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

Thank you all for joining us. My name is Bill Slattery. I'm Vice President of Investor Relations here at Ocular Therapeutix. We've got a fantastic day ahead for you. So thanks again for joining us. I'd just like to make a reminder that throughout today's presentation, we will be making certain forward-looking statements as detailed on Slide 2 as well as in our SEC filings. At this point, it's my pleasure to bring up Pravin Dugel, Ocular Executive Chairman, President and CEO. Pravin?

Thanks, Bill. And welcome to everybody. We're really excited to host our first investor meeting, and we're absolutely delighted and honored that you're here. So thank you for spending time with us. I think what you'll see is a lot of news, and you'll see what we've done in a very short period of time. You will see a transformation of a company that I think is quite remarkable. It's a transformation into a leading retinal company. And it's a transformation that's remarkable, really not only in its scope, but also in speed. Just put into context, realize that everything you'll hear about today, and there will be a lot and everything you'll see today, and there will be a lot, really has been accomplished in less than 3 months. We are poised to fulfill our mission goal which is to improve vision in the real world. This new company is really based on 3 important pillars. The first one is data. At the end of the day, it's all about data, and we'll show you a fair amount of data today. The second pillar is that of derisking of the regulatory pathway. We'll talk about that as well. And finally, the targeting of what we believe is expansive retinal vascular disease markets. And none of these would be possible without a very firm foundation that I personally am most proud of, which is the -- what I believe without being arrogant is the finest retina expertise ever gathered in this team -- in this planet with his team. So let's talk about each individually. First of all, the data. What you know about are 2 studies regarding wet AMD, one from Australia and that was remarkable because it's the only study that I know of where a sustained delivery TKI has been used as monotherapy in treatment-naive patients. So really completely naked. And the results that we saw, as you can see in the OCTs on the left, is really what you would expect to see with commercial grade EYLEA or Lucentis. The second study that you know of is a U.S. study where TKI, our TKI, AXPAXLI was compared to EYLEA on label. And here, the results are remarkable for durability. And in this study, what we saw was that up to 80% of patients were rescue free per protocol for 10 months with a single injection of AXPAXLI. And you can see why that makes us so enthusiastic and confident about our SOL-1 study where we also have EYLEA on as a control. Today, we'll drop in a third study that we're very proud of. And I dare say it's a study that I think the Street got completely wrong, which is our diabetic retinopathy study. You will see why we're very, very enthusiastic about diabetic retinopathy despite the fact that this study had only 13 patients who were treated. This study was designed for safety, but the results that we'll show you at 48 weeks, I think, is quite remarkable and shows irrefutable, in our opinion, that this drug is safe, effective and durable at 48 weeks. De-risking of the regulatory pathway. Last year, the FDA issued guidelines that were very clear and very definitive in terms of what they would do to de-risk and approve the study, both a study that was designed as a non-inferiority study as well as the superiority studies. We followed those guidelines, collaborated with the FDA. And designed SOL-1, which we believe from a regulatory point of view, is derisked. We were rewarded with a SPA agreement, a special protocol assessment agreement and Jeff Heier will talk about that in detail. But let me just say 2 things about the regulatory pathway. And I just want to make this very, very clear. We are thrilled with our collaboration with the FDA. We're in touch with them on a regular basis in regards to our SPA agreement. And this is the part that I want to make very clear. We are absolutely, absolutely confident that our SPA is completely aligned with the FDA's current thinking. And I want to make that very, very clear. In other words, nothing has changed. And I just want that to be very clear. The second thing that I also want to emphasize is that we will tell you very transparently and very clearly what we're doing at regulatory risk and what we're not doing at regulatory risk. We believe for the reasons that I've mentioned and the reasons that Jeff will talk about, that the SOL-1 study is, from a regulatory point of view, is derisked. You'll hear about another study today, a repeat dosing study that we will launch. And we're launching this for commercial impact, but it will be, in our opinion, at regulatory risk. Not necessarily clinical risk, but at regulatory risk, and we'll go into that. But very clearly, we'll tell you what we feel from a regulatory point of view is derisked. And lastly, the targeting of the expansive retinal vascular disease markets. Now you all know how large the wet macular generation market is, but what we're seeing really is just the tip of the iceberg. Realize that more than half the patients simply are not treated because the treatment regimen that we have to date is simply not sustainable. And if that dropout rate was decreased by even 5% or 10%, that market size would be exponentially greater. And that doesn't even include diabetic retinopathy, which you will see today, we're very excited about. With that in mind, there are also future opportunities that we'll explore, including PDR or proliferative diabetic retinopathy, diabetic macular edema and retinal vein occlusion. And we believe altogether, this is a huge market potential, and we're poised to exploit the entire market potential with the group that we have, the team that we have. We will solve 2 problems. There's one that you know about that's talked about often, which is reducing the treatment burden and having a more sustainable treatment option. And this is very important. But there's another problem that we'll also solve, we believe, that's not talked about, and in my opinion, equally important, which is a better long-term outcome. There's good evidence now that even in those patients who do get treated and even in those patients that do get treated after 5 years or so, the visual acuity actually gets to be worse than baseline. And the reason it gets worse is not by rebleeding. Actually, rebleeding is a fairly rare event. It gets worse because of fibrosis and atrophy. And there is good evidence that this is caused by our pulsatile nature of treatment. Every time we treat, there's a huge drug effect and goes down, a huge drug effect and it goes down. And what that means in the back of the eye is that there's constant thickening and thinning and constant thickening and thinning, which is akin to having multiple concussions in the back of the eye. And likely, this is what leads to fibrosis and atrophy and loss of vision. So we firmly believe, although this is not the purpose of the SOL-1 study, that in the long term, having a constant and continuous suppression of VEGF will allow for better visual outcomes. AXPAXLI is poised to do both them, which is to reduce the treatment burden as well as provide better long-term outcomes. And finally, the team that we've assembled that this is what I'm really most proud of. And I say this again, I don't think in this planet, there's been a finer group of retina experts and experts to develop a retinal asset than we have right now. And these are not just the people that you'll hear about, these are not just the people that you'll see on the podium. This also includes a group of legacy experts and leaders that we are very, very happy to have with us as well from Ocular Therapeutix. This also includes people that you don't see. We have a very robust group of biostatisticians, clin ops people as well as regulatory people and medical affairs people. So we've assembled an entire team, an entire group, that we're very proud of to develop our retina product. Here are the 3 take-home messages for today. What you'll hear about is that this dream team has produced results that are really quite remarkable in a very short period of time. The second is that we have a clinical trial strategy that's designed for regulatory as well as commercial success. The third is that there's compelling data for AXPAXLI, not in 2, but now in 3 studies that demonstrate favorable safety as well as durable activity. These are our presenters today include Jeff Heier, who is our Chief Scientific Officer; Peter Kaiser, our Chief Development Officer; Nadia Waheed, our Chief Medical Officer. And we're very, very honored to have 2 world-famous retina experts as our KOLs, Baruch Kuppermann, who is the Steiner Professor and Chair of the Department of Ophthalmology and Director of the Herbert Eye Institute at UC Irvine. As well as Dilsher Dhoot who's a partner in the largest retina network in this country, Retinal Consultants of American, and Dilsher is based in Valencia, California. We have a jammed pack schedule that really consists of 3 talks, each one followed by a discussion. First, Jeff will give an overview of the SOL-1 study as well as an enrollment update. Then there will be a discussion. Thereafter, Peter Kaiser will do a study -- a discussion of a new study that we're launching called SOL-R, which is a repeat dosing study, followed by a discussion. Thereafter, Nadia will talk to you in detail about the follow-up of our DR study and give you an update on Helios, followed by discussion. I'll do quick takeaways and then we'll entertain any of your questions that I will moderate in a round table. As I say, we have a packed schedule. I again want to thank you all for being here. We're very excited to present this data to you. We have a lot to discuss, and we're always available to you there after this and later on as well. Bill Slattery is the person to contact for any appointments or any meetings that you would want with us. Without much further ado, Jeff.

Thank you, Pravin, and good afternoon, everyone. Thanks for joining us today. I'm Jeff Heier, Chief Scientific Officer at Ocular Therapeutix. And over the next several minutes, I'll review the SOL-1 study design and then give you our first study enrollment update. So it's -- I think it's helpful to look at the SOL-1 trial time line as it will provide insight into the SOL-1 study design. In the first quarter of 2023, the FDA gave a drug development guidance for neovascular AMD and developing drugs for treatment. In the second quarter of 2023, the AXPAXLI pivotal trial design was adapted to these guidances. And then Ocular submitted this design to the FDA to obtain a special protocol assessment. Now let's talk about what a special protocol assessment is. It's a process in which sponsors meet with the FDA and reach agreement on specific aspects of study design. And those aspects include inclusion criteria, dose selection, endpoints and analyses. It indicates concurrence by the FDA that a study is adequately masked and acceptability of specific critical elements of protocol design. And by adhering to this protocol design, it ensures that a trial can be considered adequately masked and well controlled. And it reflects the FDA's current thinking. In the fourth quarter of 2023, we received written agreement from the FDA for our SPA. And then in the first quarter of 2024, we again received written agreement from the FDA regarding our amended design. So let's talk carefully about the guidance from the FDA because there were some components here that were very different than what we had seen in the past. And there were 2 that really affected study design. The first was that the noninferiority trials using sham injections were no longer recommended by the FDA. And keep in mind, sham injections had been the main masking control for all of the studies we've seen to date in wet AMD. And second, the FDA recommends a comparative arm in which dosing frequency, dosing adjustments and criteria for interventions mirror the investigation alarm. This posed some challenges for non-inferiority trial design. First of all, aflibercept dosed every 8 weeks, the most common historical control, had a dosing frequency that was different than the AXPAXLI arm. We already mentioned that you couldn't use sham injections. And one of the masking recommendations was saline injections. And as you can imagine, the inherent discomfort and risk of saline injections was not acceptable to the majority of patients and clinical trialists. So the study you see here is the typical study design that would have been used in the past. And you can see the AXPAXLI arm then has sham injections every 8 weeks in alignment with the aflibercept dosed every 8 weeks. And we know this would not be considered adequately masked by the FDA. So again, the FDA guidance said comparator arm should mirror the investigational drug and sham injections are not recommended. And we've worked closely with the FDA and our trial is now being conducted under a special protocol assessment. And that means that the SOL-1 trial design, both study arms, have the same dosing schedule and there are no sham injections in either arm. And what this does is this significantly reduces or derisks the SOL-1 regulatory pathway. And again, this has been done in close collaboration with the FDA. So looking at a superiority study now, we look at the end points that are -- would be necessary in a superiority study. You need one of these. You need either a statistically significant difference in 15-letter decreases. A significantly statistical difference in 15 letter increases or a statistically significant difference in a 15-letter difference between the treatment and control arm. And we selected a 15-letter decrease, which is an endpoint that has been used in previous studies. And to help with enrollment, to help with the safety of study participants, we selected a patient population that would, one, was the patients who we really want to treat. These are patients who have 20/80 or better vision. There are patients who occupy most of -- or many, if not most of the new patients we see in clinic. And there are patients who wouldn't have been eligible for many of the previous studies. And what we did is we took patients with vision that was 20/80 or better at screening. And after an aflibercept run-in period, they needed to demonstrate 1 of 2 things. They needed to demonstrate either a 10-letter gain or they needed 20/20 vision. But what this means in terms of patient safety is if they've demonstrated a 10-letter gain and then they have a 15-letter loss as the endpoint, this is really just a net 5-letter loss. We also allow the investigators to have intervention after one event, a 15-letter loss. And critically important, we have independent medical monitors, rescue monitors who are retina specialists, who are highly experienced and highly respected, one of whom Baruch Kuppermann, who is with us today, and they're available for consultation for investigators who have patients that they feel need to be rescued before the endpoint of 15-letter loss. And then finally, aflibercept is provided for a study eye rescue and patients can be followed as carefully as the investigators feel they need to be. It can be daily, weekly or monthly, and they can have the treatment as they need. So this is the SOL-1 study. It's a multicenter, double-mass, randomized, parallel group trial in which patients are randomized 1:1 to AXPAXLI or aflibercept. It's a 2-arm trial with 150 subjects per group, and the primary endpoint at 36 weeks is the proportion of subjects who maintain visual acuity, and that's defined as a loss of less than 15 ETDRS letters of best corrected visual acuity. And you'll see at the beginning that patients who do not meet the enrollment criteria, the randomization criteria will -- may be eligible for the SOL-R study and Peter is going to talk about that in much more detail. Key secondary endpoints are shown here and include patients who maintain visual acuity with a single rescue injection, patients who have best corrected visual acuity change from baseline, central subfield thickness from baseline, number of rescue injections, time to first injection and visual acuity outcomes such as 15-letter gain and 10-letter loss. So let's look again at the SOL-1 design. So at enrollment, if patients have treatment naive wet AMD, best-corrected visual acuity of 54 letters or greater on the ETDRS chart, which is roughly 20/80 and they have a central subfield thickness of 500 microns or less in the study eye, they could be enrolled. They then get 2 injections of aflibercept at minus 8 and minus 4 weeks, and then they're evaluated at day 0. And at day 0, if they have a best corrected visual gain of 10 or more ETDRS letters or a best corrected visual acuity of 84 ETDRS letters, which again is 20/20, and a central subfield thickness of less than or equal to 350 microns, then they would be randomized at that point to either AXPAXLI or an aflibercept injection. So this is a new treatment paradigm following the FDA guidance. And quite frankly, we didn't know a couple of things. One, how many of these patients are in our clinics, and two, would these patients be interested in the study. And similarly, would investigators want to enroll these patients in the study. So the first patients were enrolled February of this year. And shortly thereafter, Ocular began to put together the -- a group of clinical trial experts, clinical operations experts, study design experts. And that, in collaboration with really an outstanding team that already exists at Ocular, we started to see quite significant increase in the rate of enrollment. And the full retina team was really established by mid- to late April, and we continue to see what can only be described as a remarkable increase in the rate of enrollment. And that increase has carried through to May and June of this year. So to date, we have 60 sites activated. And we're quite proud to show we have 151 subjects who were enrolled in various stages of loading and randomization. I think you'll all agree with me this is quite exceptional enrollment and it's due to a number of factors, not just any single one. It's due to the expertise we've assembled. It's due to a tremendous team at Ocular, a tremendous operations team, it's due to very close collaboration between our team and outstanding study sites. It's due to daily communications between the Ocular team and the study sites, and really tremendous execution of these plans. And so I think as all you can imagine, we didn't know what this would look like. And we've been extremely excited and proud to see that these patients exist. They're excited to be in the study. The clinical investigators are excited to enroll them. Let's, I think, move from this, and let's talk about now we're going to have a discussion panel with our 2 experts. And again, Pravin introduced Barry Kuppermann out of UCal Irvine. Barry is one of our rescue medical monitors, and Dilsher Dhoot who is one of the lead clinical investigators and a member at RCA. So thank you, Barry and Dilsher, for joining us. So let's begin with you, Dilsher. So your practice is part of the largest retina group in the country, Retina Consultants of America. And the practices in RCA not only are very prestigious, but they're among the best retina centers and -- retina research centers in the country. Can you tell me more about RCA and how the collaboration with Ocular and RCA research will help recruit patients for SOL-1?

Thanks, Jeff. Happy to be here today, by the way. Yes, so Retina Consultants of America is a horizontal platform of retina-only group. So unlike other PE-backed ophthalmology groups, specifically only retina within RCA. And it started off with 5 groups back in 2020, March of 2020, just before COVID, and these were handpicked groups, right, preemptive practices around the country that were consistently top enrollers in clinical trials that came together to form RCA. And so one of the key points of RCA has been leveraging the research. And the network has grown now to over 25 groups and 280 retina specialists. There are 50 clinical sites for -- primary clinical sites for research in the network and over 1,000 patients enrolled in clinical trials. Some of the stats are up here. This -- the beauty of RCA has been leveraging the power of all these groups that are better together, right? And so with these study sites, there's monthly meetings, there's centralized budgeting and processing and onboarding of studies, which has been very beneficial. There's recruitment strategies that go out to help recruit patients. We have a customized research hive app, which helps investigators identify patients and refer the move to the study. There's a central hotline. And so if we have an interested patient in this trial, we can have that patient call the hotline and learn more about the clinical trial. And so being able to leverage all of these unique and innovative ideas in this research platform in this network has really helped RCA continue to be a top enroller in the largest clinical research site for retina in the United States. And so SOL-1 is a top priority for RCA. I think that a lot of the investigators are excited to see the durability play here. You look back at the pad surveying specialists at large are looking for a more durable agency. And so I think for RCA, SOL-1 is a priority and we certainly are excited about it. Just one other point I make, Jeff, is like, as you know, placing patients in the clinical trials is great. Enrolling is great. But at the end of the day, it's also about QA. And so we have internal QA as well quality assurance to make sure that the data that we're providing is of top quality also.

So Dilsher, along those lines, the narrative had always been that this study with the new treatment -- with the new design paradigm, with the rescue criteria, while derisked due to the SPA, would be difficult to enroll and it's been anything but. Why do you think that is?

Yes, those numbers are super impressive, right? This is such a short time period to see the ramp-up there. 151 subjects enrolled is amazing, and I think that there are several reasons why that is. Number 1 is this is a good vision study, right? And so this is really the largest de novo population that we have in our clinics. If you think about just neovascular AMD in general, go back to ANCHOR and MARINA, the best vision you could have in those trials was 2040. And then you look at subsequent trials, [indiscernible] you're getting to 20/30 vision because we're seeing these patients earlier in clinic. And so with this trial, you're even more inclusive, right? You're going to 20/80 all the way up to 20/20 or better. And so that's really helped this trial. The durability play here is one that resonates with not only retina providers, but also with the patients, right? It's unprecedented time in terms of direct-to-consumer marketing for durable agents. Currently, you'll see lots of advertisements and patients often ask us about the 4-month drug, right? And so having a potential to take a drug that's 9 months really resonates with patients and has helped also to enroll the trial. It's -- one of the other benefits of this trial that I've enjoyed in my own patients is that you don't have to wait for the reading center, right? So if you identify a patient, you bring them in for a screening and they're treated that exact same day, which is huge. There's no sham medication. Patients love that. And at the end of the day, in this trial, I think initially, there was some misconception about the 15-letter loss, and you very nicely explained that in the previous slide. This is a net 5-letter loss, right? And so if you're worried about patients also, you have access to the medical monitors, right? 24/7, I think Barry told me he's available. And so it's a -- so that also has really helped enrollment and made investigators feel comfortable by enrolling patients in the trial.

Yes. Thank you. Barry told me not only 24/7, but he prefers calls between 1 and 4 a.m. So that's helpful. Barry, you and I have been involved in clinical trials for approaching 3 decades.

You're referring to our gray hairs.

I am referring to our gray hairs, unfortunately. And truly, I've never seen enrollment at this rate. Why -- as the rescue medical monitor, you may have a different perspective as to what the reasons are. Why do you think that is?

Well, it's, in a certain sense, confounding because you pointed out some of the concerns that were there at the beginning. Again, there was an initial -- the design is new, and it was relatively misunderstood by some of the investigators. And I think there were calls to explain it. When it was explained, it was -- began to be not only embraced but enthusiastic embracement of it. And including the rescue monitors I want to acknowledge Darius Moshfeghi at Stanford is the other rescue monitor, and we've had conversations about it. And so this is a new study design, and that's where it's important to indicate that, but it's one that is -- has many features that are very appealing. Again, this net loss, as you pointed out, if the rescue occurs with a net loss of 5 letters, there's a 15 letter loss, yes, but it's after 10 letters, up to 10 letters gained. There's also once the patients are rescued, they get EYLEA on a regular basis. There's also many good vision patients, patients that improved to 20/20 in that rescue -- in the initial run-in, if they lose 5 -- if they lose a few letters from there, that's barely symptomatic. In fact, it may be asymptomatic in many of the patients. So that's another interesting feature of the design. And again, there's patients like clinical trials, and in particular, here, the advantage of extended durability, that drug delivery system is an appealing option. Of course, they're coming on a regular basis because it's a clinical trial. But conceptually, it's very appealing to patients. And I think they've embraced that as well. And again, there's no -- in the modern treatment of retina unfortunately, we're dealing with insurance companies and frequently, we're told by the insurance companies how to treat our patients. There's step therapy, that's all avoided in this trial. So that's again something that's a relief to many people. And again, once -- as I mentioned already, once this was explained to the patients and to the PIs, there's been clearly an embracing of this. And the rescue monitors are on board with that as well. We're excited by this new design.

Yes. Thank you, Barry. Dilsher, you've done a very good job enrolling the study, as have many of the other investigators. What type of conversation do you have with the patients? How do you interest them in the study?

Yes. Initially, these are treatment-naive patients, right? So initially, every interaction is regarding the pathophysiology of the disease and what is at AMD? And how have we traditionally treated wet AMD. And so we go over imaging, we discuss monthly injections of anti-VEGF agents primarily and go over expectations. And the reality is how long are you going to be treating Mrs. Jones? I don't know. Like you could receive -- you could be in the 10% of patients that we saw in [ Harbor ] that gets a shot every single month. Or you could be the patient that responds very well. It's a very heterogeneous disease. And then I'll discuss the actual trials that we may have. And this is a great trial that's had a very warm reception from patients because of that durability, right? So in particular, I mentioned that we have a drug here which you have -- you could potentially be enrolled into this arm with AXPAXLI, you have a 9-month medication. And patients really -- that really resonates quite well with these patients. And so this is a population that comes in with a caregiver, and so it's hard to get in the office. And so down -- in the long run, these patients are very interested in durable treatments. Being part of the study team or being a study patient at our site is kind of a concierge level of care, right? So they have access to study coordinators. They have direct phone numbers. There's a different separate area that they go into. And so these patients really do get treated quite well, and they're seeing more regularly than clinic patients, right? And for that reason, we've seen historically, study patients tend to do better than real-world patients, right? There's costless care here, too, right? So we're providing transportation, co-pay is all covered. So patients really like that. And at the end of the day, a lot of patients are altruistic, right? We'll talk about this is providing back something to science, so we can continue to have better and better treatments as time goes on. And so patients -- that really resonates with patients also. And so all in all, these discussions occur, and I found that there's been a warm reception base.

Thank you. Dilsher and Barry, I appreciate the insight. It's now my privilege to introduce Dr. Peter Kaiser, our Chief Development Officer.

Thank you, Jeff. So as Jeff said, I am Peter Kaiser. I'm the Chief Development Officer of Ocular Therapeutix. Prior to that, I served as the Chief Medical Adviser, Retina. And it is my distinct pleasure to talk to you today about an expansion of the Sol program, which is SOL-R. Now before we go through that, I also want to just kind of go through, for people who may be new to Ocular Therapeutix, what is AXPAXLI, what is this drug that we are all excited about, why Jeff, I, Nadia and Pravin all joined this company, and it's because of this particular drug. So AXPAXLI is a single intravitreal bioresorbable implant that contains axitinib. Axitinib is a tyrosine kinase inhibitor. So by definition, tyrosine kinase inhibitors block tyrosine kinase receptor activation. So some of the tyrosine kinase receptors that are out there include the entire VEGF family. Axitinib was chosen by Ocular Therapeutix because it has the highest potency on all 3 VEGF receptors. So in other words, it will block the entire VEGF isoform family, VEGF A, B, C, D and placental growth factor. And that's very important for our future in terms of retinal diseases. We combined this very potent tyrosine kinase inhibitor with our proprietary hydrogel polymer. This is a polymer that's biocompatible with 0 order release kinetics for sustained delivery. This single implant is injected with a 25-gauge needle, and it lasts for anywhere from 9 to 12 months. Is covered by patents that expire in 2041. So the SOL program consists now of 2 different clinical studies. Jeff mentioned the SOL-1 study. This study was specifically designed for regulatory approval. We comply with all the FDA guidelines. And this is shown by the Special Protocol Agreement. So if you do a special protocol assessment and the FDA agrees, it's called a special protocol agreement. They agreed with the assessment. And that's what SOL-1 is being performed under. And as Jeff mentioned, is doing very well in terms of enrollment. The SOL-R study is a little different. We designed this for commercial impact. We said we will take the risk of doing this study because we wanted to give the retina community basically the data they would need for using this drug in the real world. For instance, you need to be able to repeat dose. For instance, we want to see it against a historical control. So we took some liberties because this study is designed for commercial impact. So many of you may not know who Jeff, myself, Pravin, Nadia are. But we've been designing clinical studies for almost 30 years, some much, much longer than me. And if you look at all the drugs that have been released, and I mean all of them because I worked on the original iTech drugs and even PDT way back when. We have been involved in designing the clinical studies for almost every drug that has been improved in the retina space in 30 years. And we put our collective minds together with all the learnings that we got from designing all those studies to design this study. And I'm going to have to say that I, for one, am incredibly proud of this study design. First thing that's very important is this, SOL-R, we will initiate at regulatory risk. However, based on our other clinical studies, we feel that this study has very low clinical risk, and I'll explain that dichotomy in a moment. So the SOL-R study is a Phase III study, multicenter, double-masked, randomized parallel group study looking at Q 6-month AXPAXLI injections compared in a non-inferiority design to EYLEA 2 milligrams dosed every 8 weeks. Again, this is a noninferiority study. So a 3-arm study with 825 subjects, and we are going to conduct this at regulatory risk. So why so many patients? Any time you do a non-inferiority study compared to a superiority study, just by definition, you're going to massively number -- need to increase the number of patients to have the power for the clinical study. That's why it's 825, not like the SOL-1, which is 300. The primary outcome is something that investigators are very used to and retina specialists across the world are very used to, which is this mean change in vision from baseline at 1 year. Secondary outcomes include the need for additional rescue therapy as well as OCT outcomes, such as mean change in central subfield thickness. Patients will be enrolled in the clinical study who are either treatment naive at baseline or who have been diagnosed and treated within 3 months prior to enrollment. But the second key inclusion criteria is the most important. To get into the SOL-R study until SOL-1 is completely enrolled, the only way to get into this study is either to screen fail, load fail or randomization fail out of the SOL-1 study. And if you fail SOL-1, getting into SOL-1 that is, then you could be enrolled in SOL-R. Now we expect that this is going to be a low percentage of patients it's going to happen, hopefully, very quickly. Once SOL-1 is fully enrolled, then we will open the study up to other clinical sites in the U.S. and more importantly, the rest of the world. The number 2 inclusion criteria at that point will be amended and eliminated. So Jeff very nicely showed you the study design of the SOL-1 study. To reiterate, 2 injections at baseline. And then if you have a 10 letter or more gain in visual acuity or 20/20 vision, you receive either AXPAXLI or aflibercept. Now that means there are going to be some patients at that day 0 visit who will not get into the SOL-1 study, and those patients will then be placed into the SOL-R study. Now we expect this way to get into the SOL-R study to be actually very low. So the majority of patients we expect will get in through direct enrollment into the clinical study. Now these patients, at this point, will have received 2 EYLEA injections, and we give them a third, and then they enter a screening period. During that screening period, what we're looking for is we know what patients should do well after 3 EYLEA monthly injections. We're looking for patients who have very minimal fluid fluctuations, we're looking at patients who respond well to anti-VEGF therapy. Jeff and I actually wrote the paper from the VIEW studies that specifically looked at this population of patients, which is who did well with 3 injections of EYLEA. And those patients, by doing this, we're enriching our patient population, which will help us in this clinical study design. After they've met this screening period, they've met all our inclusion criteria, the patients then will receive another set of loading doses. So after this very robust loading dose of 5 EYLEA injections, they are then randomized in a 2:2:1 randomization scheme to either AXPAXLI every 6 months versus EYLEA 2 milligrams dosed every 8 weeks. In addition, there's a third arm, which will be a comparator arm that will be dosed at 6-month intervals just like the AXPAXLI, which we're using for masking purposes only. The primary outcome is at 1 year. And when we designed this study, we designed it based a lot on our U.S. study which had an identical study design in many aspects, except in the U.S. study, there wasn't as much of a robust loading dose. We did not enrich the patient population, and we only gave one injection of AXPAXLI in the U.S. study. So in the audience, many of you may not remember the U.S. study. So I'm going to go over it just very quickly. The U.S. study was in patients who were previously treated wet macular degeneration patients with controlled fluid. This is exactly the patient population that we're enrolling in the SOL-R study. They were then randomized 3:1 to either a single AXPAXLI injection versus every 2-month or 8-week dosing with EYLEA 2 milligrams. So you can see the study design is very similar. Now because this wasn't a registration study, sham injections were performed. But we know we can't use sham injections in terms of masking purposes. So what were the results of the U.S. study? Well, at 10 months, 80% of the patients in the clinical study were rescue free. Using criteria of visual acuity and OCT findings that will be similar to what we're using in the SOL-R study. But at 6 months, when we will be redosing the patients with AXPAXLI, 100% of the patients in the U.S. study were rescue-free per protocol. And that was one of the things that we feel clinically derisks this program because we've done it before. Now with only one injection, the results in terms of the OCT and visual acuity between AXPAXLI and Q8-week EYLEA were very similar. And we expect to be able to hopefully replicate this. So what is the significance of the SOL-R study, and we think there are several. Number one, and very importantly, although Jeff has showed remarkable SOL-1 enrollment numbers, we want to beat and be the best there is out there in terms of our enrollment. So if you increase SOL-1, SOL-R is designed at the beginning to only allow you to get into the study by either screen failing so your vision was worse than 20/80, for instance, or load fail, so they had a issue loading or more importantly, randomization failures. Now we expect that number to be low. But what this does at clinical sites, like Dr. Dhoot's site is if you talk to a patient and convince them that a durable agent is important, you now have a chance to get into 2 studies, and it's very unlikely that you're not going to get into 1 of the 2 studies. And so you're not really wasting a patient in a way, you're ensuring that they're getting into a clinical study. So patients, and more importantly, our investigators, will hopefully like this because it reduces barriers and will increase the SOL-1 enrollment. Number two, we are very careful about what we chose and who we chose for the SOL-R study. We really enriched this patient population because these are the early wet AMD patients, not burned out previously treated patients. And in addition to having an enriched population, we then gave them a very robust 5 EYLEA loading dose. And a study design that's very similar to our U.S. study, so we think we know what the outcome may be which clinically derisks this program. We used a standard historical comparator, EYLEA every 8 weeks. This is something that investigators, KOLs and just your average retina specialists even Pravin can understand. Because they've seen this before. I'm sorry, I'm not allowed to make fun of my boss, but we go back, we're friends. And finally, most importantly, for commercial, we needed to redose our drug. And we chose 6 months, not because we think it only lasts 6 months. We think it lasts 9 to 12. But like any drug out there, we would like to have a shorter interval because that will give us an even better label thereafter. So we're dosing every 6 months in this clinical study. So now I'm excited to say that the SOL program consists of 2 clinical studies. One, as we described, was a SOL-1 study, which is done for regulatory approval under a special protocol agreement; and two, the SOL-R study, which was, as I mentioned, designed for commercial impact, we are doing this at regulatory risk. But we hope that the results of the study will be one that the retina specialists will understand, would allow them to figure out how they're going to use the drug in their own clinical practices. We expect the vast majority of patients to be enrolled in this clinical study will come actually from direct enrollment, but we hope that this will also increase the SOL-1 enrollment by making it so the only way into SOL-R, at least at the beginning, is through a SOL-1 clinical site and failing screening loading or randomization. So we're very excited about this. I want to talk now with our panelists about the SOL-R study. Barry, can you please give me sort of your initial impressions? You've done a lot of clinical studies with me, and what do you think of this study design?

Well, it's -- I like the study design. It's one that I recognize. It's traditional. It's -- we understand that SOL-1 is a regulatory approval design in a new generation of regulatory approval studies, whereas I've used SOL-R as more of a hearts and mind study. This will attract the retina specialist. They'll understand -- they'll be able to interpret the data relative to Q8 week aflibercept, and that's something that helps us put a context to this. Again, it's more of a real-world study. That's also appealing. Again, we're comparing it to how frequently applied aflibercept is in the real world, and that gives us a strong feeling of its benefit. Again, you've emphasized this. I think it's interesting that this study is now at regulatory risk. It's a new era, but that's sort of an impression that we're seeing that that's there and you're making that very clear. I like the 6-month dosing interval, even though we know that this drug can last longer, as you showed at 6 months, you seem to capture everybody. Some patients need more frequent injection. So that's an appealing part of the design as well that we're going to be able to redose at a frequency that may capture again before any recurrences occur. And it's also nice timing from a clinical management in the real world once approved, that 6-month interval has a lot of appeal to it. So again, the SOL, there's a lot of safety data that we're getting out of repeat dosing, as you pointed out. That's an important part of this trial because we don't have experience with that. And again, you also emphasized this enrich patient population. I really like the design as -- in [ dry ] in each studies and now in this one, we're trying to find a way to enrich our patient populations. It makes it for a more successful study outcome, likelihood of enhancing the study outcome. That's the point of these enriched patient populations. I certainly like that this is a historical standard comparator. It feels very comfortable, as I mentioned, to have EYLEA Q8 weeks. So again, this is a new era, the SPA for the SOL-1 allows the sort of in a certain sense, once you've got that assessment and agreement, it frees you up to do, you're at regulatory risk. It's for, again, as I mentioned, to the hearts and minds part of this to convince the retina specialist, this is a product that they can understand and know how to utilize. And again, as you -- finally, as you pointed out, SOL-R will enhance, increase the SOL-1 recruitment. Even though it's done amazingly well, that still is a surprise how well it's done. But again, it provides a backbone or support for the SOL-1 patients that screen fail. So I like it. There's a lot to like about this.

Thanks. Dilsher, you've -- were trained by somebody inferior, me. And so looking into your crystal ball, what are your expectations for the SOL-R study in terms of the results?

Well, I feel like I've seen the trailer for this movie, and then this trailer, the ending was given away, right? Because you just presented the U.S. Phase I clinical trial, which this is essentially a more robust version of, right? So with several key advantages, right? Advantage #1 is the patient population is enriched, right? So we know exactly how many injections these patients have received within that 3-month diagnosis period, we know exactly where they came from, and we know their response, right? This is an enriched population. Second advantage is the multiple loadings with aflibercept, right? So you have multiple aflibercept that are provided to these patients to get them -- to assess, first, their response and then to get them going on the path to dryness. Next, you're providing AXPAXLI every 6 months. So you have more frequent dosing. And so dosing at that frequency, knowing that in the U.S. Phase I trial, 0 patients required protocol rescue at 6 months is a huge advantage. And the reality is if down the road here, you're looking forward, if your label mirrors this type of vesting frequency, you'll have a great flexibility as a physician to dose a heterogeneous population, right? So the worst thing that can happen is that this drug comes to market, and you're not able to dose this because you might need to, in a population that needs more aggressive dosing. Great majority of patients are going to be treated and extended out past 12 months even. But there are some patients that might need it every 6 months. And so you're really ensuring that you're catching all comers in this. I think the results will be very favorable, much like Phase I.

Thanks. Dilsher, what do you think, Barry? What do you expect?

There's a series of expectations because of the study design, as you see here. And again, the fact that it's -- will include at the beginning, the SOL-1 screen failure. Again, this is very different compared to other previously treated wet AMD studies because we'll know exactly how every patient has been treated because we're going to be starting with the SOL-1 failures, know the exact OCT and VA responses to EYLEA as well from baseline. So that's very helpful. Those are things that were great learnings I think we're going to get out of a study design like this. Again, this is the SOL-R has this enriched patient and defined patient population that's part of that format. And again, this is very, as you pointed out, similar to the U.S. Phase I study. So again, there's a preview already there or the trailers, you pointed out that helps define this. So I think it's -- there's a lot -- I think there will be a lot of learnings coming out of the study.

Thanks, Barry. Dilsher, RCA, one of the largest clinical trial network in the country, if not the largest. What effect do you think having the SOL-R study will have on SOL-1 recruitment?

Well, I think it's going to be great, right? So as you mentioned, I think in an earlier slide, I mean, you're getting a second shot on goal for the handful of patients that may not make it in the SOL-1, right? So if everyone doesn't get that 10-letter increase 8 or 9 letters say, then they can go into SOL-R. And so having a second shot in goal is important for clinical trials. They spend -- the centers, for example, because they spend a fair amount of time with these patients, and so you'd love to get them into the trial. And so you get a second shot here. And for the patient, too, right? The patients are very motivated to be in the trial and they're motivated to receive a durable treatment. And so I think from a trial standpoint and from a patient standpoint, it's going to be great and received very enthusiastically.

Super. So I'm going to ask you guys both to put a crystal ball on and assume that the drug is approved. Barry, how do you see using a drug like AXPAXLI in your patients with wet macro degeneration?

Well, again, I think the key thing here is and what we're all desiring now is greater durability. And that's what this provides. Again, with this drug delivery platform that has durability of 9 months or longer, but in the concept of using it every 6 months or so as this study sets up, I think we're going to be able to use it very effectively. Again, there's a lot of reasons to like this as was discussed at the beginning, as you mentioned, about TKIs, the pan-VEGF blocking has an appealing component to it as well. So again, that's -- you get this, you have the pulsatile dosing, I think Pravin mentioned at the beginning, I've been a big fan of drug delivery for a long time. I have patents in the drug delivery space. I love the notion of chronic suppression of disease states by chronic delivery of drug. All the injections we've been giving even when we got it now extended durability, we're injecting every 3, 4, 5 months, even on these new drugs, it means that there's a huge period of time where the drug has long gone from the eye and you're just waiting for the drug to -- so VEGF is being expressed during that period of time. It just not manifests as clinical disease yet, and that's the sole treat-and-extend paradigm that we've used historically. But I think underlying that, there's a lot of flaws. I think as you pointed out, over the long term, there can be very poor outcomes. And so it's this longer durability, this drug delivery strategy, we anticipate getting better out -- visual outcomes as well. So there's a lot to like. I think this is the sort of the manifestation of the dream that a lot of us have had to have a viable drug delivery platform to deliver pan-VEGF blockade for a prolonged period of time.

Dilsher, what you think? How will you use it?

Yes. I agree with Barry. I think this could really be a game changer. I mean, 1 to 2 injections per year at this population is going to be huge, right? This we know that visual fluctuations, OCT fluctuations can be deleterious to patients in the long term. And the reality is, in the clinical trials, patients that did well were receiving upwards of 10 injections in our standard anti-VEGF A trials, for example. And then we look at real-world data, and there's been several real-world trials where patients are getting 4 to 5 injections per year and so leaving vision on the table. And so I think that doctors are going to embrace this, but also patients are going to ask for this, right, because patients want to come in less. You pear this with the advent of things like home OCT, I mean, this is going to be a huge thing. And so I'm very excited to see it in my patient population for several reasons here.

Well, thanks to both of you. I'm now going to yield the floor to my good friend, Nadia Waheed, who will give you an update on the HELIOS study.

Thank you, Peter. Nadia Waheed, I'm Chief Medical Officer at Ocular Therapeutix, and it is my absolute honor today to be presenting an update on the HELIOS study, which was our study on the use of AXPAXLI in nonproliferative diabetic retinopathy. So as you're all aware, the potential market opportunity for diabetic retinopathy is large and it's unrealized, diabetic retinopathy is the leading cause of blindness in the working-age population. And there's an increasing prevalence of diabetes expected to drive future opportunity. Nonproliferative diabetic retinopathy. There are 6.3 million patients in the U.S. alone. And that kind of highlights to you the market opportunity over here. And this number over here highlights how underutilized that market opportunity is. As you can see, less than 1% of the 6.3 million NPDR patients are treated with intravitreal therapy quarterly. So in diabetic retinopathy, there is a need for an early intervention with a longer-lasting therapy. Now diabetic retinopathy, as you're all familiar, is a chronic, progressive and burdensome disease. Typically, we grade DR using the DRSS scale, which identifies patients as having mild, moderate or severe nonproliferative diabetic retinopathy. And if you look at the risk of progression, right, most of these patients with nonproliferative diabetic retinopathy tend to be asymptomatic. But they are destined to progress, so somewhere between 12% to almost a 70% progression rate, depending on where you're at, to proliferative diabetic retinopathy. And proliferative diabetic renopathy is the stage of diabetic retinopathy where patients tend to lose vision. And indeed, that's what causes complications of proliferation as well as diabetic macular edema are what caused these patients eventually to go blind. So ideally, you would like to have a treatment that prevents these patients who have nonproliferative diabetic retinopathy from developing proliferation. And what's really interesting is that we do have very effective and efficacious treatments for these patients that not only slow down or stop progression, but indeed are known to cause improvement. However, having said that, there's no established standard of care. As you saw less than 1% of patients are treated. So what is the cause for that? And the causes, what you see down here at the bottom panel, these patients need to be treated with anti-VEGF therapies that are incredibly effective for them every month or every 2 months. And the really high burden of treatment for these patients who are essentially when they start out almost completely asymptomatic is what drives gross underutilization to the point where, as I mentioned, there really is no established standard of care for these patients. And most of the time, as retina specialists, we just watchfully wait and wait for these patients to develop complications that we then go ahead and treat. There really is a need amongst this patient population to have earlier treatment to prevent progression and to have that treatment be something that's administered maybe every 6 to 12 months in terms of dosing because the current dosing schedule is just not tenable for these asymptomatic patients who are mostly working age and who really don't want to show up for injections every month or every couple of months. So this is what the HELIOS study looked like. The HELIOS study was a Phase I safety study of AXPAXLI in nonproliferative diabetic retinopathy. It was a multicenter dose masked, randomized parallel group study as I looked at AXPAXLI patients with moderately severe to severe nonproliferative diabetic retinopathy without center-involved diabetic macular edema. So pretty much most of the nonproliferative diabetic retinopathy patients qualified for this study. It was a small study, a total of 21 patients at the -- by the end of the study. And patients were randomized with 2:1 randomization to receive either AXPAXLI or went into a sham control arm. The primary study outcome was safety and tolerability of AXPAXLI and then we looked at several secondary outcomes, including looking at the diabetic retinopathy severity scale, rescue criteria, best-corrected visual acuity and changes in the central subfield thickness. So let's talk first and foremost about safety since this was the primary endpoint for the study, and this is an entire analysis conducted at 48 weeks. Overall, AXPAXLI was well tolerated. There were no ocular serious adverse events reported in either arm. All the ocular adverse events were mild and balanced across the 2 arms with no moderate or severe adverse events reported in either arm. AXPAXLI injection did not result in any reported intraocular inflammation, no iritis, novatritis and no retinal vasculitis noted in these patients. And no subjects in either arm received supplemental injections. So now in addition to safety, we also looked at the diabetic retinopathy severity scale, which, as you're all familiar, is a scale that was developed over 50 years ago. We don't use it in clinic very much, but it's important because it's used -- or it has been used in previous studies by the FDA to assess how patients are doing. And so when we look at DRSS, the sham controls are on the left, the AXPAXLI patients, 13 patients are on the right, as I mentioned, small study. About 75% of patients in the sham control arm held stable and about 53%, or almost half of the patients in the AXPAXLI arm, held stable. So if we look at patients who changed on the DRSS scale, every single one of the patients that got better belong to the AXPAXLI arm. About 46% of patients in the AXPAXLI arm experienced either a 2-step or a one-step improvement in DRSS scale and none of the patients in the sham control arm experienced any improvement in DRSS. If you look at patients who worsened, every one of the patients who worsened in this study on the DRSS scale belong to the sham control arm. So about 25% of patients in the sham control arm experienced either 1- or 2-step worsening in their DRSS scale. None of the patients in the AXPAXLI experienced worsening on the DRSS scale. So every single one of the patients in the AXPAXLI arm over the 48-week time period of the study, either remain stable or improved on the DRSS scale. What's also unequivocal from this data is just the durability of the treatment, all the way out to 48 weeks. And the fact that every single signal here is pointing in the right direction. Additionally, we also looked at something called vision-threatening complications. And the reason we look at vision-threatening complications is because these are the events that actually make patients go blind, right? These are the things that cause their vision to go down. So while the DRSS scale is a great academic scale to look at, what about patients who developed either proliferation or who develop center-involved diabetic macular edema, which are things that cause vision loss. And so when you look at the sham control arm, about 25% of patients developed center-involved diabetic macular edema, about 12.5% of patients developed proliferative diabetic retinopathy. When you look at patients in the AXPAXLI group, 0% of patients developed center-involved diabetic macular edema, and none of the patients develop proliferative diabetic retinopathy. So overall, over 1/3 of patients in the sham control arm developed vision-threatening complications over the 48-week follow-up period of this study. None of the patients in the AXPAXLI arm develop vision-threatening complications. Again, all of the data points in the same direction. And all of the data, not only does that, but also points to the 48-week durability of the medication. What about central subfield thickness reduction? So central subfield thickness reduction is important because the central subfield is what we're looking at when we're looking at patients who either develop macular edema or who are on the way to developing macular edema. And as you can see over here, there was a very -- there was a strong suggestion of a reduction in central subfield thickness over the 48-week duration of the study. And you can see the very tight confidence intervals over there, which means that, as Peter was talking about, the durability as well as the constant levels of the medication that Barry alluded to, patients maintain very tight -- very consistent macular thickness and the macular thicknesses don't fluctuate all over the place in this cohort of patients who received AXPAXLI. On the other hand, if you look at patients that were in the sham control arm, as you can see, patients tended to generally worsen over time. Also look at the large confidence bars, patients tended to fluctuate a lot in terms of their macular thickness. And here is the data on the visual acuity via stable vision through the 48 weeks observed with AXPAXLI, a lot less stability in the sham control arm whereas you can see the vision tends to fluctuate quite a bit. So now one of the other things that we looked at, and I'm going to show you some case by case examples is we looked at patients who started out with some extra foveal diabetic macular edema. And we look to see what happened to that extra foveal or extra macular diabetic macular edema over time. So this is a macular thickness map. I know many of you are familiar with this, but bear with me because I know some are not. So I just want to explain what exactly this is. This is a macular thickness map. The center of the target is the fovea, which is obviously the area that we actually get our best corrected visual acuity out of. Keep in mind, one of the recruitment criteria in this study was that patients were not to have central macular edema but could have edema in the areas outside of the center. So this is typically a heat map, green is normal, yellow is mildly thickened, red is very thick and white it is very, very thick. So think of it as white hot, red hot. And as you can see, this is one of the sham patients that started out with extra foveal macular edema, that's the macular edema off to the side over here. And as you can see over the 48-week time period, the area of macular edema expanded and the area of very severe macular edema is also expanding over time. So this is typically what you would expect to happen in a natural history, and this is a sham-controlled patient over 48 weeks. Now when we look at patients who had extra macular edema or extra foveal edema in the AXPAXLI arm, here's an example of a patient on the AXPAXLI arm. As you can see, they start out with quite a bit of thickening, as seen in the red over here. And over the course of 48 weeks, not only do they -- not only are they stable with macula thickness gets a whole lot better, and the macula starts condensing down to close to normal thickness. So here's a contrast. You see the sham control patient getting worse. You see the AXPAXLI patient getting better over the 48-week time period. But the kicker is we didn't -- I'm not just showing you the best case. We didn't just see this in 1 or 2 patients. Every single one of the patients who started out with extra foveal thickening of the macula in the AXPAXLI arm got better and sustained the improvement over the 48-week time period. And I know these are really small images, and I know some of you are going to take pictures, you can go and look at them. We are showing you every single patient on this slide that started out with extra foveal edema and every single one of them got better over the 48-week time period. So to summarize, this is a small study, Phase I. More than 23% of patients showed DRSS -- showed 2-step DRSS improvement in the AXPAXLI arm at 48 weeks compared to 0% in the sham group. An additional 23% of patients showed a one-step improvement in the DRSS in the AXPAXLI arm compared to 0% in the sham group. 0 patients in the AXPAXLI arm showed worsening in DRSS by week 48 compared to 25% of the patients in the sham arm. 0 patients in the AXPAXLI arm developed proliferative diabetic retinopathy or center-involved diabetic macular edema by week 48 compared to 37.5% of patients in the sham arm. There was a strong trend towards central subfield weakness reduction and stable vision through the 48 weeks observed with AXPAXLI, but not with the sham. And AXPAXLI was generally well tolerated and did not result in any reported incidence of intraocular inflammation, iritis, detritus or vasculitis. So as you can see, we're really excited about these results. Again, what's impressive to me are 2 things. One is the directionality. Every single piece of data points in the same direction and points towards the efficacy of AXPAXLI in diabetic retinopathy. And I think the second piece is also the durability of the data, just the fact that we have 48 weeks and a sustained treatment effect seen all the way out to 48 weeks in these patients, and that's what we've analyzed so far. And of course, we're very excited to meet with the FDA to discuss the regulatory path forward for AXPAXLI in patients with non proliferative diabetic retinopathy. Thank you very much for your attention, and I'm going to lean again on our experts over here to discuss with them a little bit around the non proliferative diabetic retinopathy data that I've presented and that you've seen today. So I'm just going to start out with you, Dilsher. Nonproliferative diabetic retinopathy without center-involved DME. It's an interesting problem. It's something that we all see daily. We have FDA-approved anti-VEGF agents to treat or improve DRSS, but they're very infrequently used. So in reality, we basically just wait for complications to develop and we treat the complications when they occur, whether that's proliferation in our center-involved diabetic macular edema. So I guess my question to you is, do you see this paradigm shifting and why?

Yes. So diabetic retinopathy is real near and dear to my heart because I spent a lot of my time practicing in Bakersfield, California. There was a ton of diabetics. They're probably the worse of the worst. But we have this population of [ Level 4,753 ], the moderately severe, severe NPDR patients that, you're exactly right. The current treatment paradigm is not to treat, right? Observation. So it's a very reactive approach. And the reason for this is, as you highlighted, injections every 1 or 2 or even 3 months is a big commitment for these patients. They're usually a working age to coming off work to come in. They usually have multiple other appointments. They could have renal appointments, podiatry appointments. I mean, the average, they have about 24 appointments per year. And so it's a tough population to hammer down. And you're worried that if you treat them, they'll come back even worse with a rebleed 6 months down the road, and we saw some of that during COVID. A drug like this, and the data you're showing is compelling. I mean, if you could give an injection once or even twice a year, and you can control these patients and prevent vision for any complications, I think the paradigm would certainly shift. I mean, I think that you have a lot of patients that would embrace that.

Barry, what are your thoughts?

No, I agree. I also -- for all that I have a lot of AMD patients. We still have a large diabetic population, all retina specialists do certainly in Southern California and in Orange County, we still have a lot of those. And again, we tend -- even though it's rather ironic. We've got approved agents for this. But it's monthly or every other month injection and these tend to be younger, working-age patients. Many of them at this phase have good vision. They have the risk of visual threatening complications downstream so that alarms them, but they're not motivated to come in for these injections. When they got diabetic macular edema, they want to come in, they want to get the injections because they see that impact. This is at an earlier time point. So what we really need is one with the durability, a drug delivery platform. That will be a way to protect them over a prolonged period of time. So again, we rarely use the approved agents. Again, patients miss injections all the time when we even try to start that. And again, we typically watch and wait, wait for the visual threatening complications and then treat reactively. And again, if it progresses and we have laser, we've got the anti-VEGF injections, but it's an unfortunate situation. It's dichotomous, so we need a better solution.

And Dilsher, how relevant is DRSS and vision-threatening complications in your clinical practice, I guess, going back to what we were talking about?

Yes. So I don't want to be labeled a heretic but I mean DRSS is not used in clinical practice, right? We -- I mean, that's a research type tool for regulatory agencies. And it's been very helpful historically speaking. But we know now that with widefield imaging, for example, they are predominantly peripheral lesions that we're missing on DRSS 7 standard. And then we're also missing forcing angiogram findings. There are many patients with wide field and forcing a geography will have findings, too. So we tend to lean more on the imaging like that, wide field and forcing a geography in terms of even how we grade patients, right? And so when it comes to -- from a patient's perspective, vision, there any complications are the things that move the needle as far as treatment goes, right? So if a patient develops diabetic macular edema or vitreous hemorrhage or antiresegment neovascularization, those are the things that are going to move the needle and it certainly caused us to react, right? And so DRSS is not as helpful in that setting.

Barry?

I agree completely. Again, we just -- DRSS, as you pointed out, is historic. It's been used for clinical trials for generations now literally, 50 years or so. But we care about visual -- the vision threatening complications. Again, it's the vitreous hemorrhage diabetic macular edema, that's what are the most important. We don't really use on a real-world sense the DRSS. Patients care about monitoring vision, and they're willing to have vision monitor, but -- and they'll come in if there's a complication. But again, the non-peripheral diabetic retinotopic care should be about preventing visual -- sight-threatening complications, except that's not the real world right now. That's not what's happening, unfortunately.

Yes. And then given that HELIOS is a very, very small, essentially a safety study, 13 patients treated with AXPAXLI and then an additional 8 patients in the sham control group. Can any complications be drawn about this data?

Well, yes, you're exactly right. It's a small trial, right? So the only 13 patients dosed AXPAXLI. At the end of the day, it's a safety trial. And so it's great to see this, first and all, the safety is in line with what we saw in the U.S. Phase I and the Australia Phase I trial. In terms of efficacy, the reality that every single metric in this small population points in a positive direction for AXPAXLI, whether it's durability of treatment, whether it's the prevention of ETCs, the DRSS improvement, every single metric is pointing in the direction of AXPAXLI is quite compelling, right? I mean, there doesn't seem to be a chance effect. So I think that's -- so you can certainly draw conclusions, and absolutely would love to see the next trial.

Barry?

I agree again. The drug seems safe. That's a safety study, and again, small numbers, but if you add it to the other experience we've had to date, it corroborates the safety that has been experienced so far. Again, small in as we've just -- as you've been very clear about, describing that again, as was pointed out, everything is an alignment in favor of the AXPAXLI group and the sham group behaves the way that natural history should be. Again, they're very impressive. There was no vision-threatening complications after 1 year, as you pointed out, with this treatment 48 weeks. And again, also, even though we're trying to prevent the DRSS that was the sort of primary goal of the study, you saw that there's actually a resolution of diabetic macular edema. That's kind of -- that's not serendipitous. It's expected, but it's an ancillary finding as well. It's very impressive to have that as well. That was not the primary thing that was being looked at, but it's certainly very visibly present there. So that gives us -- that's hope for the future with this. Again, it's -- no, they not have experienced any diabetic macular edema. That's, again, the -- they didn't develop -- they didn't progress, what was their regress and none of it progressed into the center. So all that look very promising.

And Barry, if this data were replicated in a registrational study, would you use AXPAXLI in your clinic?

Again, this is -- that's a big step but 100%, absolutely. This data, if you can now blow it up to 300 patients or whatever that is, expand it to that, outstanding results. I would say this would be -- something would become a new standard of care. Again, it's the frequent injections that exist now on an FDA-approved drugs are just not being used. We need something that's more realistic, more compatible with patients that are going to come in on the basis. So in every 6 months, for example, protocol for treatment of patients, for the patients with nonproliferative diabetic retinopathy, we tend to want to see them every 6 months. That's our standard of care without the injections. And so we can resume that standard of care, but apply the injections now if this were again approved, if this was borne out. So again, this prevents visual threatening complications. It injected in the frequency that we find appealing. I think this will be very much embraced by both physicians and patients with a huge patient population.

Great. And Dilsher, I'll end with you as an investigator in the SOL-1 trial as well as hopefully soon to be in the SOL-R study. Does looking at this data change your feelings about enrolling patients into these SOL-1 and SOL-R studies?

I think it reinforces my feelings, right? Any time I use an investigational product, I look at the clinical trials done to date especially focused on safety first, right? And so you're adding HELIOS now to the U.S. Phase I, in the Australia Phase I trial. So we're seeing consistent safety. And then you're adding also to the efficacy story here, too, right? We're seeing consistent durability which is fantastic to see. We're seeing that it's also effective, right? And so efficacy, durability and safety, keeping those 3 things in mind makes me feel better about using an investigational product. And so definitely, I'm more enthusiastic about putting patients in this trial.

Thank you both so much. And I will now pass it on to Pravin for a summary.

Thanks, Nadia, and thanks to everybody. I will make this very, very brief because I know we want to get into the Q&A, which I'm sure you're all enthusiastic about. I'll end where I began, which is that this company has transformed, I think, has transformed remarkably in less than 3 months. The 3 things that were takeaways, I do want to make sure that I emphasize them. One is that we have a dream team, not just the people that are here, but the people that you don't see who are equally important, and they produced. In a very short period of time, they produced great results. The second is that we have a clinical trial strategy that's designed for both regulatory as well as commercial success, very carefully thought out to make sure that our priority remains the same. The priority of this company is enrollment in SOL-1. And everything we do is done in order to increase enrollment in SOL-1 and I think you've seen that today even with SOL-R. And the third and last one is that we have compelling data. It used to be that we had 2 pieces of data, the Australian study and the U.S. study. We're actually very, very happy with the diabetic retinopathy study. Even though there were -- the patient numbers were small, you'll see, as you've seen here that every single piece of data, every metric was aligned in exactly the same direction. So we're very proud of that. So with that in mind, let me go ahead and move on to the Q&A stage. And I think we're going to change some seats over here. Bill, maybe you can help out with that. As you're doing that, what I'd like to do is to introduce 2 additional people Donald Notman, who is our Chief Financial Officer; and Sanjay Nayak, who's our Chief Strategy Officer. We will change seats. We will make sure that Barry and Dilsher get the bar seats and with nothing in hand as yet. But I'm sure it will be coming. With that in mind, why don't -- Bill, are you going to be going with the microphone out there? If any of you have any questions, as you may, please go ahead.

Do you have another microphone? All right. So we are moving into the Q&A portion of the event. If you can state your name and affiliation when you get on the microphone for those that are listening in, that would be fantastic. I'll give the team a second to get settled here. Let's get started.

I'm Tara Bancroft at TD Cowen. So my question is regarding SOL-R. So can you explain a little bit more of your reasoning of why you went with 6 months versus 9 months, which might be more differentiated? And if you're going to be using the same dose?

Yes, Tara, thank you. It's a great question. And I'll shoot that to Peter because Peter is so shy, make sure that I pull them out right away. Go ahead, Peter.

So one of the issues with -- in clinical practice is that many companies try to do the super long durability and then we get into clinical practice, and we don't get to that level. So for instance, right now, we're talking about every 4-month dosing of some drugs that are out there, and it's simply not at that point. So we took the opposite tactic, which is we know this drug last 9 to 12 months. So we're going to do a shorter interval. And by doing a shorter interval, then we would capture 100% of the patients. So when you have a sustained release drug, you want to be able to say to a physician, you don't have to see the patient for 6 months for sure because this percentage of patients are going to do that well because that's what they want to know. And then if you see them at 6 months, you're doing great. You say, well, maybe I'll see them 3 months later. So we expect the label then to reflect 6 months, but we certainly can go longer, which is what we would expect most of us would use it that way.

Yes. Tara, I think what I would add is it's a very heterogeneous disease. There are some patients that require very frequent treatment. There are some patients that may require less frequent treatment. And what you really want in your label is to be able to accommodate all of that. Ideally, if you ask a retina specialist how -- what cadence they would like, it's really every 6 months. But having said that, there are some patients that may go on for 9 months or 10 months or more. And I think this will allow the flexibility to personalize medicine and allow that flexibility in terms of treatment.

Tazeen Ahmad, Bank of America. Going back to the SOL study. I just wanted to get your thoughts, Pravin, about hitting that 9-month time period. I think in the past, you've talked about -- based on the powering of the study, about 20% of patients would reach that 9 months. Based on the increased enrollment rate that you've seen and based on the baseline characteristics of the patients, can you just talk to us about your confidence level in those numbers today? And potentially, do you have higher confidence just based on the enrollment rate so far?

Yes, Tazeen, thank you for that question. Look, my confidence has never been higher. And as you've seen, we produced the results to validate that. Here's what I would say. That 20% mark is important. We absolutely are very confident about it. The way that it was derived is through some internal modeling as well as with some publicly available data. We haven't guided you as to those internal modelings. We may in the very near future. But here's what I would tell you. There are 2 things that are really important to understand regarding that. One is retreatment. I realize that every single patient who's retreated, whether on protocol or off protocol, must be counted in the primary analysis. And that's very much in our favor, which means that there will be many more such patients in the EYLEA group as opposed -- we believe, as opposed to AXPAXLI group. So they're all counted. They're not censored, but they're all counted. So that's a really important statement. The second thing I will tell you is in terms of powering. In terms of powering, we are powered, we believe that there will be a delta of 50% based on what we just said. Between the AXPAXLI group where we expect more than 70% of patients to maintain vision as opposed to the EYLEA group where it would be approximately 20% for the reasons that I mentioned. So 50% delta. We are -- we need a 15% delta, 1-5, to be statistically significant. So we have a very, very large safety net there, even if there should be something unanticipated in the control group, which we don't think there will be based on our modeling.

[ Akash ] from Jefferies. So Dr. Kaiser, just on the point on the SOL-R study. If you think about EYLEA, right, it's like 1/3, 1/3, 1/3. 1/3 of patients are on monthly, 1/3 or maybe a month to 3 months and then the rest are kind of in this treat and extend. If I'm understanding your protocol for SOL-R, you're effectively weeding out the 2/3 of patients who may have poor VEGF half-life. And so you're enrolling for the patients who are probably super responders to EYLEA anyway. I feel like the idea of high-dose EYLEA was you're going to normalize the PK variability in those 3 populations. But then how can you feel confident that in a real-world setting, that 6-month durability holds up because you're effectively only dosing for patients who would respond well to EYLEA anyway?

So we're not talking about [ EYLEA HD ], to be clear, that every 2-month dosing is with EYLEA 2 milligrams, so regular EYLEA first off. So to us, we -- when you do a non-inferiority study, the key thing is to eliminate as much variability as possible. You're trying to be equal to your control group. That's the goal of a noninferiority study. So you want to eliminate the patients that will mess up these statistics on a study design standpoint, and those are the patients who have a lot of fluid fluctuations, and those are the patients who will do very poorly after 3 injections at baseline. And so during that kind of screening period, we're screening out those patients. The goal is to get those patients that we expect irrespective if they're an EYLEA arm or an AXPAXLI arm. At the end of 1 year, they're going to be the same. And that's the goal of enriching the patient populations. To hit that goal, we're very carefully looking at, which is unlike any other study, if you think about it, both 1 month after 3 injections and 2 months after 3 injections. And at both those checkpoints, those screening points, we're ensuring we're enrolling the correct patients to meet a non-inferiority. We're not trying to beat them, we're trying to be the same. Does that answer your question?

I guess, the point being is how would you feel confident that [indiscernible] and those 2 responder patients wouldn't be able to get 6-month duration looking at the Regeneron data that they published at data last year where the majority of those patients were able to stay on 6 month treatment regimen?

So I'm not going to speak to other companies' products, but I'll just say this. If you really look at that study, which I designed, you'll know that in the second year, it was the only time it can get up to 24 weeks and very few patients did. It was at the next visit. So the fact of the matter is it's not a 6-month drug. It's not even close to a 6-month drug. And many of us are having trouble with some of these 4 "month drugs" because you can't dose in more than 7 weeks. In fact, we have to come off them. So in that study design, the key thing is it's designed to prove something, and they designed it to show to their drug for better or worse lasted longer than EYLEA 2 milligram. In this study, we designed it very specifically to be able to show that our drug is going to be very similar, not inferior to EYLEA every 2 -- every 8 weeks. We think that enriching our patient population, we won't meet that primary outcome at 1 year. That was the entire exercise of designing the study.

So Akash, what I'd also say is, look, it's not just enriched patient population that we have and it's enriched in 2 different ways, one is having the loading doses that we have and the other is that period of time that Peter described, which is really important to make sure that there are no fluctuations in that patient population. So the one thing I'd look at is, I'd look at the enhanced enriched patient population, which is really important, very carefully thought out. The other thing is I appreciate your question. Your questions are appropriate and very thoughtful. But remember, this study is not going to be out there in isolation. This study is going to be in the context of the SOL-1 study, which we hope to be successful. The SOL-1 study will give us a great deal of information regarding durability, right? So in the context of that study being positive, with this study being a positive in a non inferior way with repeat dosing, I think physicians will have a very, very good understanding of how to use this product.

[indiscernible], Piper Sandler. Maybe starting with SOL-1 and the 20% threshold for the EYLEA arm. Pravin, you talked about publicly available data. Which trial should we be looking at? Is it [ Talen ] where think about 19%, 19.5% of patients on EYLEA had an every 16-week administration? Or is there another trial that you could point us to as it relates to that threshold? So that's the first question. And then on SOL-R, you went through -- Dr. Heier went through the FDA draft guidance. How does SOL-R fit into that FDA draft guidance in terms of endpoints as well as sham? And then I guess third question on SOL-R is, as it relates to the comparator arm, is that a sham arm? Or is that an active arm?

All great questions. Let me just go one by one. I'm old enough that I'll try to remember each one of them. If I forget, just tell me. The first one, look, I think Talen is one of them that's publicly available. Again, there's a model that we've used that we're very comfortable with. We haven't guided you as to that. We may as we get closer. But I will ask you to remember that the retreatment that I just mentioned, which is -- and that's a really important fact, which is that the retreatment, even off protocol, these patients are not censored. These patients are counted and that's very important for us. And the second thing also is the powering. We feel very, very good about the powering. The second question that you had, you're going to have to repeat this for me because my age is such that I can't remember all 3 questions at once.

No worries. So on SOL-R, how does that fit into the FDA draft guidance in terms of endpoints and use of sham?

Yes. We made -- as I said in the beginning, I said we made it a point of making sure that we tell you what we're doing at regulatory risk. The fact of it is, we haven't had a meeting with the FDA regarding SOL-R as well -- as yet. And that's also why, to your third question, we're not ready to give you details of the comparator arm until we have that meeting with the FDA.

[ Catherine Okoukoni ] from Citizens JMP. I have just a question about the NDPR study and the results there. I know a lot of patients kind of had no change over that 48-week period. I'm just wondering how that kind of fits into what you're thinking about trial duration and just getting a delta over placebo.

Again, a great question. Here's what I would say. Again, I don't know what the trial design would look like. That's pending a meeting with the FDA. The emphasis here is that we're very, very enthusiastic about a diabetic retinopathy trial what -- the discussion that we'll have with them relates to the strategy of how we'll design that trial, again, once we have that meeting with them, we'll guide you to that, but we haven't had that meeting as yet. We intend to, though.

[ Clara ] from Jefferson. So in SOL-1 patients are monitored monthly to monitor their vision. Just curious how this is going to pan out in real life and whether the expectation is that patients will not need to get their checkup between the injections in the 6 months interval? Like what's exactly the criteria really to decide how often the patients need to be seen not for injection, but just for like a checkup?

Great question. Let me ask our 2 KOLs. Dilsher, why don't you go ahead?

Yes, sure. So I think that initially, it's always an evolution, right? When you get a durable agent like this in your hands, your comfort grows with that agent. So I think initially, we'll probably see these patients and not inject them in between, right? And so maybe I'll see these patients 3 months and then 4 months and then get very comfortable and then start going longer and longer with them. So I think that's -- it's going to be an evolution with each of the patients. How would you do, Barry?

I agree. I mean, the easy -- the first thought is that, again, we're going to learn over time. I would consider quarterly for the first year, for example, with every other visit an injection until we -- and that would be for all my patients potentially in the first year or 2 of experience with this, but then it changes over time. And if it really is 100% at 6 months, then we're going to -- that would change our approach, but not for the early going. We certainly do -- I wouldn't do monthly. I'll probably jump right as you point out, every 3 months at the beginning and then adjust from there.

Jeff?

Yes. Thank you. That's an excellent question. And you have to keep in mind that when we look at the real-world data, and this has been shown over and over and over again from different databases in different countries, the real-world data never approaches anywhere close to what you see in the Phase III randomized trials. And there's a lot of reasons for that. Probably the biggest is the treatment burden and the fact that patients don't get treated nearly as much as they did in the clinical trial. So when you have an agent that has the potential to go not 6, 9, 12 months. We know there's going to be an inherent loss of patients coming in as they should. And so an agent like this is almost certainly going to give better long-term data than you would see with the conventional approved agents.

Yes. And I keep on saying this, please don't -- I know the sustainability part is extremely important. Obviously, that's our path to regulatory approval potentially. But please don't forget the potential improved outcomes. I think that part is sometimes forgotten that's really important. I think Colleen.

Colleen Kusy with Baird. So how many of the 151 patients that are in process have been randomized? And how has the screen failure rate been so far in SOL-1?

Yes. So Colleen, excellent question, a very appropriate question. What we wanted to do today was to give you a line of sight as to the increased activity with this team on board. What we're showing you is exactly what we said, which is the number of patients that are currently enrolled and in various stages of loading and randomization. We haven't given -- guided you into any further details than that. We're very, very, very happy with the process. What I'll also tell you is that as far as the failure is concerned, we're thrilled with that. It's a lot lower than we've modeled. And that's why I think you heard Peter emphasize several times that we feel that the bulk of the patients in SOL-R will be external and not necessarily from the failures from SOL-1.

Got it. So are you -- is there more specific guidance on when you expect to reach full enrollment on SOL-1?

Yes. So we haven't formally changed -- again, a good question. We haven't formally changed the guidelines as yet, but I think it'd be safe to say that we're very, very, very happy with the enrollment, and we feel that it will be sooner than expected.

Great. And then maybe just another one on SOL-R. Can you clarify, is that going to be your second pivotal study to support approval? Or is that purely for commercial purposes? And would you run a second study that looks like SOL-1?

Yes. So again, as I told you in the beginning, we're going to be very, very clear and very transparent with you. We're going to tell you what we're doing at regulatory risk and what we feel from a regulatory point is derisked. At this point, we have not met with the FDA as yet regarding SOL-R. So that's one of the reasons that we're telling you that we are launching this or we're proposing this from a regulatory point of view before meeting with the FDA, we feel that we have to say honestly that this is a regulatory point of view at risk. And we're happy to do it at risk for the reasons that were mentioned here.

Sean McCutcheon, Raymond James. Can you speak to the updated AXPAXLI formulation for the Phase III? We've now seen some preclinical data in nonhuman primates, so with all caveats for those preclinical data, but it looks like higher concentration at 3 months maybe a little bit of a lower concentration at 6 and 9 months. So understanding one of the engineering problems you were looking at to solve was the upfront dilution rate. What do you think is a critical threshold to meet for the axitinib release rate and tissue concentration for an effective dose to be in the eye to obviate the need for an additional aflibercept loading dose at 1 month after AXPAXLI like you used in the Phase I?

Yes. So again, a great question, very appropriate. What I would say is this, look, what we have done is we have an optimized formulation. The sole purpose of that optimized formulation is to have a higher amount of soluble TKI available on a daily basis, okay, on a daily basis. That's the only -- that is the reason this is an optimized version. We're not trying to solve any other problem. We really have no stacking issue. When the drug is gone, the carcass is gone, there is no stacking. And we're very happy that there is going to be an increased amount on a daily basis. Other than that, as to the actual numbers, I don't think we've guided you to that as yet.

Yi Chen, H.C. Wainwright. Are the rescue criteria the same between SOL-1 and SOL-R trials? And if a patient gets rescued, will the patient ever get AXPAXLI again in real-world practice? And lastly, have you explored the possibility of rescue using AXPAXLI, basically a redose instead of using aflibercept?

Yes. So again, great questions. As far as SOL-1 is concerned, the rescue criteria are very well defined. As you saw, it's 15 letter loss, which is net of 5 letters. As far as SOL-R is concerned, again, we still have to meet with the FDA. We haven't done so yet, as I say. There are no studies that we have done where we've rescued with AXPAXLI. I am sure that if we're fortunate enough to have this drug in the market and be approved, there will be many such studies done. But as of now, there is no study where AXPAXLI is used as a rescue.

But from real world standpoint, maybe you guys can talk about if you have AXPAXLI and say the patient need a rescue with aflibercept, what would you do? Continue AXPAXLI rescue? What's your protocol, you think?

I think it all depends, the most common answer. Every clinical case is different. It depends on what the recurrence was, how much fluid. But I would certainly anticipate, again, it depends on what the -- when the recurrence happen, what was -- how that planned out, but I think it would be very easy to consider redosing with AXPAXLI in that situation.

Yes. A lot of times in the real world just boils down to the payers, right? So if a payer allows us to redose within a given time, then I think that we have to do that. But a lot of times with a lot of the drugs we have in our hands now, redosing really depends on the payer. But I think if a -- payer issues aside, I think that I would -- if we're getting towards the tail end of the durability, I would certainly redose early on, I probably might give a booster shot with an anti-VEGF to see how it goes. But it would be great to have the durability.

Any other questions? No? Great. I want to thank, especially our 2 KLOs, Dilsher, Barry, thank you so much for making the time to come here. A great amount of work done here. Peter, thank you, Nadia, Jeff, Donald, and Sanjay and Bill, who put a tremendous amount of work into this. And I want to thank all of you for spending a few hours with us. I really appreciate your interest, and thank you for joining us in our first meeting. We're available to you. We would be delighted to chat with you. If you'd like to chat with us, please go ahead and call Bill. He will -- Bill, and he will set it up and we'll be around here. I think there's a cocktail hour. Is that right, Bill? And we will be around over here. So thank you again very much for coming today.