embed shape. And that's not an ideal outcome. So every 6 months, I think, would be definitely tolerated by the patient population, ideally, 6 to 12, somewhere in there would be the best. I think then would really make huge strides forward in this patient population.

So the HELIOS data shows very clearly that we can do 1 year. And that -- if you think about it from a clinician and patient standpoint, that's perfect. But the beauty of doing it a little less -- a little more frequently, 6, even 9 months, is that then you know that if the patient misses that visit or something comes up, they have a deadline they have to hit -- they're still covered, and that's the beauty of this durable treatment. With anti-VEGF, we don't use it because the most we can probably go is about 3 months between injections, maybe pushing it to 4. And if you start missing those injections, they're going to be -- there's probably going to be a rebound. There's going to be an issue. So the sweet spot is somewhere around 6 to 9 months.

So Sean, the way that I look at with the statement that you made is really more of a derisking opportunity than anything else, right? What we have is a validated target with a validated mechanism. If you inject a patient with moderate to severe nonproliferative diabetic retinopathy with either Lucentis or Avastin or EYLEA. And if that patient comes back to see you in 48 hours, you're observing a practical mirror. I mean it's amazing, the fluid, the blood goes away, the vessels look better.

The problem is that it just doesn't last. So it's an absolutely validated target -- there's no -- it's completely de-risked because we're not reinventing the wheel. All you need is to get something that's going to be more sustainable. So the question then becomes, well, what's sustainable? once a year is certainly sustainable. I mean dentists survive in getting teeth cleaning, right? I mean people come in for their teeth cleaning when their teeth is not aching or falling out once a year. That's not unreasonable. Right? And you don't need much of a percentage of the population because it's such a massive patient population. In fact, we kind of have a wheelhouse of saying, look, every 6 months is really when I want to see patients for a chronic disease. I mean that's kind of our comfort zone.

The other thing I'd also point to is look at HELIOS 3, we're going to have really important data there. There were powered to show a statistically significant difference in treatment between 6 months versus 1 year. And why did we do statistical significance and why not a trend, it's simple because we really want that data. And that data needs to be definitive data by being statistically significant or not, but powered to be statistically significant because no matter what happens in that analysis, we will win. One scenario is, look, the 6 months will look better than the 1 year. If that's the case, the doctors may say, "Hey, you know what, for my most severe patients? I'll bring him in every 6 months, and most of them are symptomatic as well. And that's not unreasonable. But for everybody else, they'll go 1 year.

On the other hand, if there is no difference and they're empowered for statistical significance, we do every 6 months and 1 year, now this drug is firmly cemented as an every year drug. So remember, there's a beauty to the trial design in Helios, again, not designed by my smarter people over here. But we will win regardless, and we will have a definitive answer to 6 months versus 1 year, but either of them going to be viable.

Pravin, if I could just say a couple of things. There are a couple of points here that are really important. The first is any of our patients who have NPDR but also have some degrees of edema. In other words, all of those patients that we showed images of that had edema and all of them got better those patients, that means I would be following those patients at least every 3 months.

Arshad ask -- I'm sorry, Jeff. has to leave for plan. Actually, that's what he's saying, but the rental on a shoes are expiring.

I always have the worst job of ending a good conversation, but unfortunately, we're at time.

Okay. We're out of time. Thank you all so much. Look, I want to end where I started. I hope you understand why I said what I said, which is the decisions that are made in this company. every single decision that's made in this company, including what you heard today is made from a position of confidence. And I just want you to remember that is made from a position of confidence. This courageous company. This is a bold company -- this is a company that's opportunistic. And this is a company that will not just succeed and will not just dominate, but this really is a company that's going to redefine this entire field.

And we couldn't be more confident couldn't be happier, and we couldn't be more enthusiastic. And I want to thank all of you not only for being here, but for all your support. I realize that we wouldn't be here without your support. You will find us to be the most available group of people there is. We love to tell our story, reach out to us any time with any questions at all. We do have a cocktail party for you, which is right across over there. I think I picked the wine, so the wine should be good.