Ocular Therapeutix, Inc. (OCUL) Earnings Call Transcript & Summary

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.