Good morning, everyone. I'm Lisa Walter, Biotech Analyst here at RBC Capital Markets. Thanks for joining us at RBC's Ophthalmology Conference. This session, we have Pravin Dugel, Executive Chairman, President, and CEO of Ocular Therapeutix. Pravin, thanks so much for joining us today. How are you doing? I'm doing great, Lisa. Thank you very much for having me on board here. I'm very grateful to have this opportunity. Thank you for having us. Well, glad to hear it, and it's a pleasure to host you this morning. Pravin, maybe just to kick things off, can you give us a big picture overview of the company and give us an idea about where things stand, with the lead program, AXPAXLI, for retina diseases? Sure. I mean, to be fairly brief about it, as many people know, we're in a phase III program at this point. We have just completed a study that we call SOL-1. It is the first and only superiority study versus an anti-VEGF to succeed. In our opinion, it succeeded with a very robust p- value of 0.0006. Being the first and only superiority drug versus an anti-VEGF makes us feel very proud and very much validates AXPAXLI. We also have a second study, a phase III study, a non-inferiority study that we call SOLAR. That is ongoing, and so far we've said publicly that that will be reading out in the first quarter of next year. Got it. Thanks for that, Pravin. Maybe before we kind of dive into some of the SOL-1 results and your vision for AXPAXLI and the company more broadly, I'm just wondering if you would like the opportunity to comment on an announcement that came last Friday after the close? I'm happy to. As you know, we received a legal action. Again, because it's a legal case, there's only so much I can say, but let me just be general about this and say this. To us, it was sad, it was shocking, and I think that's true for the whole community, and it was unprecedented. You know, one of the things that is important in our community as clinicians and scientists and developers of drugs is that we communicate, and we go ahead and ask questions all the time. It provides us the greatest degree of scientific scrutiny, especially when it comes to safety, and I think that's part of what you sign up for when you're here in this industry. When there's a misalignment, questions are asked, and questions should be asked, or when there's a misunderstanding, questions should be asked, and people should be able to answer those questions with data. If you recall, that happened recently with what we described as floaters, which were actually drug. We answered the questions with, I think, 129 slides in our Macula Society symposium. There was no legal action involved, and we answered the questions with data, and we put to rest what is a very important safety aspect. I think that's the way to handle things, not with a legal action, but rather with the data. Look, the questions won't go away. The questions will still be there. For the sake of patients, I think those questions should be answered, but other than that, because it's a legal action, that's all I can say. Got it. Thanks for that, Pravin. Very helpful. Well, maybe let's talk about SOL-1. This was your pivotal superiority trial. This just read out in February. You know, now that it's you know, been over a month since the readout, I'm just wondering, what has been the feedback from the medical community that you've received after they've had a little bit more time to digest some of the data? Yeah, it's an interesting question. You know, it's a question of who gets this and how quickly, right? The medical community got it very, very quickly. They realized the significance of having a drug that beat EYLEA. EYLEA is a phenomenal drug, and this is a drug that beat EYLEA with a very robust P value, as I said. The medical community got it immediately. As we dig deeper and deeper into the dataset, we will have two themes that we will talk about, which I think will be very important for everybody, particularly the medical community, which is the disease control of this drug and the durability of this drug. I think the Street is getting it now. I think the tide has turned following the Macula Society meeting. That symposium was very important in just being able to clarify the data. There's only so much you can put in a press release, as you know, and certainly strategics get it right away, and there's a great deal of strategic interest that's increased, you know, following a successful superiority study. Again, being the first and only superiority study to an anti-VEGF that has ever succeeded in the history of the planet makes a big difference, and that's a very big achievement. The more and more we look into the data, the more and more data we present, the better and better this drug looks. Got it. That's helpful. Maybe let's talk about the BCVA results from SOL-1. There's been a lot of focus on this in the non-rescue population that you shared. Patients in the treatment arm had about a three-letter loss at nine months. On the one hand, you know, you have this situation where everyone in SOL-1 who was enrolled had to have a 10-letter gain or reach 20/20 vision. Baseline BCVA was very high. Patients ended up with a good vision, 20/25 at randomization. They lost three letters from there. However, if we look at other studies like TENAYA and LUCERNE for Faricimab. You know, patients enrolled at baseline had a mean of 60 letters only, and this ended up resulting in a 6-letter gain. Your baseline, your patients at baseline in SOL-1, they had 80 letters at randomization, lost three. With the Faricimab studies, they started at 60, but gained six. I mean, I guess if you do the math there, the SOL-1 patients still had better BCVA. Is that kind of the right way we should be thinking about it? Lisa, I'm glad you asked the question, but the fact of it is that, very respectfully, absolutely not because the design of the studies and the purpose were entirely different, in fact, opposite. In most studies, patients are selected to improve vision. In this case, specifically because of the way the study was designed, again, validated by SPA, as suggested by the FDA, patients were selected to lose vision. It's really the opposite, and comparing the two really makes absolutely no sense. Remember, what we did was we had patients that we selected who were most anti-VEGF dependent, and we took away the drug in order to allow the vision to drop 15 letters. That's what was mandated. That was done once, and then the patients were rescued, and the delta and the rescues is what was calculated. The purpose and the patient selection is entirely different to the point of being opposite. It certainly isn't comparable at all. The other thing that I would also say that I think is really interesting is if you listen to the talk by Dr. Adnan Tufail in the Macula Society symposium, what he shows there in looking at three different databases is that for patients that have very good vision like we did in SOL-1, there is a ceiling effect. That ceiling effect is almost identical to what we see in SOL-1 to what is seen in not just the IRIS dataset, but also in ANCHOR, MARINA, et cetera. His conclusion was that this drug, meaning AXPAXLI, did as well as it could possibly do given the patients that we selected. In fact, it did as well as Lucentis did in ANCHOR and MARINA given every month. That's a pretty strong statement, and there's a lot of data there to back that up in regards to how this drug behaved and how patients behaved. Those things are really not comparable to other studies whatsoever. Again, I want to repeat, patients were selected to lose vision. That's exactly what they did. Patients are selected in other studies to gain vision. That's exactly the opposite. The translation to the clinic, when this goes to the clinics, is actually quite interesting. In the 30 years that I've done this, there's been no drug, and this is logical, that has gone from a phase III study to the clinic and actually performed better in the clinic. That simply hasn't happened, and that makes sense because we super select patients in clinical trials who are going to be most responsive in a positive way. This will be the first drug that will actually do the opposite. This will actually do much, much better in the clinic than it did in SOL-1, despite hitting a superiority primary endpoint. The reason for that is because the patients that are selected in many ways are the most difficult patients. These are patients that are chosen to fail. This drug will undoubtedly do better in the clinic than it did in SOL-1, despite the fact again that we hit a superiority primary endpoint with a very robust p-value. Got it. That's a very interesting way to think about things, but it makes sense. Patients in the real world are not gonna be the ones who have 20/25 vision to start. That makes a lot of sense. Maybe just talking about real world, you know, I think I've heard from at least one KOL that I've spoken with, that they were considering dosing AXPAXLI if it were to be approved, if they were to start patients on treatment that they would actually start dosing in tandem with an anti-VEGF, meaning they would dose AXPAXLI and use the anti-VEGF on the same day. Two injections into the same eye on the same day when they were starting treatment for the first time. SOL-1 was designed a little bit differently, but I'm just wondering if you think that is an appropriate way to potentially use AXPAXLI in the real world. Well, it's certainly not inappropriate. Let's answer the question about what kind of patients and how this drug is gonna perform, and then answer that question in terms of how this drug may be used. It's a really good question, and it's an interesting question to discuss and to ponder. First of all, if you go to a doctor's office and they've got 50 patients to see, they may have one new patient or two new patients. In the vast majority of patients, the way this drug is going to be used initially is a patient may come in, Ms. Jones may come in, the doctor may say, "Ms. Jones, you know, I know I've had to use EYLEA every eight weeks on you, and I know you're frustrated, I know it's difficult for you to come in. I've got a new drug that I believe is better. Why don't you go ahead and let me use that, and then come in anyway in eight weeks. I just want to make sure you're doing okay." Then she'll come back in eight weeks, and the doctor will say, "Wow, you're doing great, and let's extend that," and extend that until the doctor feels very comfortable extending that to, you know, six months or 12 months or nine months. Those are the kind of patients that the vast majority of the doctors are gonna use this drug in. The bar for success for this drug in terms of durability is actually very low in the real world. This drug will definitely I believe do very well in the real world and be adopted immediately. In terms of using it with an anti-VEGF, I think the jury's still out on that. Now, I personally believe that this is a first-line drug, and the reason for that is that we have some patients, albeit not many, in the study in Australia where we used it as a first-line agent as monotherapy in a treatment-naive patient population, and the drug performed as well as one would expect from commercial-grade EYLEA or Lucentis. Admittedly, that's not a lot of patients. That's not something that we studied. We had a loading phase in this study and also in SOLAR to super select the patient population. Doctors will figure it out, and if a doctor uses a couple of EYLEA injections and then uses this drug after that for the rest of the patient's treatment, it's not gonna change the forecast at all, and I'm not gonna fight that here whatsoever. What I do know is doctors want this drug in their hands. They're ready for it. They're enthusiastic about it, and they'll figure out how to use it. We always do. I mean, look, you know, we use treat and extend in all of our patients. Treat and extend is not in any label, right? I'm confident that this drug will be easily and rapidly adopted, and doctors will figure out how to use it. Got it. No, that makes a lot of sense. When things are commercial, people will figure out how to use them, and often they use drugs differently in the real world than they do in the clinical studies. We've seen that, of course, with the anti-VEGFs. Pravin, maybe just on safety in SOL-1, I do wanna touch on the floaters. You know, there was a 12% rate of the floaters in the treatment arm versus about 1% in the control arm, and you really walked through this at Macula Society, and you kind of explained that these floaters are really drug particles. I guess I have a few questions on this. Did any of these floaters or drug particles end up resolving naturally in patients? Do you have some evidence of that? Yeah. Lisa, it's a very appropriate question. It's a very fair question. What I'd first point out is look at the way we handle that question, right? We didn't shut you down. We didn't do anything. We basically showed you data. The question that came out appropriately was, what are these floaters? There's a difference between the two arms, and people were right. What we showed, again, to reiterate in the Macula Society, is to say these floaters are actually drug. We asked doctors to look for this, specifically the masked PI, so that we would know if the drug was eluting when it should be. The way they looked for this was with indirect ophthalmoscopy, which means that the drugs are exactly where they should be, which is far out in the periphery away from the visual axis. This was all reported by the doctor. Very importantly, this was all reported by the doctor. We showed in the Macula Society that the drug was seen when it was supposed to be seen, around the nine-month area. We showed the chart with the appearance. We also showed that it had no impact on vision whatsoever. We also said very clearly that there's a MedDRA reporting, a system with MedDRA coding, and there is simply no code for drug particle. There just is no code for that whatsoever, so we asked doctors to code as floaters. We just didn't think that this would cause this much concern. When it did, it was easy to address. We addressed it. Your question is very appropriate, which is, did they disappear? What I would tell you is they behaved like a drug did. A drug would be expected to disappear. You will see that data very shortly. I don't wanna get ahead of the medical team, but we have another symposium coming up in a couple of weeks in the Vitreous Society meeting in Las Vegas, and there will be a lot of details that will be shown there. I think your very appropriate question will be answered in a very positive way. Got it. Well, we look forward to that presentation and that additional data. Maybe just one more on the floaters. In SOLAR, this is your non-inferiority study that's still ongoing. Patients are dosed every six months. Is there potential for a higher rate of floaters given the every six-month dosing? I'm just wondering how we should think about that. Yeah. Look, I think the question is gonna be, you know, is this something that's gonna be bothersome? Is this something that is of concern? What I can tell you is, first of all of these drugs are very far away. That's why an indirect ophthalmoscope is necessary to see them. They're nowhere near the visual axis. I want to reiterate that this was all reported by the doctor because the doctor was asked to look, again, far away with an indirect ophthalmoscope. It had absolutely no impact on vision whatsoever, and this did not bother the patients whatsoever. I doubt that this will ever become an issue for the patient. The drug is simply doing what it's supposed to do. The other piece of evidence that I can also tell you is remember, in SOL-1 itself, there's a lot of experience that we have with redosing because remember, every patient at week 52 is redosed. Everybody at week 52 now is already redosed. We have a lot of redosing experience in SOLAR. We have a data safety monitoring committee that observes this very closely, and there have been simply no issues whatsoever. We don't expect there to be any issues. Got it. Thanks for that, Pravin. Well, maybe let's talk about SOLAR. Just curious, have the SOL-1 results maybe informed your view of maybe what to expect for SOLAR? I know SOLAR is ongoing, and it's blinded, of course, and everything like that. But maybe I should ask, what are the data points from SOL-1 that you would point to for maybe investors to gain more confidence on SOLAR potentially being a successful non-inferiority trial? Lisa, great question. Look, one of the things that I did say was to say one of the things we have to do when we have the SOL-1 readout is to provide people even greater confidence in SOLAR. A lot of people did ask me, look, the patients are completely different. They're almost opposite, and that's true. But still, there was no way to not at least look into that, and we did. What we were able to show is that given the SOLAR rescue criteria, that almost 80% of patients in SOL-1 would have been rescue-free. It's not just that that number is really impressive, and it is. It's actually even more impressive when you think about the patient population. The patient population in SOL-1 is exactly the opposite of SOLAR. These patients, as I mentioned earlier on, are designed to lose vision, and that's what they did. In SOLAR, there's an extensive ramp, the longest ramp that we've ever seen. Remember, there are three injections, and there's a 2-month opportunity to observe to see if there are any fluctuations whatsoever. If there are, those patients are weeded out, and then they have two more injections, and only then are patients randomized. So patients are super selected to be absolutely stable. So, my point is that, look, if we can get a rescue-free rate of almost 80% in SOL-1, in technically the most inappropriate patient population for success, we believe that we can do far better in SOLAR, and that should give us all a great deal of confidence. Pravin, maybe just on SOLAR, you know, you're doing this, the longest ramp ever seen, as you put it. I guess for the primary endpoint, it's non-inferiority BCVA. Should we essentially not really expect a BCVA gain from baseline given you're doing this long ramp? Should we pretty much expect a BCVA to be pretty stable? Well, again, it's not an unfair question. I hate to sit here in a study that's masked and guess what we can expect or not expect. I think what we've done here is what we're supposed to do, which is to get the most de-risked patient population possible, to try to do everything we can to hit the primary endpoint. The primary endpoint, as you know, is at week 56, which is an optimal time point for us. It's not blended. It's a single endpoint, which is exactly what we would want, optimally. Also, realize that we have the largest non-inferiority margin that the FDA allows, and we've said that previously and publicly, which is 4.5 letters. Now, what I would guess other than that in terms of, you know, visual acuity and so on and so forth is something that I don't know. What I do know is that we have selected very, very carefully and very logically the most de-risked patient population that we can possibly select. Now we have evidence from SOL-1 that there's a great chance of success in our opinion. Maybe just one last one on the non-inferiority margin. Very well understood that it's 4.5 letters with the FDA in the U.S. What about ex-U.S.? Yeah. So again, we've had a very productive meetings outside the U.S. We certainly are aligned with the OUS regulators. What we haven't done is to formally disclose those meeting details. What we have said is that there are changes that we've made. As you know, there was a change that was made in the rescue criteria of SOLAR, and there are certain changes that we've made. One of the reasons for the changes, a major reason, was to make sure that we're completely aligned with OUS regulators, and we believe we are. We believe that we have a very clear pathway to approval following the success of SOLAR with OUS regulators as well. Got it. That's helpful. So SOLAR, it's, you know, a well-understood non-inferiority trial design, quite versus SOL-1 was a very novel superiority design. Do you think the results from SOLAR that these will ultimately be needed to fuel a stronger commercial launch should AXPAXLI gain approval? You know, I don't think it's gonna be necessarily needed. I think it's gonna be very helpful, obviously. Remember, you know, yes, SOL-1 is novel, but having said that, SOL-1 also has a SPA. SOL-1 is designed for regulatory approval. SOL-1 also has a great deal of information from a clinical point of view that already is very helpful to my colleagues. That's why they've already said, "Look, I'm gonna use this right away. I can use this now." Really, what's most helpful to them is how they decide whether a drug is working well or not, how they decide whether the disease is well controlled or not. How do they decide that? It's not by waiting for a 15-letter loss, right? That's a regulatory endpoint. That's an important regulatory endpoint for a superiority pathway. The way they decide is by looking at the OCT. If you look at disease control, it is unprecedented to think that the majority of patients with a single injection at month nine had an OCT control within 30 microns, is absolutely unheard of. If somebody had said that to me prior to these results, I'd just say that's just not even possible to have that level of OCT control. That's what doctors look at. Will SOLAR help? Certainly. Is SOL-1 sufficient? Absolutely, because the most important thing there, which is disease control and durability, is already proven in SOL-1, period. Pravin, I do wanna touch on the regulatory path. You know, you've been very clear that the plan is to file for approval with the FDA solely on SOL-1 without waiting for SOLAR to read out. Do you have any updates on your conversations with the FDA? Do you have any idea of when you could possibly file an NDA? Well, here's what I will say. We are more confident than ever that we'll be able to gain approval with SOL-1 alone. Given the fact that we've checked every box, given the fact that we have a SPA, given the fact that we have been successful with a very robust p- value. That in and of itself gives us a great deal of confidence with the fact that the FDA, as you know, has said publicly that they will seek studies that are well-designed, well-powered for a single trial approval. That has also been cemented with the New England Journal of Medicine editorial, as you know. There are a couple of things that are really important to say here. One is that the FDA considers this, as per the New England Journal editorial, not an option, but a default position. Now, that's really very forward-leaning. The second thing, perhaps even more importantly, the FDA, as per that editorial, does not consider this a lowering of their standards. In fact, it's an increase of their standards. They want a perfect study that is well-designed, well-masked, and properly powered, and we've already checked all those boxes. We have a SPA. We're not using any sham. We believe that we've done everything possible to allow the FDA to look at this study positively. We've also said from the podium that process of a single trial approval has already begun, but what we won't do right now is to give you the details for our FDA discussion. That wouldn't be appropriate. When appropriate, we certainly will. Suffice it to say that I couldn't be happier with the progress and with the collaboration that we have with the FDA. I fully understand, you know, you're not gonna share ongoing discussions. I guess one question that we do get from investors is, you know, likely by the time you file the NDA for SOL-1, SOL-R is going to possibly read out while, you know, AXPAXLI is under review. Is there a possibility the FDA turns to you and says, "Hey, we just saw the SOL-R results. You need to include this in the NDA. You need to add this in"? Is that something that could happen? Let me just go back and say how confident we are with the SOL-R results for many of the reasons that we've already discussed. We have no issues with everybody seeing the SOL-R results. We're very, very confident in those results. SOL-R is still ongoing. We're executing extremely well in SOL-R. And we're very happy with what we're seeing. Again, we're masked, but we're very happy with what we're seeing. Other than that, look, it'd be inappropriate for me to hypothesize what may or may not happen or even discuss our discussions with the FDA. Suffice it to say again that I'm very, very happy with the collaboration and support that we're receiving from the FDA. Got it. Thanks for that, Pravin. Well, we're kind of at time here. Pravin, thanks so much for joining us today. It's really been a pleasure hosting you this morning. Lisa, thank you for having us. I'm always very grateful for any kind of open dialogue we have like this. I think the community ought to have a lot more of these open dialogues and ask each other questions all the time. Thank you again for allowing me here. It's been a pleasure. Well, thanks everyone for listening in. This ends the session. Take care.