All right. Good afternoon, everyone. We're going to go ahead and get started here. Welcome to the Ocular Therapeutix 2026 Investor Day. There we go. During today's presentation, certain statements we will be making constitute forward-looking statements under the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially as a result of a variety of factors, including risks and uncertainties identified in the Risk Factors section of our annual report on Form 10-K and our other SEC filings. With that in mind, it is my pleasure to introduce Dr. Pravin Dugel, Ocular's Executive Chairman, President, and CEO.
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Good afternoon. Thanks for being here. This is a terrific day for us. I really appreciate your spending the afternoon with us. You'll hear a lot of data today. You'll hear a lot about our strategy today. You'll hear also why we're so incredibly excited to have you here. The last time we were here in this very place was in September. At that time, for those of you who were here, which I think is most of you, I said that I would like to have this company defined by three characteristics. Those are that this company is courageous, it is bold, it is opportunistic. Today, you'll hear the confirmation of that. That is absolutely true. With everything we're going to say today, you'll hear that that stands, even more so than ever.
When you are courageous, bold and opportunistic, you do things that people say you can't do. When you say you're going to do it, there are going to be naysayers. I realize that we have naysayers. What do you do to combat naysayers? It's really easy. You establish credibility. How do you establish credibility? The way you establish credibility is by executing and executing and executing absolutely flawlessly and consistently without failure. That's what we've done. Let me just review some of the things that we've done. When we first got this team together in 2024, we were told that SOL1 would be an impossible trial to recruit. You remember that. In fact, the enrollment has not only been outstanding, but it has been well ahead of schedule. We've executed that flawlessly.
Later on that year, we were told that SOL1 would have poor retention and many off-protocol rescues. In fact, the retention and the on-protocol rescues have been exceptional. Good that they're better than any other retina study. That has been executed flawlessly. We were told last year that the modifications that we'd made in SOL1 would negate the SPA. They haven't. The SPA has been retained because we had complete FDA alignment, as you'll hear about today as well. That has been executed flawlessly. Earlier this year, we heard that SOL1 was going to fail. In fact, we heard from some that SOL1 had already failed. In fact, SOL1 succeeded spectacularly and AXPAXLI did something that no other drug has done.
It reached superiority against an anti-VEGF, which had never been done with a p-value that had never been gotten, less than 0.0006. We executed that flawlessly. Today, you've been told that there's no way the FDA will accept a single trial for NDA submission. In fact, what you'll hear today is that we have complete formal and documented, yes, I know this has been going around, we do have FDA minutes. We wouldn't be doing this without the minutes, obviously. Documented alignment with the FDA that we will have a complete package for submission with SOL1 alone and safety only data from SOLAR at the end of this year. You'll hear the details today. We will execute that flawlessly as well. This is not a new thing. You look at this, you'll see that there are other trials that have been approved.
In 2025, there are 28 single trial approvals. This is 61% of evaluable approvals. This is almost half of them are non-orphan diseases. Tomorrow, there'll be another narrative. There'll be another bear narrative. We will do what we have done over and over and over again to combat that. We will execute flawlessly, as we always have, whatever that narrative is. Here's what you'll hear today. You'll hear that the further we dig into SOL1, the more confident we are, the more convinced we are about the impact that AXPAXLI is going to have. The durability and the disease control is absolutely unmatched with a single dose. You'll hear about that more today. You'll also hear that there's a clear path to market.
You'll hear that we have aligned with the FDA formally on a complete package submission that we will have in the fourth quarter of this year. Many of you may wonder why we haven't already submitted. Why we haven't already submitted our NDA and filed. What I said earlier was that we were courageous, we were bold. We're opportunistic, but we're not reckless. Speed without guidelines kills, right? Our guideposts are the U.S. FDA. We have waited until we have full and formal alignment with the FDA. That is why we're talking to you today. We will wait until we have the complete package. That is why we will submit responsibly and completely in the fourth quarter of this year. The goal here is the same. It's the fastest path to FDA approval with the least amount of regulatory risk.
We are doing this carefully, thoughtfully, and responsibly. Because all the timelines have been pulled up, we have to be ready for launch. You'll hear today that we're absolutely ready for launch. You'll hear our commercial strategy as well. What have we learned from SOL1? What we've learned from SOL1 is we knew that Eylea is a good drug. It's a great drug. We also have learned that Eylea lasts a long time. We also learned that AXPAXLI is better. Much better. It lasts longer and is a lot stronger. It's much better than we ever thought it would be. We're thrilled with it.
When we learned that the FDA did not require the SOLAR efficacy data for our complete package, we had the opportunity to go ahead and not just hit the home run, because we already hit the home run with SOL1, but to go for the grand slam, which is a superiority versus high-dose Eylea, having already secured the superiority versus regular Eylea. If we are able to do that, this will secure this drug for decades and decades to come. That's what we're going after. Why wouldn't we with newfound confidence? As you go through this today, what I'd like you to understand is not just the things that you're going to hear, but who you're going to hear from. You'll hear about regulatory from Art Ciociola. There's no one in this planet who has had more drug and device approvals than Art.
He's simply the most experienced regulatory person there is. I wager that the three people behind him put together are not nearly as experienced as he is. Other than Peter. You'll also hear from David Robinson. There's no better person to lead our launch than David Robinson, who's already led the launch and architected the most successful launch in retina in Eylea. On top of the team that we already have, there are no finer people to do this.
What I would ask of you today is this. It's regulatory heavy. I realize that, and that's appropriate, and that's the way it should be. For a successful submission, there are really two things that are required, right? We always talk about the one but not the other. The second one is equally important. The one that everybody talks about is speed, and that's important, I get it. The one that people forget is risk. Speed kills without guideposts, as I said.
Today, when you hear what we're going to do, you'll get the details, but for everything we say, think, "How have they de-risked this? How have they de-risked the submission? How have they de-risked the shareholders?" That's a really important thing, because the goal remains the same. We're not just going to be best in class now. We're going to absolutely be first in class. Gives me great pleasure to welcome three of the finest retina physicians in the planet, who I'm absolutely honored to call my friends, people that I've known for a very long time. Their words matter today. Their words will matter even more when AXPAXLI is approved. I think you know them all. Arshad Khanani from Reno, Nevada, Lejla Vajzovic from Duke University, and Darius Moshfeghi from Stanford University.
Now I'm going to go ahead and hand it over to someone that I said last year was the greatest CMO on the planet, and that's truer today than it's ever been, Dr. Nadia Waheed.
Thank you so much. Thank you, Pravin. I need the little clicker.
You have the clicker on the side.
Thank you so much, Pravin. Oh, thank you. It is an absolute pleasure to be here today, and I'm excited to walk you all through our clinical program for AXPAXLI, starting with our SOL1 study, highlighting the unmatched durability and sustained disease control shown by AXPAXLI. I'm also going to talk a little bit about why clinicians will use this when it gets to market. SOL1, as you all know, is a superiority study designed to compare head to head a single injection of AXPAXLI versus a single injection of aflibercept. The primary endpoint at week 36 was the proportion of subjects who maintained visual acuity, defined as less than 15 ETDRS letters of loss from baseline at week 36.
Even though the primary endpoint was at week 36, patients were followed for rescue to week 52 to evaluate the 52-week durability and up to 12-month dosing of AXPAXLI. Patients received a second dose of AXPAXLI at 52 weeks. The second year of the study was designed to evaluate safety of acute six-month dosing. Accordingly, patients continued in their treatment arm and received treatment every six months. SOL1, as Pravin mentioned, is the first successful superiority trial of a novel agent versus an approved anti-VEGF. The SOL1 study showed AXPAXLI had unmatched durability, sustained disease control, and was well-tolerated by patients. First, let's discuss in more detail the durability of AXPAXLI. The SOL1 study met its superiority primary endpoint with a high statistical significance and a P value of 0.0006.
The study showed an observed difference of 18.3% and also had a highly clinically meaningful risk difference of 17.5% for patients treated with AXPAXLI compared to control in maintenance of visual acuity at week 36. I will also show you some evidence downstream on how the Kaplan-Meier curve data is especially exciting for us as clinicians. At month nine, three out of the four AXPAXLI patients maintained vision with a single injection, demonstrating a strong potential for annual dosing. At month 12, we saw two out of three patients maintain vision with a single injection. 90% of the patients maintaining vision at month nine continued to maintain vision at month 12, clearly demonstrating both the durability of AXPAXLI as well as the predictability of response in these patients. Here is a Kaplan-Meier curve demonstrating extended durability, significantly delaying the first rescue injections in the AXPAXLI arm.
As you can see, the time to approximately 30% of subjects requiring the first rescue is a whole six months later for AXPAXLI than it is for aflibercept. You're all used to seeing some time to 50% event rates in Kaplan-Meier curves, and of course, you're asking why we're using 30% here instead of 50%. That's because AXPAXLI patients never actually hit a 50% rescue rate, even at the one-year time point. Besides great durability, we also see sustained disease control with AXPAXLI. How do we evaluate disease control? As retina specialists, we rarely just look at vision. We look at anatomy, and specifically, we look at fluid in wet AMD patients. As you may know, sustained fluid control leads to better maintenance of vision over the long term. Let's discuss fluid control and what that means in clinical practice.
This graph shows time to 75 microns increase in central subfield thickness from week 8. 75 microns is significant because this is often used as a threshold for retreatment in wet AMD clinical trials. Our SOL1 study showed a five-month delay in reaching 75-micron central subfield thickness gain from week 8 with the use of AXPAXLI. Again, evidence of exceptional disease control in patients. Wait, there's even more. What's more interesting to look at for clinicians is to look at a threshold of greater than or equal to 30-micron increase in CSFT. The reason I say that is because 30 microns is a very small amount of increase in CSFT, and because also fluctuations in retinal thickness of greater than 35 microns are associated with fibrosis and worse long-term visual outcomes.
AXPAXLI showed about a six-month difference in time to a 30-micron CSFT increase from week eight versus aflibercept, again demonstrating outstanding sustained disease control. Now that we've covered fluid control, let's move on to vision control. I think all of you are familiar with this graph. Here, we see the mean change in vision from screening. AXPAXLI demonstrated strong vision control up to nine months with much fewer rescues than in the aflibercept arm. As you know, this represents close to three-quarters of the patients in the AXPAXLI arm that remained rescue-free at week 36 versus only 56% of the subjects in the aflibercept arm. Now that we have dug into the unmatched durability and sustained disease control demonstrated by AXPAXLI, let's discuss how this is tolerated by patients. AXPAXLI was generally well-tolerated in the SOL1 study.
There were no treatment or procedure-related ocular serious adverse events, and no subjects discontinued the trial because of adverse events. Most importantly, there were no cases of endophthalmitis, occlusive retinal vasculitis, or non-occlusive retinal vasculitis observed with AXPAXLI. We are now in year two of SOL1, where mass safety data is being monitored while we evaluate six-monthly dosing, and the DSMC recommends trial continuation. To summarize, SOL1 results highlight AXPAXLI's groundbreaking profile. SOL1 is the first phase III trial to demonstrate durability out to more than nine months, showed up to 52-week visual and anatomic stability, and demonstrated a well-tolerated safety profile. Now that we've demonstrated that the SOL1 results are highly positive and we intend to submit our NDA based on these results, let's talk a little bit about what value each one of the SOL trials now brings going forward.
SOL1 establishes efficacy and safety out to week 52 that will be the foundation of our NDA submission in wet AMD. This trial will support both our U.S. and ex-U.S. regulatory filings while maintaining strong commercial relevance given the strong superiority results of the study and the possibility of bypassing step therapy. Now that SOLAR year one efficacy data is no longer a requirement for NDA submission, we are in the extraordinary position of using the SOLAR trial to best serve our long-term strategic objectives for AXPAXLI, which are to be the best-in-disease agent for wet AMD, as Pravin mentioned. We're now adding a new key secondary endpoint of superiority compared to aflibercept eight mgs EYLEA HD in SOLAR, which will be evaluated at week 96. We also hope to demonstrate prevention of fibrosis and atrophy with AXPAXLI relative to aflibercept two milligrams at this time point.
Moving to SOLX, our open-label extension study, subjects who've completed two years of safety follow-up in either SOL1 or in the SOLAR study are eligible to enroll in the SOLX trial for an additional three years of safety follow-up. We initiated SOLX enrollment in April and believe this will be a tremendously valuable program, both from a commercial relevance as well as a long-term safety perspective. SOLX outcomes may further expand AXPAXLI's potential by highlighting the need to start AXPAXLI treatment early or potentially risk worse long-term visual outcomes due to potential fibrosis and atrophy that may be seen with today's pulsatile treatments. Finally, let's talk about how SOL1 success has impacted our diabetic retinopathy program, which we call the HELIOS program. As you may recall, we first unveiled plans for our registrational program in diabetic retinopathy during our September 2025 Investor Day.
We announced two complementary phase III superiority trials evaluating every six and every 12-month AXPAXLI regimens using a novel primary endpoint that we aligned on with the FDA, which is an ordinal analysis of a two-step change status on the Diabetic Retinopathy Severity Score, or the DRSS, as it's commonly known. Today, we're happy to announce that we will be streamlining this program to prioritize HELIOS-3. This superiority trial will evaluate every 12-month AXPAXLI versus sham, and we will continue to target a broad diabetic retinopathy label by including subjects both without center involved diabetic macular edema, as well as patients with non-center involved DME. The primary endpoint will remain as the ordinal DRSS two-step change status. Here is an overview of the HELIOS-3 superiority trial design. We intend to randomize approximately 620 subjects with moderately severe to severe NPDR without center involved DME.
These subjects will receive either AXPAXLI or sham at randomization and week 48. The primary endpoint will be taken at week 56 from baseline, and subjects will be followed until week 96 for safety. As you will notice, we've removed the Q six-month dosing arm from this study. Why did we make these changes to the HELIOS program? Following our strong SOL1 results, combined with the tremendous evidence that we have already generated in the HELIOS-1 study, we can now confidently say that AXPAXLI will show durability up to 12 months in NPDR, where we know that a once-a-year regimen is highly preferable, and therefore, we streamlined the development to focus on this approach. Importantly, HELIOS-3 will also support our global regulatory objectives. Having said that, I'm now going to pass on to Peter to present to you the highlight of the day, which is our regulatory strategy.
Thanks, Nadia. It's now my privilege to share with you our U.S. regulatory strategy in wet macular degeneration. Here's what we're going to cover today. First, what are the FDA regulations and guidelines that clearly support a single trial submission? Second, why does our SOL1 study meet all these FDA guidelines for a single adequate and well-controlled study that we could file our NDA? Finally, what are some of the confirmatory evidence which are required to support the SOL1 trial as part of a single trial submission? Let's first start with why we can do this. Section 115 of the 1997 FDA Modernization Act specifically amended and defined what the substantial evidence rules were and explicitly allows one adequate and well-controlled trial plus confirmatory evidence to receive FDA approval.
The 1998 and 2023 guidance reiterated that a single trial plus confirmatory evidence meets that statutory requirement for substantial evidence for approval. As was mentioned by Pravin earlier, this is not new. The use of a single trial for FDA approval has been used in the past and in fact has become increasingly frequent over the past few years. In 2024 and 2025, the majority of CDER approvals actually utilized a single trial approach. Moreover, over 40% of these approvals were in non-orphan designations. The 21 CFR Part 314 specifically defines what is an adequate and well-controlled trial. A study that uses sham, for example, which introduces bias, is not adequate and well controlled, and therefore can only be corroborative and cannot be used as a single standalone trial. SOL1, therefore, was prospectively designed to meet all the requirements as defined in 21 CFR Part 314.
What about this thing, the SPA? Well, a special protocol assessment indicates the FDA has agreed specifically on the study design, clinical endpoints, study size, and most importantly, the statistical analysis plan, that they are adequate to address the scientific and regulatory requirements that support approval. SOL1 is the only active wet macular degeneration study that is being conducted under a special protocol agreement. Is this important for a single trial submission? Of course it is. Dr. Boyd at the recent Retina World Congress actually said that a special protocol assessment is an official agreement between a sponsor and the agency that we will accept a certain trial design, and if successfully completing that protocol, that this would be highly supportive of the approval of the product. The Division of Ophthalmology has also stated that p values less than 0.001 could be potentially supportive of a single trial approval.
At that same meeting, Dr. Boyd reiterated and stated specifically that a single adequate and well-controlled trial can support approval, often with very strong p values, reiterating less than 0.001. The Division of Ophthalmology has also approved drugs like OZURDEX for instance, for non-infectious uveitic macular edema based on efficacy from a single trial. The PEACHTREE trial met its primary outcome with a p value less than 0.001 and only 96 patients on study drug. The safety package include 296 patients, with those additional patients coming from the open label AZALEA study. As Nadia mentioned, the primary endpoint of SOL1 was highly statistically significant, and the p value was 0.0006, and this was supported further by six pre-specified sensitivity analyses of the primary endpoint that were also statistically significant. SOL1 is the first study to show statistical superiority in preventing vision loss against an active anti-VEGF control.
Moreover, almost 70% of the patients were rescue-free at one year. As Nadia mentioned, there was a six months difference in between that first rescue injection between aflibercept and AXPAXLI. Finally, three hierarchically controlled secondary endpoints were statistically significant, showing that the clinical meaningfulness of SOL1 is that we demonstrated the superiority on the primary outcome, we had a strengthening effect size over time, we had consistent visual and supportive anatomic outcomes, and together that creates a very highly persuasive efficacy argument. The guidelines clearly define that one trial can establish effectiveness, but what they doesn't mention is the FDA still requires adequate safety exposure. The 2023 guidance tells us that a minimum 300 patients with at least nine months follow-up are required. The AXPAXLI safety data set will include more than 300 patients on AXPAXLI for 12 months. How are we going to do this?
Well, we're going to take the 170 patients from the SOL1 study who have 52-week safety results. We will perform an interim safety analysis of the SOLAR study, looking specifically at patients who have passed the 52-week time point, and this will add more than 130 patients to the safety data set. An alpha penalty will be taken for this analysis, no masked efficacy analysis will be performed on that SOLAR data. We also maintain SOL1 masking into year two, specifically to be able to use this data for labeling purposes. At the 120-day safety update, we intend to add the year two SOL1 safety data to support repeat dosing. The 2023 guidance also defined what can be used as confirmatory evidence to support a single trial NDA submission, and we have broad confirmatory evidence to support our single, highly statistically significant SOL1 study.
What are some of these? One, mechanistic evidence. We know that the role of vascular endothelial growth factor is one of the primary drivers of wet AMD. We also have agency reviews that acknowledge axitinib's potent and selective pan-VEGF receptor blockade. Class consistency is another evidence that they look for. In other words, do other members of the same pharmacologic class behave similar to the observed effect in SOL1? Is it consistent in terms of mechanism action, disease, endpoints, direction of effect? There's extensive evidence, obviously, of the use of anti-VEGF and vision and anatomic gains in wet macular degeneration. AXPAXLI's effect in SOL1 is in the expected direction, magnitude, time course, anatomic relationships, and safety for this therapeutic class in the same disease. We also have strong pharmacodynamic evidence showing axitinib blocks all three VEGF receptors, as well as both PDGF receptors with very high potency and specificity.
Most importantly, this data aligns with the pharmacodynamic evidence from the INLYTA NDA. Animal models show that axitinib inhibits angiogenesis and parasite sprouting, as well as in the gold standard rat CNV model, it inhibits angiogenesis and leakage. In a VEGF challenge model where you sustain VEGF, suppression is crucial to prevent vascular leakage. Traditional extracellular VEGF inhibitors work only in the short term, whereas AXPAXLI shows sustained inhibition of vascular leakage for the entire 90-day duration of the study. Natural history evidence can be used to support, which shows untreated wet AMD patients lose vision, while inhibition of VEGF maintains vision. Real-world evidence support the use of anti-VEGF in wet AMD from the IRIS registry, as well as in our own analysis of a SOL1 emulated population where the visual acuity and OCT results were identical or similar to SOL1, but didn't require nine anti-VEGF injections.
This is what we plan to do. Per the FDA type C written minutes, our planned NDA package will include the SOL1 efficacy data at 52 weeks with no SOLAR efficacy data. The safety database will include both the week 52 safety from SOL1, as well as the interim safety review from SOLAR to submit a complete NDA with more than 300 patients for safety review. At the 120-day safety update, we will provide the agency with year two of the SOL1 safety data. No additional data will be provided that would trigger any major amendment while submitted during the NDA. Specifically, as mentioned before, no SOLAR efficacy data can be submitted because we will remain masked until our key secondary endpoint at 96 weeks. This is what the timeline looks like.
After our release of our positive SOL1 study on February 26, we moved very quickly to align with the FDA to de-risk our NDA submission. In May, we had our in-person type C meeting. We have the written minutes that have reflected what was agreed to at that point, and that was that the FDA agrees we could file our NDA with a single SOL1 trial plus our confirmatory evidence. In the third quarter of 2026, we will have a pre-NDA meeting, which is planned to align with the FDA in terms of the formatting and logistics of those final exhibits. The NDA and what is submitted in the NDA has already been agreed to in a type C meeting. In the fourth quarter 2026, we're going to perform that interim safety analysis of the SOLAR study, as I mentioned.
Once we have that data in hand, we will file our complete NDA package in the fourth quarter 2026. 120 days later, we will provide the year two safety data as mentioned. No additional data that would trigger a major amendment is planned during the entire NDA review cycle. Another important aspect of our submission is not so obvious. The normal pathway is the 505(b)(1) pathway. That's a standard full NDA submission pathway for a new chemical entity. In contrast, the 505(b)(2) pathway is a hybrid pathway. This NDA is used for drugs that are similar to, but not identical to, an approved drug. This hybrid application relies on the safety and efficacy of the previous submission, and this accelerates approval timelines for new formulations, routes of administration, or indication.
Axitinib, as you know, was approved for renal cell carcinoma in 2012. Therefore, we plan to use the 505(b)(2) pathway. Why? Why should we do this? Well, if you submit a hybrid NDA using this pathway, it could speed up the review time by up to 60 days versus a traditional 505(b)(1) pathway, speeding approval timelines. Ocular Therapeutix is submitting a complete hybrid NDA package via the 505(b)(2) pathway that meets the FDA's substantial evidence of effectiveness and safety requirements. We have one positive, adequate, and well-controlled study that was performed under a special protocol agreement with the FDA that has a highly statistically significant result of 0.0006.
Our data has internal clinical coherence and is consistent with the data in that three out of the five key secondary endpoints were met with statistical significance, as well as many of the other secondary endpoints, which all point in the same direction. We have a sufficient safety package that meets all FDA guidelines, having more than 300 patients exposed for nine months or longer. We have broad confirmatory evidence to support the submission of SOL1 as a single study. Now I'd like to invite Art to the panel area up here. Our regulatory head, we'll have a little Q&A session. Art.
Thank you.
One of the things that many of you don't know is who this man standing next to us, or sitting next to us is. He won't talk about himself, so I'm going to do it for him. He has extensive ophthalmic experience in numerous indications as a regulatory person. He has 35 years in both big and small pharma. He's been at Novartis, BNL, Pfizer, GSK, and most importantly, he has overseen the global approval of over 18 new chemical entities. It was a coup for us to get here. Art Ciociola, before you joined us, you were having a very successful consulting career, enjoying your "retirement." What made you decide to join Ocular full time?
Thank you, Peter, for your kind words. I have a small story I want to tell about why I decided to join Ocular. When I was at Pfizer, there was a drug called Macugen, and it was the first drug approved for the treatment of AMD. It was the first VEGF. It was a co-development agreement with a company called Eyetech, which actually has offices, was very nearby here. I remember early on, I was introduced to the project team, and they told me about this drug aptamer, and they said, "Oh, it has to be injected." I assumed this was some sort of infusion, biologics or such. They said, "No. Patients are injected in their eye. It's an intravitreal injection." I said, "Patients would accept this? They continue in the trial?" They said, "Yes.
They're not comfortable with it, but they do," and so on. Peter, fast-forward 20 years. Lots of good drugs approved for AMD. Lots of good drugs. Peter, there still remains patients who are injected every month, every other month, and I believe that puts a significant patient burden on them, on the caregivers as well. Peter, I think this drug has that potential. Patients been waiting, if you don't mind, 20 years for this drug, and I believe this will have a huge impact on patients' lives, patients' families, and I would not pass up the opportunity to join you, the other members, as I look at Nadia, she's waving at me, Jeff, to get this drug approved for our patients in AMD. That's why I joined.
We're glad you're here. Let's jump to the question I think is on everybody's mind sitting in this audience. We've talked about our regulatory discussions. We talked about how we can submit an NDA on SOL1 alone. I think everybody in the audience wants to know, why haven't we submitted the NDA already?
Peter, it's a good point. As you kindly shared with the group, I have multiple NDAs, and I have multiple sNDAs. The key for me, Peter, is this balancing of speed and risk. Speed and risk. Yes, we all want to submit these applications as soon as we can. We want our patients to get these drugs as soon as possible. That being said, Peter, if you do not submit a complete, comprehensive NDA, FDA can reject that application, of course. We don't want that. Of course, we don't want that. Peter, here's what's really important for me as well, is we've aligned with the contents of the submission. The agency understands what we're going to submit. As you nicely described here, we did it under a SPA. We have safety database. We will have established already effectiveness as per the guidance.
What's really important, Peter, is we want to do it in a manner that the reviewers will take our application and review it in a timely manner and not ask extraordinary excessive number of questions, which always delays your application. Peter, that is key for us as we go through that, is that our development program fully aligned with the agency, their expectations through several meetings over the years, written correspondence, and of course, as you described, our recent Type C meeting results.
Well, let's talk about some of those interactions. The most recent one is probably the most important for what we're discussing here. Could you give the audience a peek behind the curtain, so to speak? They weren't in a room where it happened. What happened?
Yeah. It was good. I'm smiling. Many of you know our previous Commissioner, Dr. Marty Makary, he wrote an op-ed article in the New England Journal of Medicine and said that FDA's policy would now go from two trials to one trial. I got lots of questions. They said, "What does that mean? Is FDA changing their standards? What is that?" I said, "No." I said, "We've always had that option." Peter, as you described, since the '90s, okay? There's a guidance, 2023 guidance that was issued. It's actually very clear guidance. It says, yes, you can establish effectiveness based on a single adequate and well-controlled trial. Peter, as we discussed that, we said, "Yeah, it's a possibility." I always said, "It depends on the results of that study." FDA will require the Division of Ophthalmology, a highly significant, clinically meaningful benefit has to be demonstrated.
Peter, in February, when our results were announced of a p-value of 0.0006. With a clinically meaningful difference of 17% at week 36. I still remember that, hearing, "Oh, no, here we go." This is the basis for our discussions, and it meets the substantial evidence of effectiveness based on a single study. Hence, Peter, we requested a Type A meeting. I apologize, Type C meeting, and asked literally a single question. Would the agency accept an application based on our, I'm pointing at the screen, SOL1 study data plus confirmatory evidence, Peter? That was the discussion that we had at FDA. During that discussion, FDA said, "You have presented a compelling argument. Your data package is significant," and that they will accept that application for review.
Peter, that's where we are today. Right now, my team is working real hard on assembling that NDA and progressing this as quickly as we can.
Well, today we shared that in the fourth quarter 2026, we're going to submit the complete NDA. What are some of the gating items that we need to worry about? Specifically, what do you expect the role of SOLAR to play in that NDA?
Peter, you make a really good point here. As you described there, we have to submit a complete, comprehensive data package for FDA to review this in an expedited manner here. Peter, the gating item for us is the adequate safety database. As per the 2023 guidance, we need 300 patients exposed to AXPAXLI. That's what we plan to do by the fourth quarter of this year here. That will be part of that submission. At the time of application, we will submit more than 300 patients who've been exposed to AXPAXLI for 12 months. That is the real key gating item for us here. As I shared, I've got a very experienced regulatory team, experienced in numerous NDAs. Frankly, Peter, I will look at every page of this application when it goes in. We're assembling that application now and pulling that together there.
Frankly, we're going to give FDA exactly what they have asked for and what they require to expedite the review of this particular application. That's what's gating us.
Perfect.
Peter, I have a question for you here. You just talked about the SOLAR data and the impact on there, the change to week 96 top-line data a bit later. I've gotten some questions. Give us some thoughts on that.
When we talk about the SOLAR study, there's a few things that are very important. First of all, what has not changed? What has not changed specifically is, first of all, the primary outcome, which is week 56, non-inferiority to EYLEA 2 mgs, and how and when we're going to evaluate that. There's no change to the non-inferiority margin. It's still four and a half letters, and because it's an adequate and well-controlled study with no sham injections per CFR 314, if we had to use a sham injection, that would have reduced our margin.
That's why we didn't use a sham injection. There's no change to the study conduct. I think the most important thing that has not changed is our absolute confidence in what we expect SOLAR to show. We expect to meet the primary outcome, and that confidence has only been increased since the results of SOL1. Specifically analyzing the rescues and the visual and anatomic data from SOL1 just gives us even more confidence that we are going to hit that primary outcome. What has changed? When we received the written guidance or the written minutes from the Type C meeting, everything changed.
Now all of a sudden, SOL1 was all we needed for our NDA, that means we could use SOLAR specifically for commercial advantage. That's really the important thing. SOL1 will hopefully give a superiority label to 2 mg EYLEA, if we hit this superiority outcome in SOLAR, theoretically, we could have a superiority label to EYLEA 8 milligram, which would be an immense commercial advantage. We have this potential to hit both these things. Remember, in SOL1, the initial primary outcome, or the end primary outcome is at week 36. Initially, we were going to unmask at week 36, we decided to hold off. We made an amendment, we decided to unmask at week 52.
It was really important that we did that, because since we were masked, we had an outcome measure at week 52 that we could use, which was specifically talking about the fact that two-thirds of the subjects at 52 weeks were rescue-free. This is an incredible feat and something now that we have potential differentiator if we were to put that into the label. Had we not changed the masking regimen of SOL1, we would not have been able to get that into the label. We're doing the exact same thing in SOLAR. We want to maintain masking for that key secondary outcome of superiority to EYLEA 8 mgs. By doing that would allow us to be able to put it into the label. That was our thinking behind doing that.
Okay. Makes sense. Totally understandable, Peter. Let me just ask a follow-on question here. I've gotten this question. Why don't we just look at a comparison of EYLEA HD at our week 56 time point?
If you look at anything when you do a study change like that, there's a lot of thought put into it. First off, when you're doing a superiority evaluation, the first question you should ask yourself is: do you have enough patients to meet that superiority outcome? The answer to that question is, of course, yes. The SOLAR was sized specifically for this purpose. It's not something we talked about in the past, we did do this on purpose. Second, the test should be performed when you have the highest likelihood of success. Our highest likelihood of success in SOLAR is meeting a non-inferiority versus EYLEA two milligram Q8 at 56 weeks. Superiority to EYLEA eight milligrams at 56 weeks would be a hard bar. Why? If you remember, everybody was reinjected at 48 weeks.
So that would be two months later, we would be doing the superiority test. In contrast, at the 96-week time point, the previous injection of EYLEA HD would have been six months prior. So in terms of hitting a superiority outcome, the highest chance of hitting that superiority outcome would be at week 96, not at week 56. Because of that, we decided we hit a home run as Pravin says, we want to hit a grand slam. The home run is superiority to 2 mg. The grand slam is superiority to 8 mg, and that's our goal by moving our key secondary to week 96.
That's good. Thank you for that, Peter.
Art, there are some confusion about the way we're going to be doing this, and specifically this 120-day update. Perhaps you can comment what is expected at the 120-day update from the FDA.
Yes, absolutely. Thank you for that. Just for folks in the audience, as many of you know, 120-day safety update is a regulatory requirement. It's outlined in, as Peter, as you said, 21 CFR 314 as well. Frankly, the intent of this really is to update the agency on any new safety risks that have been identified. Think about it. It's now four months after the application has gone in. Your database cut-off is prior to that. The agency wants to know anything new that has been observed in clinical studies here.
Importantly for us, as you outlined here, is that at the four-month safety update, and that was discussed with the agency at our Type C meeting, is that we will be submitting the SOL1 two-year data, which will provide us evidence to support repeat dosing in our labeling, and that is really important for us. The agency will want to see this long-term safety data, hence that two-year data that we will submit at the four-month, 120-day safety update as such. The SOLAR data, as you pointed out, Peter, SOLAR efficacy data will not be submitted in that. I know there have been discussions about that as well. That being said, Peter, by doing it in this manner, this is the fastest regulatory pathway to our approval.
Anyone can submit an NDA at any time, but the question is: will the FDA actually accept that submission for filing? Basing everything we know so far, based on all our discussions with the FDA, what is your confidence level that the FDA will accept the submission? Number one. Number two, are you worried about a RTF, a refusal to file? Are you worried about having to do any major amendments?
Yes. Thank you for that, Peter. As you probably can understand, my expectations and confidence in accepting this application, the agency, it's incredibly high. Given what we've done, outlining all of the criteria, the SPA agreement here, the statistical analysis, the results, our interactions with FDA, incredibly high, Peter. Peter, you're making me smile with a refusal to file, okay? There are many reasons for refusal to files, Peter. As you shared, I've done a number of submissions, NCEs. I've done dozens and dozens of other sNDAs as well, BLAs as well. Peter, I've never gotten a refusal to file. I'm smiling as you ask me that question here. Hence, I'm confident. As I shared with you, we will ensure that that application is complete, comprehensive, all the hyperlinks work, everything.
I not only have an experienced regulatory team, Peter, I also supervise the quality team, who will also do QC on this application as we go through this. I'm very confident we will not get a refusal to file.
Perfect. Glad to hear that. We talked about this third quarter pre-NDA meeting. Some people will say, "Well, everything they just told us is complete BS. They haven't agreed to anything. They still have to do this pre-NDA meeting, and everything could change at this pre-NDA meeting." For those of us in the audience who don't understand what a pre-NDA meeting is, what do you expect the FDA to say or do at that meeting?
Yes. It's a good question, Peter, and pre-NDA meetings, I have every single application that I've submitted, we had a pre-NDA meeting. Basically, these are operational meetings in that you align with the agency on the formatting Okay. It can be font size. It can be any of those types of things. That's what the focus will be on. What are the agency's expectations in how they want to see the data positioned? That will be the focus of these meetings here.
It's not what we've already talked about.
No, that will not change. We have this in our written meeting minutes, as you know, and that will be the content of our NDA. We want to ease the review of the reviewers. We want to present them with the data how they want to see it presented, and that is the key. Peter, as you know, if a reviewer has questions, doesn't understand, what they'll do, they'll ask the question, they'll put your application aside, they'll move on to somebody else, and I want to minimize that. Our goal is to minimize those numbers of questions. Having that pre-NDA meeting, I've asked for it to be in person, I want to sit across from the reviewers and say, "Hey, how would you like this? Hey, how would you like that?" That's the focus. It's an operational perspective.
Perfect. You've said multiple times today, and even Pravin has mentioned, that we actually have the meeting minutes in hand. I'm curious, can you tell us anything about what's in the meeting minutes that may help us here?
Sure. Absolutely, positively. The key for me, Peter, in the meeting minutes was that FDA stated they concluded that Ocular has presented a compelling data package, and that this application would be reviewable.
They didn't say it would be approved or anything like that? Kidding. They don't put that.
No, sir.
Another thing that people have said is why don't you do a rolling submission? Wouldn't that be easier? You just file what you have with SOL-1, when the data comes in from SOL-R later in this year, you just put it in, wouldn't that be faster?
Yes, Peter, I'll answer your question here. Rolling submissions are an option, of course. The key here, Peter, for me, is for rolling submission, a lot of people don't realize, with a rolling submission, you can submit various modules as you go through. Here's the but part. The FDA will not start their review until the application is complete. Not until it's complete. Peter, I think what we've outlined today is the fastest and de-risked regulatory approach here. We've aligned with the agency. They know what they're going to get from us in that application here. We will support that with confirmatory evidence. We have an agreement on our safety database, 300-plus patients exposed to AXPAXLI for 12 months. Peter, this, I believe, is a complete comprehensive submission package, it's the fastest way to get this new medication to our patients.
Well, I really thank you, Art. Before we wrap, any final comments, closing comments?
Peter, I think we've touched on a number of points here. To me, it's balancing the speed and risk aspects of it. We've talked about this. We've discussed this many times as we go through that, frankly, I think we've optimized our pathway as we go through that here. I'm most excited about this application, the approval, so that we can provide a longer durable treatment with better visual outcomes to our AMD patients, Peter.
Thanks, Art. Appreciate it. Get back to work. Now it's my pleasure to invite David Robinson, our Global Chief Commercial Officer, to the podium. David is one of the most accomplished commercial leaders in retina, with deep experience in launching therapies and building franchises. He was the key architect for the EYLEA launch during his time at Regeneron, arguably the most successful launch in retina history. He has end-to-end launch experience, including strategy, planning, execution, and market access. Most recently, he was the Chief Marketing Officer for global ophthalmology at Merck, where he helped lead the global ophthalmology strategy and franchise. It's my pleasure to hand the podium to David.
Thank you, Peter. There's nothing that makes a commercial guy happier than somebody with the enthusiasm of Art Ciociola. I have to say. Nothing makes me any happier. One of the things that I'd like to speak about today is not only preparing for a successful launch, but to give you a little bit of background. As Peter said, I started in the retina space in 2011. One of the things that always has stuck with me is that patients love usually their retina specialist. They love the therapy. They love the fact that they had not only a therapy that would stabilize their disease, but in many cases, improve their disease. I was always taken aback by patients and physicians always ask us when we come in the office, "Can you improve the number of times I have to come into the office a year? Can I come less?
How can we do that?" One of the things that Eylea gave us was the opportunity to increase the opportunity not to have to come into the office so often. Again, it was only eight weeks. If you take a look at what we talked about today, Peter just discussed, been discussed many times today, following successful Type C meeting, we will be filing the NDA in fourth quarter of 2026 and preparing for our launch in 2027, assuming approval. If you take a look at AXPAXLI's potential, this is one of the things I'm the most excited about. This is a $15 billion market, but it's commanded right now by short-acting VEGFs. We have an opportunity to drive this market with AXPAXLI with a change in how often patients have to be seen by their physician.
If you think about that marginally, if you look at Vabysmo, they have seen a small durability change drive a big market. After year three, they had already generated $4.4 billion in revenue. We feel that the durability of AXPAXLI is unmatched by other current agents. You've heard a number of times today, 12 months with a rescue-free rate at 69% rescue-free rate after one year. That gives us the opportunity to have up to a 12-month dosing parameter and gives us the opportunity to have a label that's three times that of the current market today. The question I usually get is, "Well, what's your market? Where are your patients going to come from?" If you look at how the market breaks down, it breaks down in three big buckets.
That is, number one, patients that are on therapy and within the PI, patients that are on therapy and not within the PI, either shorter or longer than, then a group of patients that discontinue. In fact, I always have felt it's interesting the fact that there's a 44% discontinuation rate even after year one. We feel that AXPAXLI gives us the opportunity to bring patients back into the market, keep patients on therapy longer, as well as have an opportunity to switch those patients that are currently on VEGF-on label and ones that aren't on label. If you look at where we feel like we can go with AXPAXLI, in the beginning, we feel like it will be switches from current anti-VEGF patients.
In the longer term, we feel like we not only have an opportunity to continue to get switches from VEGF, but an opportunity as well to take the naive patients starting on AXPAXLI and continuing on the drug longer. Since we released SOL1 top-line results, we've been talking to many, many retina specialists getting feedback from them. One, physicians are telling us that this product will be rapidly adopted. Greater than 90% of retina specialists would adopt AXPAXLI within the first year of launch. Broad utilization in the fact that retina physicians say that improved disease control and predictable greater than six-month duration will drive broad use. It's easily incorporated into a retina physician's office and into the practice. By that, what I mean is the prefilled intravitreal injection is ordered, it is stored, and is delivered in the same way as an anti-VEGF.
You put it into the practice, incorporate it quickly into the full account. In fact, retina specialists post SOL1 have told us that 80% of them would use the product based on SOL1 results alone. If you think about that, 80% of physicians, four out of five, say they will use AXPAXLI broadly when they have SOL1 data alone. Our payer team has been out proactively calling on payers. In fact, to date, they have seen 100% of the carriers that cover Medicare Advantage in Tier 1. They have also seen 100% of Tier 1 commercial lives payers as well. Payers are telling us that they acknowledge that a label with superior durability potentially transforms the market and could command premium pricing in the market. A little bit about launch preparation.
If you look at the current challenges in the market, we have no superiority label in the market today. That means approvals have up to date been based on non-inferiority design, which means minimal differentiation in durability between agents or efficacy. Payers cite that lack of differentiation is making it difficult to choose between treatments. Biosimilar entrants into the market, increased competition to discount or rebate means that the focus is a lot of times on financial and not safety, efficacy, or durability parameters. We feel that that gives us a clear market opportunity to differentiate based on a superiority label with predictive, durable dosing, and positive long-term vision maintenance outcomes. We feel that the market is perfectly set for a product like AXPAXLI. There's 1.8 million wet AMD patients in the market today, but they are seen by a very concentrated call point.
There are between 2,500 and 3,000 retina specialists. More important than that, when you dig under that, about 600 physicians account for 80% of the utilization in the market. According to claims volumes. Not only that, there's a very high initiation rate in AMD because of the fact that it can be a catastrophic disease, as well as a high switch rate, and that's among physicians and patients requesting a switch to particularly a more durable, longer-lasting agent. Our team is ready today. We have a team out there in the field right now of 65 people, 50 salespeople, as well as 15 reimbursement people. That's our DEXTENZA team. Been in the market, still in the market, very stable in the market. As well as a world-class retina leadership that's been responsible for decades of combined experience in the industry, as well as in retina.
Here's some of the key launch preparations that are ongoing. Nowhere close to an exhaustive list, obviously, but in three major buckets. Commercial strategy, predominantly there, launch scenario planning. We looked at a number of scenarios based upon all the work that's been done. This change of looking at our new filing, et cetera, has really pushed us up, and it's really meant that our teams have had to do extra work. I have to say, this is one team that I've worked with, and I haven't worked with a team like this in a long time, of preparation, really being ready to go, and really working on differentiatable plans and differentiatable programs in this market, and I'm very proud of this team. Launch infrastructure, especially looking at patient support hubs.
As you know, patient support hubs help patients get on drug, help physicians' offices get patients on drug. Organizational enablement, particularly looking at talent planning and organization, as well as training readiness. We are very committed to have our team ready to go day one when the product is ready. This gives you just a view into what we're looking at as far as our path to commercial readiness. Obviously, every line here, every arrow here, has 100 arrows under it. They're really in three big areas: preparing our team, preparing our market, and preparing our product to be ready for launch. We feel AXPAXLI has the potential to redefine the retina market. It's a large market size, and there's a global opportunity attached to AXPAXLI. AXPAXLI redefines the retina treatment dosing in the market.
Superior label positions us to put AXPAXLI in a class of one, all of that delivers to our payers, physicians, and patients economic predictability. Thank you very much. With that, I want to introduce Dr. Jeff Heier, our Chief Scientific Officer at Ocular. Jeff.
Thank you, David. As I sit in the audience for events like this over and over, I'm repeatedly grateful to have the opportunity to be with a team of such exceptional and passionate experts. Experts like Pravin, Nadia, Peter, Art, and David, and our teams back home. On top of that, to be part of a team that can bring such an important and impactful drug to really the patients I've dedicated the last three decades of my life to caring for. Over the next several minutes, we will review key design elements of SOLAR that align with FDA guidance and increase the likelihood of study success, we'll follow that with some concepts of outcome analysis.
As we've really discussed in depth over the past two years regarding the SOL program, alignment with the FDA, both in terms of the 2023 draft guidance and public and written communications, is critically important to de-risking the regulatory process. The FDA guidance for non-inferiority trials allows for the investigational agent to be compared to label dosing of either aflibercept two mg or ranibizumab 0.5 mg with a non-inferiority margin of minus 4.5 letters. AXPAXLI dosed every 24 weeks is compared to aflibercept two mg dosed every eight weeks. However, the FDA guidance also states that a comparator arm should have the same dosing schedule as the investigational drug. For that purpose, one arm has aflibercept eight mg dosed identical to AXPAXLI with the same dosing regimen and intervention criteria, satisfying the desired masking intention.
As both Nadia and Peter have described earlier, AXPAXLI will be compared to eight mg of aflibercept dosed every six months for superiority. In addition, sham injections are not recommended due to inadequate masking, this has been emphasized several times by the FDA, both in our communications and in public settings. As such, there are no sham injections in SOLAR. While SOLAR was designed entirely in line with FDA guidance, given the strength of SOL1 that you've heard repeatedly today, our recent FDA feedback, year one efficacy is no longer a requirement for NDA submission. Because of this, we are amending the design of SOLAR and extending the masking period to week 96 to evaluate new important secondary endpoints.
At week 96, we hope to show potential superiority in best-corrected visual acuity over aflibercept eight mg, we hope to demonstrate prevention of fibrosis and atrophy with AXPAXLI relative to two mg of aflibercept. Why are we not taking these measures at week 56? Well, in addition to what Peter described, eight mg of aflibercept's dosing interval in wet AMD was recently expanded for up to every five months after one year of treatment. This new key secondary endpoint will be evaluated at week 96 to align as closely with the aflibercept eight mg year two approved dosing interval as possible. Let's talk about the importance of patient selection. Many, if not most studies, encounter hard-to-treat patients that can disrupt outcomes, this has been apparent in numerous non-inferiority studies.
Several of the leadership team at Ocular were intimately involved in this analysis of patients with early persistent fluid from the aflibercept VIEW phase III program. When you look on the left, when this fluid is present, patients required monthly aflibercept for the best outcomes, and this was superior to every eight-week aflibercept or monthly ranibizumab. When you look on the right, however, without early persistent fluid, all three arms practically overlap. In the Kodiak DAZZLE trial, which was conducted with the old formulation of their drug, patients were placed in dosing regimens based on disease activity. Not surprisingly, this wasn't adequate for some patients. In fact, per Kodiak's own commentary, this was insufficient for some patients.
Each of these last two programs that I've shown you had patients with high need that could readily disrupt non-inferiority outcomes. The SOLAR criteria were carefully selected to exclude those high-need patients that typically require more frequent injections regardless of the intervention. Such patients have been seen in virtually every study and are most likely to disrupt non-inferiority outcomes. In SOLAR, following three monthly anti-VEGF injections, subjects were observed for eight weeks without treatment and had to have a retinal thickness of less than 350 microns and could not increase by more than 35 microns from the lowest CSFT or retinal thickness at any prior visit. Both of these criteria select for stable, well-controlled subjects. Another component of study design involves monotherapy following randomization. The trials for the first and second-generation anti-VEGFs, Eylea, Beovu, Vabysmo, EYLEA HD, dosed only investigational product post-randomization in the active arm.
Non-inferiority trials for agents aimed at extended duration on the order of 6- 12 months and longer are often preceded by anti-VEGF therapy in a loading phase, but then rely upon investigational product only post-randomization in the active arm. This is the case for SOLAR, as well as Susvimo, the port delivery system. Some studies do include mandated supplemental injections with control product post-randomization, but run the risk of being considered combination therapy, especially if additional supplemental injections are required. Keep in mind that once considered combination therapy, a superiority study is typically required, and the bar for such studies is quite challenging to achieve, as we have seen with some recent failures, despite them having early phase promise. Given these considerations, how should the outcomes of non-inferiority trials be interpreted?
The Susvimo FDA review highlighted that efficacy outcomes may be impacted in patients who receive rescue or supplemental therapy. Key considerations include not only the number of rescues, but their cadence and timing relative to the primary endpoint. Subjects requiring rescue therapy, especially more than a single rescue, may be considered either treatment failures or combination therapy. The implication of either of these designations can have a significant impact on regulatory review of efficacy outcomes. In addition to the number of rescues, the timing is equally, if not more important. Rescues close to the primary endpoint, and certainly within the 3 months leading up to the endpoint, garner more critical scrutiny. Such rescues are believed to have a visual acuity impact, meaning they artificially increase the visual acuity measurements, making this a significant review issue for regulators.
Needless to say, such factors are critically important to obtaining a clear interpretation of trial outcomes. Let's summarize this section and identify key components to understanding a non-inferiority trial evaluating extended durability agents. We will highlight a few key points. First and foremost, did the trial meet its non-inferiority endpoint? This is both obvious and intuitive. One should look at the rescues. How many subjects were rescued? If rescued, how many subjects required more than a single rescue? Of rescues, how many were in close proximity to the primary endpoint, especially within three months? Of course, was the trial protocol in alignment with the FDA? This includes attention to the comparator arm, study interventions and rescues, and masking. Along these lines, does the use of other agents, both mandated and rescue or supplemental, constitute combination therapy requiring a superiority design?
All of these factors contribute to the interpretation of study outcomes and require careful analysis in order to fully understand and appreciate study success. Thank you. With this, I think it would be appropriate for us to step to the question and answer session. As Pravin already introduced, we have an exceptional panel of key opinion leaders, clinicians, clinical trialists in Arshad, Lejla, and Darius. We're going to move right to them. I'm going to ask all of you this. As you heard earlier, we met with the FDA and have alignment on submitting our NDA based on SOL-1 efficacy alone in the fourth quarter of this year. Were you surprised when we shared this news with you? Arshad, let's start with you.
Jeff, thanks for having me here. It's great to see everybody. This is fantastic news for the field. It's fantastic news for our patients, their caregivers, physicians, and payers. It's not surprising to me because Peter presented very nicely that it's a very high bar of evidence that you need to submit one trial for approval, and SOL-1 met that. The reason for that is the 1st superiority study, it's adequate and well-controlled because of the SPA. Does not have sham injection because it follows the guidance. As a clinical trialist, you do a lot of clinical trials. You've been doing much longer, Jeff, than I have.
Much longer than anybody in this room except Pravin.
Must. I've been doing it for last almost two decades. This is a very unique thing for the field. I think this is what's going to drive the field forward, where many others will try to get there. It's a very high bar. You and I have been with many trials that have failed. Superiority is not easy. Yeah, very excited about it. Now Monday morning, I can go back to my clinic and tell my patients that something is coming sooner than I was telling them. I was telling them 2028. Now there's a potential to have this in 2027, and this provides great hope for our patients.
Thank you, Arshad. Lejla, I'd love your thoughts.
Thank you. Thank you, Jeff. True pleasure to be here with all of you. I will echo what Arshad just said. For the first time I heard the statistic that you just mentioned in the survey, I would agree that, I'm going to join my colleagues, retina specialists, that 80% of us are comfortable in using this product on day one after approval. Why am I so comfortable, and why am I going to fit into this 80% positive report is because the data is giving me confidence to use it on day one. I'm excited by not only efficacy, but definitely safety. When we talk about PAT surveys, the American Society of Retina Specialists does a yearly survey for retina specialists, and they ask us what is the biggest unmet need. We always talk about safety being one. This trial gives me confidence in safety.
Second thing is going to be duration and treatment burden. To see the efficacy and durability of this product is very exciting. I think coupled all of this gives me great confidence to use it on day one, and I'm super excited now to know that we may have this option earlier than we thought.
Thanks, Lejla. Darius, anything you want to add?
I was completely unsurprised by that announcement. The data is very compelling, rigorous, well-controlled study addressing a superiority outcome against the undisputed market leader, the actual gold standard, aflibercept, for the last 15 years, with a meaningful clinical outcome, which is maintenance of visual acuity. Not just any kind of visual acuity, excellent visual acuity. You're losing four and a half letters at 52 weeks at a baseline of 80 letters. There's no study that has ever exited at 75 letters at the end of 52 weeks. It's crazy vision. Then on top of that, you're controlling for the 40% or 50% of patients that we lose in year two and three. They're just disappearing from us, and we've got six months, nine months, 12 months.
We have 80%, 75%, and two-thirds of the patients are making it to those time points with excellent fluid control, great vision control, and that's an extra safety measure, and that is not lost on the FDA. For me, it's a no-brainer. You made an agreement with the FDA. You delivered on your end of the bargain. It's delivering for the unmet need. Why wouldn't they want to get this approved?
Thank you, Darius. Arshad, over the last few months since the results have come out, there's been a lot of discussion about the SOL1 results. Can you comment on the significance of the trial hitting its superiority primary endpoint? Why is that different?
Yeah, Jeff, as I said earlier, we have been involved in so many trials, and it's a very high bar to hit superiority. I think there are three things I want people to keep in mind. Number one is this is a treatment that is superior to standard of care, as Darius says, aflibercept. This is the first time we are comparing head-to-head durability based on FDA guidance. This is the only trial that has shown 9- 12 months durability in-clinic injection. I think those three things are super crucial because that has not been shown before. What do physicians care about? Physicians care about OCT and anatomic control. The data we have seen with patients with less than 30 microns of fluid, majority of them had that till one year.
If you have good anatomic control, you have durability head-to-head, so there's no marking the water with anti-VEGF rescues. This is clear durability, head-to-head, and safety, and we saw the safety that is well-taught. Those three things on top of the efficacy, I think is very compelling from this data set. I think as Lejla said, and David said, 80% are excited to use it, and physicians are going to use it the way they think is best for their patients.
Great. Thank you, Arshad. Darius, as we've heard over and over, SOL1 is a first-of-its-kind study, and in some respects, the results have been different to interpret than others. When you've been at meetings, what type of questions have you heard regarding the study, and what issues or what types of results seem most unclear?
Yeah. It's really hard when you have something new and it changes your perspective on what's going on. I really just try to focus on when I'm talking with my colleagues about the three things that really stand out to me about this study. Just because it's a new study doesn't mean it's not going up against a high bar. We focus on the superiority outcome right off the bat. You're beating, again, the gold standard in a meaningful clinical outcome, which is maintenance of excellent visual acuity. The next thing is safety. There is no safety signal here whatsoever. You have 94% and 97% of patients completing enrollment all the way through. There's no cases of endophthalmitis, intraocular inflammation of any severe kind. You don't have any occlusive or non-occlusive vasculitis. Then, of course, you get the durability.
We felt very confident coming out of the phase I trial, monotherapy, AXPAXLI, you got patients making out to 52 weeks with good vision and fluid control. Why is that 52 weeks important? Because if you want to get to a 36-week outcome, you got to get a majority of your patients to 52 weeks in order to make that 36-week outcome. We felt very confident. Working in conjunction with the FDA, you got to make sure that it's safe for the patient. How do you make it safe? You choose a responder population, and in this case, the responder population is both on, you get at eight and four weeks, you get aflibercept, and then you test to see if you get the 20/20 vision or gain 10 letters, then you can qualify on the functional aspect.
You also have to make it on the disease control aspect with respect to OCT fluid. You have to get below that 350 microns and show that you're a fluid responder. Interestingly, this results in this very nice group of patients with the best fluid control, 220 microns, roughly, at baseline, and a visual acuity of 80 letters. What does that mean? It means you can only go downhill with respect to vision.
They push back at me and say, "Hey, you got randomized to AXPAXLI or aflibercept, but that's not how I treat my patients." I said, "Really, frankly, I don't care how you treat my patients because you're not going to get a better outcome Even if you're treating monthly with aflibercept, because when you look at the MARINA data with ranibizumab or other data from aflibercept, if you do monthly treatments at six and out to 12 months, the best you can do if your vision is at over 75 letters is lose five letters at six and 12 months. Okay. That's with monthly injections. Here you are, you're going out there and you're getting one injection, and you're going out to 52 weeks, and you're giving up four and a half letters.
The light goes off because now they see, "Hey, this is actually paradigmatic change that's meaningful." Wait for it, I'm walking away at 75 letters of vision, higher than any other trial has ever achieved. For me, once they see this and get it, and they start thinking about it, now they get it.
Great. Thank you, Darius. Lejla, probably among the data that's considered most impactful to clinicians has been the time to first rescue. In this room and on the webcast, we have many of the top investors in the country, if not the world. How should they look at this data and interpret it?
Yeah. Well, Jeff, I completely agree. The time to first rescue, to me, is really the most clinically meaningful measure. Why? Because it really gives us the practical measure of durability in clinic. When the retina specialists look at this data, they really see evidence that rescue-free rates for AXPAXLI were significantly better than aflibercept rescue-free rates. As a matter of fact, if you look at the data itself, you see that AXPAXLI outperformed aflibercept by a measure of six months. We're giving ourselves duration of six months flexibility for our patients. When we talk about, in general, recurrent treatments, patients missing appointments, missing treatments, we know that unfortunately, all of that leads to poor visual acuity outcomes.
When we now have a six-month advantage over currently approved and most commonly used therapy, I would say that is going to yield a really remarkable outcome in the real world. Injection-free or rescue-free rates, I would say, are measure that we talk about in clinical trial. How about the real world? When I see a patient, I'm not thinking when was the last time I injected him. I'm looking at the OCT in front of me. As a matter of fact, my patient is asking me, "How is that OCT looking?" Because we are all focused on anatomy. From the current data, what I see is that OCT, that anatomic measurements were very much solid all throughout the program, and at nine months, really barely variated within a 30-micron difference.
That data for me is even more significant because it really is going to mimic my real-world use of this therapy.
Yeah. Lejla, you mentioned the OCT and how we use that to gauge our treatments. When patients come in and look at the OCT, I tell them, "Fellows have spent two years learning how to read the OCTs." Then they tell me, "Well, I've been with you for eight years, so I feel I'm an expert as well." Arshad, there's been discussion around how to interpret and understand the patient population of SOL1. As we've touched upon, this patient population had the best starting visual acuity of any study we've seen. How do you interpret that from your clinical population?
Being part of dozens of naive wet AMD trials, this patient behaved like what they usually do. They got the two aflibercept injections. They gained vision as expected, so they were at peak vision, and after randomization, the goal was to maintain vision. They're not going to gain any more vision. That's one thing. The second thing is that when I started recruiting for this study, I know a lot of patients in almost all trials, but especially here, the recruitment was really fast because the patients coming in with naive wet AMD are much earlier now than what they used to be back in the day. In this study, we allow good vision patients. What that did was led to very fast recruitment of the trial.
This kind of reflects the real-world patient population that we have in our clinic, which means that when we see this data where two-thirds of the patients are going one year in it translates into very quick adoption in clinic. I think the only difference here, obviously, as I mentioned, is that patients started at randomization with very good vision, but I'm not surprised. This is what patients do. They gain vision, our goal was to maintain it, and we were able to do that.
Yeah, I agree with you. We see now more frequently than not, these are the patients. This is how they present with wet AMD.
Because optometrists have OCTs. We image them much earlier than what we used to, and catching the disease early actually is beneficial for patients.
Absolutely. Darius, you've talked in the past about how durability itself is a safety feature. Can you describe what you mean by this?
Again, another excellent question. I may be unfamiliar to a lot of you guys for a couple of reasons. One is I'm a pediatric retina specialist by training and love. That's what I do. The second thing is my niche has always been safety. I've served on over 20 data safety and monitoring committees. In fact, when I first started working with these guys, I was the independent rescue monitor, and that's what attracted me to this company, is its commitment, driven from the top by Pravin, to ensuring patient safety. When you look at this drug and what it offers, is it gives us peace of mind. What do I mean by that? Well, Nadia, you and everyone here on the panel has alluded to that we monitor patients with OCT technology, okay?
We either use fluid as a proxy to intervene, or we use visual acuity. If we see either of those things, then we can treat right then and there, and if we don't, we feel safe in extending the next time they're going to come. We extend in two-week intervals. Keep in mind that the longest currently approved interval for a single bolus injection is 16 weeks in this disease, okay? We feel comfortable extending you out to ± two weeks in that window. Otherwise, you could lose vision. You could get too much fluid and get permanent loss of vision. You could get too much hemorrhage and get permanent loss of vision. Now, think about this. We're talking a drug now that goes out and we're measuring outcomes in months and years, okay? Not weeks. We're sitting there at nine months and one year.
We have 80% of patients are making six months. Three quarters of the patients are making nine months. Two thirds of the patients are making it out to a year on a single injection. Okay? Now I know that if my patient has an accident, has difficulty getting in, either because they can't afford it or because a family member isn't available, because they want to go to a wedding, they're traveling, or they just want to live their life, they can go out there and I can very happily know that this patient is safe. When 75% of my patients are going to make it out to nine months, if they miss their six-month appointment, I'm not sending out SEAL Team Six to hunt down that patient, ensure that they can come back in and not be at risk for losing vision. That's what I'm talking about safety.
It's complete peace of mind.
Do you have any safety concerns at all, not just about the durability?
Yeah. I was involved in almost every single rescue call along with Barry, and there's no safety signal here. Right off the bat, all you have to do is look at how many patients completed the trial. It was essentially 94% and 97%. There's no cases of endophthalmitis, occlusive or non-occlusive vasculitis. The floaters were related to the drug platform breakup. The timing was consistent with that. There were no visual acuity impacts from that. In that last follow-up, all of the drug particles had spontaneously resolved. There is no safety signal here. The nine cases of intraocular inflammation were mild or spontaneously resolved on their own accord. This is as completely safe a drug that has been introduced in the last 15 years, as a guy who sat on over 20 data safety monitoring committees.
Thank you, Darius. I'm going to ask each of you this question. If you had to simplify the takeaway message from SOL1 for practicing retina specialists, what's the single most important message from SOL1? A corollary to that is, given what you've seen from SOL1 and submission of a single study, is there enough here for you to initiate treatment? Arshad.
Jeff, for me, it's durability 9- 12 months. I think we have never seen that in our field for an in-clinic, easy injection. I think that correlated with anatomic control and the well-tolerated safety profile that Darius mentioned. I think it's enough for me as a retina specialist to start using AXPAXLI as soon as it's approved. SOLAR is important for redosing and more for commercial reasons. I have a question for the audience. You came to me if you had wet AMD, or your parents have wet AMD, and I offered you a two-month drug versus a nine or 12-month drug, how many in the audience will take a two-month drug? Raise your hand. Zero. How many will take a 9- 12? Majority will be untreated, looks like. We don't not treat wet AMD. Let's do it again.
They're filming in the back.
Two-month drug. 9- 12 month drug. Majority, right? Simple answer from a retina specialist as well as the patients.
Yeah. Thank you. Lejla?
Really well said, Arshad. I would completely agree. Disease control, not only disease control, but maintenance of really good vision, visual acuity, and all of that coupled with great safety. No questions. Arshad is asking me, but really my patient is going to be asking me to use this because they very well will come to me saying, "Doctor, I want the nine- to 12-month drug.
Yeah, 100%. Darius?
Yeah, absolutely. It's the durability, plus it just raises the entire visual acuity floor, if you will. We're maintaining excellent vision out to 52 weeks. We have durability that's 125%-200% more than any currently approved dosing regimen on the market today. Who knows, it might even go longer, Jeff. We didn't hit that 50% rescue at one year. We're going to learn a lot more about this drug, hopefully pending its approval. I think my phone's been ringing off the hook from my patients, like, "When can that drug be available for me?
Great. Darius, we've just been finished talking about SOL1 superiority. As we look at SOLAR, which is a non-inferiority, how do you look at the difference between non-inferiority and superiority trials?
This is an interesting one. I think we all get superiority. This drug is superior to that drug. Non-inferiority is a little bit trickier. You weren't superior, but you weren't inferior. You were non-inferior. What does that mean? When I look back on 30 years of clinical medicine, I've never once had a patient, not once, come into my clinic and say, "Hey Doc, can I have the non-inferior drug?" Just hasn't happened. They ask me for the best drug, and they ask me for the long-acting drug. Just like you all said you wanted the durability, my patients want the durability. When we look at non-inferiority trials, they're aimed primarily at getting to the key secondary outcomes. One of those is durability.
What they do is they give you this metric and they say, "Hey, the functional outcome, maintenance of visual acuity is your primary outcome." That's assessed at a certain time point, let's say 52 weeks. Typically, they give you a non-inferiority margin anywhere between one to five letters, and it's usually on the minus side. Let's say you make it to minus five letters at 52 weeks, then hey, you're non-inferior to the gold standard. Immediately the discussion shifts to the key secondary outcome. My drug made it eight weeks. Your drug made it four weeks. I'm superior on durability, and that's what moves that product in the market. However, you got to remember that little visual acuity tax you paid, five letters, because the FDA's keeping track of that. Every 52 weeks you're going to lose those five letters.
The FDA says, "Hey, you got to protect the patient somehow." They give you rescue criteria, which is where I come in, because then I deal with the sites to help them adjudicate these rescue criteria. If you get too much fluid or you lose too much vision, then we give you a rescue therapy, typically with the gold standard. That goes towards your evaluation of did you make the durability. The second tax that the patient pays is how many rescue therapies did you get. You went to 52 weeks, you lost five letters, and you got three rescue injections, but your durability was longer. Is that a win? I don't know. We have to leave that up for the patients to decide. In superiority outcomes like AXPAXLI, we don't have to worry about any of that.
We beat them, we're superior, and we give the greater durability.
Great. Thanks, Darius. Arshad, how should we think about rescue treatments when we're looking at non-inferiority studies?
Yeah, I think Darius made some good points. I think the key is that we need to make sure that we pretty much have no rescues or minimum rescues. As you said, recently many of you were at clinical trials at the SUMMIT, we had Wiley Chambers, asking the question in a panel, I was the moderator, how many rescues are allowed and the timing of the rescue. He said any injection given after randomization is considered rescue. Imagine if you're randomizing a patient and giving him your drug plus an anti-VEGF versus EYLEA. That's a rescue because this is post-randomization. They don't care about the run-in phase, but after randomization. Imagine if you have your own drug and you have aflibercept q8 weeks, the delta, if you're giving a six-month drug, is only four injections in the middle. Right?
The other one group for a year will get six. Your six-month injection will get two, so the delta is very small. If you're giving two injections or you're giving an injection a month before primary endpoint, as you said, Jeff, it's going to change your BCVA. Wiley Chambers said anything after one, you get a penalty, and then the rescue has to be greater than three months from the primary endpoint. Also for us as a clinician, if you are giving two or three rescues and giving another treatment, it really doesn't address the unmet need of durability and treatment burden. I think the non-inferiority design, as Darius said, is an easy way to go, but it comes with a lot of criteria because we don't want a drug that will need a lot of rescue because we already have good drugs.
I think that's why superiority design is ideal, but it's a high bar for approval or to win in terms of primary endpoint. Yeah, it was very enlightening for me because I've been hearing from a lot of people, so I asked Wiley Chambers myself directly, and he was very, very strict and very to the point.
Yeah. Yeah. Lejla, can you comment on the design of non-inferiority trials with regards to the selections of patients, one, and the use of multiple drugs after randomization? Arshad sort of touched on it there.
Yeah. I echo what both of my colleagues here have said. First, it is very confusing for non-inferiority trials, and certainly we don't talk about that with our patients. They want the best drug, most certainly. When we are digesting this information, you really have to look at two aspects, very important aspects. First is the loading phase. That can happen pre-randomization and times post. When you load pre-randomization, you are selecting for the right patient to enter that randomization and continue the trial. That we have done in prior trials. ARCHWAY, for example, one of them, and most certainly SOLAR. That is a key aspect and really gives us a clean data to understand and for us as retina specialists to really digest. I think what gives us even cleaner data now that we randomize the patient is this co-administration.
If you give monotherapy post-randomization, you're really looking at the efficacy of that drug alone. You will fully understand what is efficacy versus if you're co-administering, you're administering the study, the targeted drug, versus what is approved currently on market. One may wonder which drug is really truly giving the efficacy down the road. Is it what we're studying or is it really the therapy that's already approved in market? I think that really murkies the waters, and from clinical perspective, from scientific, from regulatory, it is harder to tease out information when you have co-administration of the drugs. How does this apply to clinical care in just general real world? Well, I can tell you and assure you that co-administering drugs on the same day in clinic is impossible. There's no way any of us will be able to accomplish that.
Why do I say that? Because it's simply logistical nightmare. It's also approval nightmare. There's no way that insurance currently allows us to approve two drugs on the same day to give to the patient. I'm not sure how that's going to change in future, but I doubt it would.
Jeff, I just had a follow-up on that. Even with our complement inhibitors, patients who have GA and neovascular AMD, I'm not treating the same day because it is hard to get paid for it, even though there are two different codes. Here, if you are doing two injections at the same time, you have to use the wet AMD code. Injection, you're not going to get paid for. Forget that, but I don't think the drug will be covered either because you are injecting two drugs the same day for same indication. I don't think that's very practical in also the busy clinic. Patients don't like two needles.
We may suggest come back for another day to do this, but let's be quite frank. We talk about minimizing number of injections for our patient, minimizing treatment burden. Any time we're talking about additional procedures, we're just adding to complexity.
Yeah. Then there's a 28-day thing that you cannot do wet AMD treatment less than 28 days based on the current anti-VEGF injection. I think it's going to be very complex, actually impossible, to give two injections the same day.
Yeah. I think the point about separate days in Boston, they'd rather go to Europe than come from Cambridge to come back to Boston. Let's switch gears to some commercially oriented questions. Darius, how should investors think about the real world questions of treatment burden? We've talked a lot about the unmet need. Is there truly an unmet need from treatment burden?
Absolutely there is, Jeff. As you pointed out earlier, we're doing OCT-guided treatment, 97%, 98%, I think, from the most recent preference and trend survey from the ASRS. We look at the OCT. We are making a determination, which means we're giving every single patient individualized care. Okay. You may have 5,000 patients with this disease, that's 5,000 different treatment plans. On top of that, every one of those patients has a varying degree of fluid control, predictability, responsiveness, and it is completely unpredictable from patient to patient. You just showed up there the data from the VISION trial. If you had fluid early on or VIEW Vista. Yeah, sorry. VIEW Vista trial where you had fluid early on that adversely impacted how the patient would respond later on.
Here, what you have now is the potential, and it seems counterintuitive and maybe not what you would like, to move away from individualized care and to standardize the practice. What this leads to is predictability. If I can get 80% of my patients are going to make six months, I'm going to see that patient twice a year. It's easy. It's going to promote ease of scheduling. It's going to promote inventory control in my office. It's going to clear up my parking lot. It's going to be very predictable as to who's going to be there. You guys laugh at that, parking right now, people spend two hours circling around the Byers Eye Institute at Stanford looking for free parking. It's a big deal when you're moving 550 patients a day, and you never really think of it.
If you can have predictability and normalization with maintenance of excellent visual acuity, no safety concern, and no worry if the patient misses the appointment by, wait for it, three months, they're still under control. This is a game changer for how we are going to transform the clinical practice and make it more predictable and less reliant on the OCT.
That's great. It's interesting you said they'll drive around for two hours to look for free parking. In Boston, they'll drive around for two hours to look for $50 parking. Arshad, if AXPAXLI were to be approved on SOL-1 alone as our NDA submission, where do you see it fitting into the treatment paradigm for your wet AMD patients?
Jeff, that's a great question, and I think the answer is majority of the patients, right? When I think about my patients and a new drug, we have all these patients, hundreds and hundreds of patients in the clinic that are on injections, right? We have two buckets. We have the one who are high need four to six weeks, and then we have the ones that are stable on the second generation treatments anywhere from two to four months. If I have a patient going two to four months and I tell them, "I give you this new treatment that can go 9- 12 months," they're all in, just like our audience. Then you have these patients who are on four to six weeks, very active treatment.
You will give AXPAXLI to them, because of sustained disease control, they may not need supplemental. If they need supplemental, we are going to give supplemental injection on top, but they're not going to be coming in every four to six weeks, but maybe every three to four months. Right? It's addressing majority of the patients that are in our clinic. The third is the smaller number is naive patient, right? We do a lot of trials, many of them go into clinical trials, but if they don't, they'll come in, they'll get an anti-VEGF, and then one or two, and then once the disease is controlled, you'll give them AXPAXLI. I think Darius made a really good point. I treat patients differently than Darius. I don't do fixed dosing. I do treat and extend.
Our experience with Port Delivery System is the same. I have patients who only come and see me once a year for their refill, I have patients who come in every 6 months, I have a few that need supplemental in between their refills. I think I'm more of a treat and extender, I won't be surprised that with AXPAXLI, I have those three to four-month patients now coming in once a year to see me.
Yeah, it's a good point. Given the results of SOL1, I've looked in my clinic in a similar manner, I agree with you. I think the large majority of patients are going to benefit from AXPAXLI. Lejla, given SOL1 had a unique patient population, we've talked about it, earlier diagnosis, better vision, how do you think about the potential impact of AXPAXLI if approved in the broader population?
First of all, Jeff, while we call it a unique patient population that was enrolled, I would say that is really the patient population that's representative of the modern practice. What do I mean by that? While all of us are much more aware of disease itself, the awareness of what age-related macular degeneration in our community among our optometric referral, our general ophthalmologists, and our retina specialists is much further than it has ever been. That's leading to earlier diagnosis. What's leading to even earlier diagnosis is actually OCT, amazing image technology that we have readily accessible everywhere. One day it's, I'm sure, going to be available in grocery stores to be imaged. We're diagnosing patients earlier, identifying patients, now we're actually talking about great visual acuities because we're diagnosing them earlier, we are saving and maintaining the visual acuity long term.
The bar is very high for certain. I do feel comfortable that this patient population is very much the one we see in our practice. On top of it, we do know that results were quite impressive, but also the enrollment was exceeding expectations. Clearly, the rest of the retina specialists agreed that those patients are very much seen in our practices. When you talk about broad label itself for wet AMD, I will just look at historic trials. When I look at, for example, for approval for geographic atrophy drugs, OZURDEX being one of the great examples, patients enrolled in that trial were extrafoveal GA patients. They showed efficacy, and the drug approval is for general patient population, geographic atrophy.
It gives the retina specialist liberty to use it for geographic atrophy alone and for us to learn in a real-world setting how that behaves. I know we're talking about superiority trials, and it's very unique to now have a positive superiority trial. Why is that beneficial? I hope that it's going to translate to greater access for me to utilize this drug for any patient that I deemed that would benefit from. I think that's the biggest limitation now we have. It's really having to go through step therapy and get there, and I hope the superiority trial is going to allow us to now have this accessible to all our patients.
Great. To wrap things up, I'm going to ask each of you this question. We've talked a lot about retina specialists and investors, how they've interpreted the SOL1 data set. What impact would a therapy like AXPAXLI have on long-term patient outcomes if we're dealing with the improvement in adherence, follow-up, and disease control? Arshad?
I think our hope as a field, all of you are here doing this because we want to optimize the outcomes for our patients. I know that patients who come less often are more compliant than patients who have to come every four to six weeks, and not because sometimes they don't want to come. It's just life comes in the way. They don't have a driver, they got sick, they got admitted, and they miss one or two or three injections. They come in with a catastrophic hemorrhage, and now they're blind, and we cannot recover that. That's my hope. We are doing this because we want to have better vision for our patients, and based on the SOL1 data, this clean data set. That's the key, is there's no contamination. It's a clean data set.
We have a drug that can go up to a year in two-thirds of our patients with good anatomic control and safety. I think that's the bottom line, that the excitement is there from the retina community after they understand the trial, and I think patients are waiting for it.
Great. Lejla?
I'm going to tackle on the adherence question portion. The real-world studies over and over tell us that we lose about 50%-60% of our patients in year one to two, and that's primarily due to adherence. Missed appointments because real life happens. Accidents happened, hospitalizations, other events most certainly, too. Now to have a drug that's going to be a safeguard for my patients, so in case that life event happens, they will have therapy that's controlling their disease. I think that really, truly, in the long term, I hope when it translates to even better real-world results than what we see in clinical trial.
Thank you, Lejla. Darius, we'll give you the final word.
You know I always like that, Jeff. I look at it very strategically for the patient population overall. The problem with bolus therapy and increasing durability is that we know that the more injections you give, the better your visual acuity is, the converse is also true. The fewer injections you give, the worse your visual acuity is with current bolus anti-VEGF therapy. We've seen now with two studies, the surgical implant and now with AXPAXLI, that if you have continuous drug release, you can maintain visual acuity for Up to years going out. This addresses one of the central fallacies of the treat and extend OCT-guided regimen, which is that you should only treat for fluid, there's no functional benefit from continuous VEGF inhibition. The visual acuity decline is a late drop-off. Fluid comes first, then you lose it.
If you only always wait until fluid, you're always behind in the functional outcome score. I think if you look five, seven years down the road, you're going to see what I see with my patients. I was just preparing a case report the other day of a patient that I've done about 140 injections now, originally with ranibizumab, then with aflibercept, and now with Vabysmo over the last 10 or 12 years. That patient has fluid in both eyes, convex foveal contours, and he's 20/25 in both eyes. You continuously suppress a patient on monthly or every other month injections for a long term. What I see happening is that guy who's getting 130 injections, 10, 12 years in, could get by with 20 injections, that is a win for the entire patient population. Not just here, everywhere that we have wet AMD.
I think that if you look at the IRIS database, which is run by the American Academy of Ophthalmology, and you go and say, "Hey, look at the visual acuity between 2015 and 2025," we see that patients eventually lose vision because they get fewer injections. What you'll see is they're going to get fewer injections, the visual acuity is going to go up because we're having continuous suppression with long-term predictable durability.
Great. Well, I want to thank the panel. Your insight and expertise is invaluable. With that, I'll invite Pravin to come back up and give us a summary and takeaways.
Thanks, Jeff, and thank you. Great job. Great job. As you guys move around for the Q&A part, please go ahead. I'm not going to take long with this. You heard me say when I started out, look, there are three characteristics that define us. We're courageous, we're bold, we're opportunistic. I also told you that I hope you take away from this that we're careful, we're thoughtful, and we're methodical in what we do. We look after this company like no other.
We look after what we do step by step, even if you may not hear it every day. The fact of it is that we're not just going fast, we're going fast, but with very, very firm guardrails. At the end of the day, I hope you realize how deeply infused that is in our culture. How many times today did you hear the word de-risked? How many times today did you hear the word FDA alliance? How many times today did you hear the word Peter from Art? Okay. Thank you for being here. Look, I hope you realize with this, our hope here, our intention, our goal, and we're right on track, is not just to be best in class, is to be first in class. We'll do that quickly, but we'll also do that responsibly and thoughtfully.
Let's just go to the Q&A. Please go ahead. Biren, go ahead.
Yeah. Thanks, Pravin, and congrats to the Ocular team. A lot of updates, so wonderful job. I've got to admit, you guys always keep us on our toes with all the updates. I've got a list of 10 questions, maybe I'll just go with a multi-part.
Go with number nine.
All right. There you go. Maybe to start on the requirement for confirmatory evidence for the NDA submission. Will the pre-NDA meeting in Q3 discuss the confirmatory evidence that you shared with us, or have you already shown that to the FDA? That's the first question. Second question, of the six components that made up the evidence for confirmatory evidence, were there any weightings assigned to the six? Is there a preference of order, for example, such as SOL1 IRIS data? Then I guess in the context of SOL1 study, what's the weighting of the confirmatory evidence relative to SOL1 data set that the FDA is going to apply to that section?
All great questions. Let me have Art start off, then maybe Peter would like to jump in because Peter is kind of an Art wannabe. Go ahead, Art. Why don't you go ahead?
Let me answer your question. Thank you for your question. As I stated a little earlier, we've always agreed with the agency about what the content of that application will be. That is the SOL1 data plus the confirmatory evidence, plus our 300 patients' worth of data. The agency, as I shared with you, has confirmed that this is a compelling package and that it will be reviewable. The pre-NDA meeting is, and I've done a lot of these pre-NDA meetings, really more about the formatting of those same data. In other words, I want to sit across the table from the reviewer and say, "We're going to format it this way for this table. Is this acceptable?" That'll be the discussion. It's really in operational aspects of the formatting of that application. I hope that answers your question.
Okay. This is like asking a man starving of thirst across the Saharan Desert to be a water critic. Peter, anything to add?
Just a few things. First off, yes, we have presented to the FDA confirmatory evidence. In terms of weighting, that would be asking crystal ball in terms of what they would want for the weighting. Certainly, the most important is a positive, well-controlled study with high statistical significance. That's what matters most. A confirmatory is that. It's confirmatory of that study. The fact of the matter is it's the breadth of our confirmatory evidence that probably made the agency say the things they said in the minutes. Again, doesn't mean we get approved, but it just bolsters our position, I guess, is the best way to put it.
Do you want to repeat what Bill said regarding a SPA?
Yeah, I've been to many FDA meetings, certainly more than Pravin. Usually when you get to the end of these meetings, they have a gajillion questions, really the fact of the matter is Bill probably said at least three or four times that our presentation, our evidence, et cetera, is very compelling. That word actually shocked me. The next thing that shocked me was they only had really one question, which was, "When can you file?" To me, that statement and the fact that there were no questions to us was an incredible meeting, quite frankly.
Go ahead, Nadia.
I will say the big differentiator for our program was that we went in with data. We had obviously benchmarked against what has been published before, previously by the FDA, as well as what Dr. Boyd had said. We did go in, when we went into that meeting, with our data in hand and with the confirmatory evidence in hand. We were able to have a conversation that was not theoretical, but more benchmarked in what is already available.
Yep. Very important point. We went in with data. Anything else to add, anybody? Okay. Next question.
Hi.
Hi, Tara.
Is it already on?
Yes.
Okay. I'll use this one instead. I'm Tara Bancroft from TD Cowen. That was all super helpful context, especially in underscoring your confidence in this particular pathway. We also have to understand contingency plans in the however unlikely event of a refuse to file or a CRL. What would that plan be? Would you say that it's a CRL at the time? Would you wait for 2028 SOLAR data? Would you unmask SOLAR at the time? Something else? Anything to describe what would happen in these events would be super helpful.
Let me try and take a crack at it, then maybe Jeff and Nadia, Peter, anybody else can answer as well. It's very important to state that our confidence in SOLAR is greater than ever. I can't say that enough. I used to say that because of the ramp, which is extraordinarily well designed by this group. Now I can say that more factually because of what we've seen in SOL1. Let me just repeat that because it bears repeating. Realize that using the SOLAR rescue criteria in SOL1, 80% of patients at six months were rescue-free, and that's remarkable. It's even more remarkable when you think about the patient population. This is exactly the opposite patient population that one would choose for SOLAR, right? For a non-inferiority study, you'd want a patient population that's absolutely stable.
For SOL1, we had a patient population by design that was absolutely unstable. They were designed to lose vision. Despite that, we have an 80% rescue-free rate at month six. Clearly, when you go ahead and look at the ramp and you look at the way we've super enriched and super selected patients for stability, we fully expect that number to rise, that's with good reason. Our confidence in SOLAR has not changed. It's gotten greater, if anything, by far. Right? That's the first thing that I would say. The second thing that I would say is we're not doing anything to SOLAR. Right? As far as the primary endpoint is concerned, we're not changing anything. We're still masked, it's still running. That's available to us at any time. It's entirely flexible.
I will reiterate that it became very clear to us that a complete package for the FDA has nothing to do with the SOLAR efficacy data. That's it. That gave us the green light to really use that data for the best leverage we can get in the community. Why would we repeat the same trial and show the same results? Why not show with our newfound confidence in AXPAXLI that we can actually hit a grand slam when we've already hit a home run by going all the way and showing superiority to high-dose EYLEA? That's logical, that's exactly what we're doing. Anybody else want to add? Peter, Jeff, Nadia, Art? Anybody?
I think just to reiterate, the flexibility is tremendous here. We haven't changed anything. We're still running the study exactly the same. The opportunity to demonstrate superiority to 8 mgs of aflibercept at 96 weeks is just too great to not take.
Tara, also realize that we have the opportunity at that point also to look at atrophy and fibrosis, right? Under masking. If we're fortunate enough to show a delta there, which we think we will, there's potential of including that on the label as well. Imagine if we're fortunate enough to do that, what that gets you. A label where you're shown to be superior to EYLEA and high-dose EYLEA, potentially with a delta in fibrosis and atrophy. That will corner the market for decades to come. Nobody's going to do a superiority study, I don't think, based on what we've done. It'll absolutely solidify the market for decades. Why would we pass up that opportunity? Bill? Who's next? Where? Oh, go right ahead.
Hey, guys.
Sorry, I can't see because I've got-
I leave it on
the light shining right on me here.
Hey, guys. Daniel Giraldo from Bank of America. Thank you for the presentation. I had a question on your confidence that submitting the 104-week data from SOL1 will not trigger a major amendment for the review. Is that something you discussed with FDA during the type C meeting? How should we think about ex-U.S. regulatory path? Do you think you will need SOLAR for that?
Yeah, I can take a crack at that, and maybe I'll pass it on to Art, and to Peter, or anybody else that wants to comment. Look, the words major amendment was never ever discussed in any of our meetings. It's a totally different path. There's nothing to see. There's nothing to show. We're masked. I don't see any way that there would be a major amendment whatsoever, when we're not unmasking data at all. I think that's completely off the table, that's never come up. As far as the OUS part goes, David, that's a great question. Look, to be very honest with you, in a company such as ours, our job is, we're not a large strategic that can fire at everything at once. Our priority, unabashedly, has been the U.S. FDA.
Now that that's there, we will continue and intensify our engagement, which has already started with OUS agencies. Having data that goes all the way to 96 weeks in this kind of a study will only add leverage to that, and they would love to see that kind of data with a fairly familiar study design, but with twice as much information. That actually is completely aligned with what we expect in our early conversations with OUS agencies. Art, any more about the major amendment?
I can just add something quick. During our Type C meeting, we did not discuss the SOLAR. Our strategy was focused on single trial, adequate, well-controlled, meeting the evidentiary standards for effectiveness, and then our safety database that we would add to it. That was our focus. I'll give you our OUS perspective here. We're working through that strategy now. As you know, European and other health authorities have a very, very different perspective than FDA at times. I really just think it's moving forward as we pull that strategy together and have those conversations with those regulators.
They would love a study where you can provide two-year information. Yeah, Lisa, go ahead.
Thank you. There we go. Thank you. Thanks for the event this afternoon, Ocular team. Really appreciate all the detail here, especially on your thoughts on the regulatory path and the rationale. Just a couple of questions from me. Your competitor has a non-inferiority trial ongoing right now, that's going to read out soon. Should this fail, either due to efficacy or a safety issue, would you consider unmasking SOLAR under this scenario, or could the FDA ask you to unmask your ongoing SOLAR trial?
Lisa, yeah, thanks for the question. Look, this has nothing to do with anybody else that's out there whatsoever. We're doing our thing because we have a study result that nobody's ever been able to achieve in the history of this planet. It has nothing to do with anybody else. I have no idea what they'll be doing. Good luck to them. At the end of the day, no matter what happens, the way that I see it, what you've heard today, I think we'll all agree, has completely immunized us from anything that happens to anybody else, which is exactly what we want to have. We want people focused on us, what we're doing, because what we've achieved is something no one else has achieved. Whatever happens anywhere else, we're completely immunized from. Bill?
Good afternoon.
Sorry, I've got to go like this because I can't actually see anything from the spotlight.
Hi. Serge Belanger from Needham. Thanks for hosting us this afternoon. First question for the company. Based on the regulatory path you outlined today, what are your expectations for the label? More specifically, how do you think it'll reflect the product's duration as well as the repeat dosing that you're looking for?
Yeah, Serge, it's a great question. I'll give you a quick response, let me use this as a way to bring in our three KOLs as well in terms of what a label means to them and how they would use the product. Look, from our point of view, with this strategy, I don't see why we can't get the label that we are hoping for, which is a label that is the first and only superiority label with dosing from six to 12 months. They'll have all the information for that. As Art outlined earlier on, there's a lot of redosing information that they will have as we continue with this strategy. Again, we haven't had labeling discussions with the FDA. It's premature to do that. I think the other impact of this is how will the label impact the use of this drug?
What I'll also remind you is, look, the label is very important and, in my perspective, at least when I was practicing, not necessarily from how you use the product. All of these KOLs and everybody in my field goes to tons of meetings. Nobody uses any drug that I know of in my field per label or per the phase III trial. Nobody does. At all. At the end of the day, this company's goal, because we always say this, we're for retina by retina. This company's goal is to have this product in the community, period. They'll figure out how to use it. They will. There's lots of questions to answer. They'll answer all of them. We believe that this will be the most impactful drug in the history of retina, but how it'll exactly be used is going to be determined by them.
Why don't, Lejla, why don't you start off and then we'll go from there?
No, happy to. Exactly what you said. We're going to use it most likely off-label, because I completely agree, all of the drugs that are out there approved are, we really use at liberty to help our patients. What is the help we currently need? What is the community asking for? Longer duration therapy that's maintaining visual acuity for our patients. Yes, I will feel comfortable based on the trial design and the efficacy that I see that I will feel comfortable using in my brand-new patients that are diagnosed with wet AMD, and I want to maintain their visual acuity long term. I'll also feel very comfortable to use it in all my patients that are currently being maintained on therapy, and that's the majority of my patients.
In a 50-patient day in a clinic, probably one or two of those patients are newly diagnosed wet AMD, but the rest of them are really kind of continued therapy and maintenance dose of our patients. I assure you I'll be very well feel comfortable using it with those patients, especially based on the efficacy and the safety I'm seeing on that. All of them, literally all of them, new or recurring patient, will very much ask for longer duration therapy from me.
I agree with you. I think for me, this label is a little bit more important than others because of superiority. We have about— When I started 16 years ago in Reno, we had about 80%-90% Medicare straight patients. Now we have about 50% Medicare, others are mainly Medicare Advantage. We have to go through the step therapy of Avastin to biosimilar LUCENTIS, biosimilar Eylea, Vabysmo, and EYLEA HD. We are seeing that with the Port Delivery System that I offer that to my patients, and many of those programs are not accepting as an option because they want you to go through the steps. I think the unique thing here is that if we can get the superiority label in there, that's going to make a huge difference for the patients, right.
Now and practitioners, we can get this drug on demand anytime we want, now we can use it as a monotherapy switch, as a layered therapy for our patients. I think here, that's the part I'm more interested in. The other one is flexible dosing, right. We saw with EYLEA HD, I always said even before the data came out, we want monthly and every six weeks, and they did not have it, and that impacted the adoption, and they had to do the ELARA study to get the four-week label because we had to go seven weeks, and when an anti-VEGF bolus comes out, we usually go with the high-need patients. I think superiority will be huge. It will avoid step therapy. Number two would be every six months dosing. Those are the two things I'm looking for.
Darius?
Yeah. Both of them brought up the excellent points. The key is the flexibility on the downside, the six-month dosing. Not because I am worried about patients who are going to fail at six months, because I want to bring them in, standardize, normalize my operation. I want to see them twice a year, give them the injection, take them off the board forever, and have always six months of vision safety in my pocket. Okay. They want to go on safari. They want to go up to Mars. Whatever it is that they want to do, I don't have to worry about them. They're off the board. Okay. As a safety kind of guy, that's how I view it. If I don't have that, and I have nine months or 12 months, which seems amazing, but it's actually impacting how I manage my patient.
Yeah, that's because your patients live in Marin County, right. That's why they're like that. I hope nobody lives in Marin County. The other thing that I would say is, look, I keep saying this to people. In my 30 years that I did this, we have never had a single drug with good reason that goes from a phase III to the community with better results. Logically, it shouldn't happen because what you're doing in the phase III is selecting the best patient population. We also have a need when we launch to make sure that the first experience is really good. This is exactly what's going to happen with this drug. This is going to be the first drug that ever is going to do better in the community than it did in the phase III study, meaning SOL1.
Clearly, the first experience the doctor has with this drug is going to be fantastic. Let me just explain that. In the SOL1 study, what we did was we picked patients who were designed to lose vision on purpose. That's not your regular patient population that you see. If this drug did this well in that patient population, it certainly will do a lot better in a stable population. In a regular doctor's office, the doctor may see 50 patients, let's just say. Of those, I don't know, one or two may be new. The other 48, 49 are going to be patients that the doctor's been seeing on a regular basis and are stable. They're frustrated, but they're stable. The first interaction will go something like this. "Say, Mr. Jones, I've got a drug that I just got.
The results look great, and I know you're really frustrated that you have to be taking Eylea every two months for five years. Let me see if this drug can help you. But I still want you to come back in two months." That patient will come back, and the doctor will say, "Wow, you're looking great. Well, let's just extend that a little bit more, and let's just extend that a little bit more." If you can take a patient who's been on Eylea for five years every two months to every six months, they're doing back flips. They're thrilled. The bar for success for this drug with the first experience, with the first encounter is very, very low. That's exactly what we want.
We want everybody to have their first encounter to be absolutely fantastic for the patient and the doctor, and that's exactly what we're set up for.
Pravin, can I just jump in there?
Sure.
Pravin has alluded to it, that it's a patient population that's designed to lose visual acuity. This patient population, at best, is quartile four. It's 20%-25% of the overall patient population. They lose vision because their vision is so good to begin with. The remaining 75%-80% of those patients, they all gain vision. They have not been exposed to this drug yet. Those patients are going to lock in high, and they're going to carry it forever. It's going to be transformative when this gets out into the wild.
I just have to add one more comment is, our interest is real-world studies, TRUCKEE, TAHOE, SUMMIT. I'm already designing the study. Maybe we'll call it the Dugel study or something. We'll do it because we want to know, understand how the drug delivers in the real-world patient population. As you said, majority, almost 90%, 95% start would-be previously treated patients. I think there we'll learn, right? That's what we learned about Vabysmo, right? Vabysmo had TENAYA, LUCERNE at different lanes in naive patients, eight, 12, and 16. We had no experience on previously treated patients, and we found out through TRUCKEE that we were adding two weeks on top of Eylea, two milligram with Vabysmo, and that really helped the community understand the anatomic control, and now it's a blockbuster.
We will do that study, and we'll also want to establish real-world safety. I think more of those studies are going to come. We just need the approval.
Just make sure that you start the Dugel study early because now clearly it's going to be pulled up a little bit now. Yep. Bill?
Thanks.
Oh, Sean. Hey.
Thanks, guys. Couple questions from me, maybe require a little bit less pontificating. I know the study is masked through 96 weeks. Will the DSMB notify you if SOLAR hits or misses the primary endpoint at 56 weeks? If so, will you communicate that to investors? If it misses, does the study start or will it continue or stop? Does it continue to week 96? Can you speak to your handling of rescues in the SOLAR stats plan?
Yeah. The first part I can handle, I'll maybe have Nadia step in here for the second part. What I would say is, look, it's a masked study, right? The unmasking is going to happen at week 56. The DSMC hasn't made any comments, thankfully, at all.
Week 96.
96. I'm sorry, 96. That's just a pure safety committee. The answer to your question is that it'll remain masked because we want to preserve the integrity of the study until it's unmasked at week 96. Nadia, do you want to handle the second one?
Yeah. I think it's a very traditional non-inferiority study, that's what our stats plan speaks to. We have had discussions with the FDA, Art can probably talk about this a little bit more, we have a standard non-inferiority margin of 4.5 letters. Outside of that, everything is detailed in our confidential protocol and discussions with the FDA. I'm going to stop over here.
Yeah. Sean, I think it's a very standard way that we're going to look at things, what I would say is you've heard today from Jeff, you may want to comment. What the FDA has said, I think is very, very clear. They haven't changed. All right? What they've said, if you don't have a combination agent, and that's a big if you don't have a combination agent, the first rescue is going to be allowed as long as it doesn't impact the primary endpoint, they traditionally consider that within three months of the primary endpoint. Every other rescue thereafter is going to be under review. I don't know that it could be any more clearer than that.
What I would say is that in any non-inferiority study, what you would want is you would want the whole gamut of information, as Jeff very nicely put out the checkbox, which is to say, "Look, we want to know the number of rescues. We want to know when the rescues occurred." It's good to know how many patients required multiple rescues. I think those are standard questions that will be answered by us and should be answered by any other non-inferiority study. Jeff?
Yeah. I think it's pretty clear. We've heard it from the FDA in communications, you've also seen it at meetings such as the CTS this weekend, that the injections that are different than the investigational product matter. If everybody gets one, that's a rescue. If you get them throughout the course, those are additional injections. When you get them close to the primary endpoint, those are viewed differently as well. They all matter.
Unfortunately, we only have time for one more question. We will have a cocktail reception to follow for any follow-up.
Lachlan, you're the only thing that stands between their happy hour and the question. Go ahead.
All right. I'll go to the long one.
No, no. Go ahead.
Yeah. Lachlan Hanbury-Brown, William Blair. Maybe another on the confirmatory evidence. I think historically, the level of confirmatory evidence is sort of inversely related to the strength of the main trial. You obviously outlined several lines of confirmatory evidence that you have. Did the FDA tell you that you need all of those lines of evidence or that you need a particularly strong degree of confirmatory evidence? Was there any language to that effect or talking about the level of confirmatory evidence that you need so?
Well, what I can tell you is, look, I'll give this to Peter. Knowing Peter, if there's one line of evidence, he'll give you 50 just to make sure that you got it. I think that's exactly what we did to the FDA. Peter?
Yeah, I agree. It wasn't like they said, "This is what we want," or, "This is what we need." It was more like we presented everything that we presented, and they were like, "Yeah. That's great." To me, as you said, if you have a weak primary study, then you need stronger confirmatory evidence. We have both. We have strong confirmatory evidence, and we have a strong study. It just adds to the package. Yes, like I would do anyway, we're going to give them absolutely everything and more.
Peter's learning how to be a regulatory officer, and Art is teaching him, by the way. Again, we have a cocktail party over there. Please go ahead, and proceed over there. Hopefully, the wines will be good. Thank you again for coming here. This is a fantastic day for us. It's a milestone, and to share it with you is really an honor and a pleasure. Thank you for being here. We'll make ourselves available as we always do after this. If you have any questions, we're around. Please let Bill Slattery know. We'll be happy to be on calls with you, answer any questions. As always, look, you'll find us to be about as available as any company, and we're happy to answer any questions and invite any questions from you. Thank you again.