Good afternoon, everyone, and thanks for sticking around with us at our ophthalmology conference. It's our pleasure to have Ocular Therapeutix as the next fireside chat. We have Pravin Dugel, who joined Ocular Therapeutix as the Executive Chairman, President, CEO, covered all the bases there. That was just over a year ago. You know, why don't you just tell us how things have gone? Tell us a little bit about the background of what drove you into Ocular Therapeutix after a spectacular sale, right? How has that company evolved over the course of the year?
First of all, thanks for having us here. It's really a pleasure to talk with you again, and we're always very grateful for any opportunity to tell our story. My story about how I joined you is really very simple. I was very happily retired for all three months. I had absolutely no intention of coming back, although I loved every single second that I spent in Iveric Bio. Absolutely loved it. The reasons are very simple. It's because it was a confluence of factors led by the fact that having practiced for 30 years in the real world, I know what the need is. I know what the bar is for success in this need. There is a known target, and we're simply not able to reach the amount of patients that we need to reach, given the medications that we have.
We can talk about that later on. That was one, the need that was there. The second is the technology that Ocular Therapeutix has. I was very familiar with this technology because I looked into this in my previous company. I was very, I am and was then very convinced that this is the way to go as a tunable, completely dissolvable hydrogel. The third is the data that I saw. The data was absolutely consistent with everything I'm saying, which is that this is an extremely safe product that is efficacious. The data to me was very convincing. Again, we can talk about that in detail. Finally, it was the regulatory path forward. That is credit to the team before us who obtained the SPA for the first study, which is the SOL-1 study.
It was clear that there was a very clear and obvious regulatory path forward that was consistent with the FDA's most recent guidelines. Those are the reasons that I joined. Since then, the company has evolved quite a bit, as you know. I couldn't be happier. I couldn't be more confident. I'm delighted that I came back. I'm loving every second of this even more.
Okay, so maybe we can go into each of these factors. You know, obviously, we all know the anti-VEGF market's been around for 20 years. The market is starting to evolve with longer duration assets. There's obviously still unmet needs. You know, I guess I'm looking for you to tell me how you see AXPAXLI disrupting this market. Some people say the sweet spot of treatment is around six months. People want flexibility. How do you see AXPAXLI sort of disrupting this market and what your, you know, your TPP is, your target profile or TPP, sorry, target product profile? Like, what is the ideal profile for you?
Yeah, it's a great question. Let me just give you sort of a bit of a context historically. I can do this because I'm old enough to do so. You know, remember that when I was in training and when I had hair almost as long as yours, we had absolutely nothing. You know, we would watch these patients go blind. Then came really essentially a miracle, which is the anti-VEGF. They are really a miracle. You know, when you think about watching people go blind day after day after day and suddenly something called Lucentis comes in and the vision actually improves, not just maintains, but improves. Then Eylea comes in and then the second generations come in. It is absolutely remarkable to have lived through that evolution.
I think what a lot of people do not realize is the following: as miraculous and good as these drugs are in a known target, in this country alone, 40% of patients, think about that, almost half the patients in the first year drop out of treatment. I mean, that is tragic and that should be absolutely unacceptable after more than three decades. The reason they drop out of treatment is because it is simply not sustainable. Patients simply cannot come in for a needle in their eye, you know, every month or every other month. It simply is not happening. These patients are going blind. That is tragic. The second thing, which people also may not realize, is that even those patients that are able to come in, of those patients after about two to five years, almost inevitably, they all end up getting worse than baseline.
Now, we used to think when we saw that data it was because of rebleeding. As it turns out, rebleeding is actually quite uncommon. It is because of fibrosis and atrophy. When you think about what is happening, the way we are giving these medications in a pulsatile manner in the back of the eye, which is nerve cells, there are oscillations. The nerve cells in the back of the eye, the retina, get thick and thin and thick and thin. It is akin to having multiple concussions. It is not surprising that there is atrophy and fibrosis after that. What we are trying to do here at Annabel is to solve two problems. The first problem is the obvious one, which everybody talks about, which is that of sustainability. It is a known target. We know how important this is.
If you just look at how, if you look at Lucentis, for instance, that had a seven-year head start on Eylea. Eylea is not stronger. It is not safer. It may last a week longer and totally overtook the market. Now you see that evidence with Vabysmo. Again, Vabysmo is not stronger, is not safer, but has dominated the market because it may last two weeks or so longer. There is a real thirst for that. We are trying to solve that problem. The second problem that we are trying to solve by not having these oscillations is that of better long-term outcomes. Those are the two problems that we are trying to solve.
Okay, great. Obviously, we've heard now from a number of companies today, and there's a lot of different approaches to this, whether it is, you know, with other TKIs, whether it's other forms of VEGF, whether it's gene therapy. You know, maybe you can sort of tell us where AXPAXLI fits in that and how you might be different from, you know, say, a gene therapy or another TKI, or are physicians comfortable with a TKI versus going to a, you know, new and improved anti-VEGF? We've heard it all today. We're coming from that context.
It is really quite simple. This is something that I have said when I was on the other side, and I was a physician that was working with, you know, 40-some-odd companies. There are companies that would say, look, what is it that is necessary, and that is really what you are asking, to supplant the standard of care that we have right now, which is anti-VEGFs? Because rarely, I would say, and maybe you know some exceptions, but I have yet to find one in the systemic market where a single target, a single version of a drug has dominated for this amount of time. The reason for that is because these drugs are darn good. They are really, really good. What do you need to do? Here is what you need to do. It is really quite straightforward. There are three boxes that need to be checked.
Those boxes need to be checked sequentially. If you do not check one, you cannot go to the other. The first box is that of safety. These anti-VEGFs are extraordinarily safe. Lucentis and Eylea and the second versions are extraordinarily safe. If you do not have a safety profile that is at least as good as theirs, that box is never checked. You are done. Simple as that. The second box, if you get past the first box, is that of efficacy. These drugs, these commercially available anti-VEGFs work in 100% of patients unless you have got the diagnosis wrong. They may not work as well as you want them to work or last as long as you want them to last, but they work in a known target. If you have got an efficacy rate that is, you know, 60%-70%, that second box is not checked. You are done.
The third box is that of adoptability. We have changed our practice entirely with these anti-VEGFs. We have these large practices where we see 50-80 patients a day. There is an economic advantage to injecting. There is an overhead that we have. If this drug, if a drug cannot fit in that workflow and cannot be easily adoptable and easily adaptable, then you are done. Those three boxes need to be checked. They need to be checked sequentially. I believe that AXPAXLI checks all of those boxes very easily.
Okay, got it. In the real world, do you see this as completely shifting the treatment paradigm, or do you still see a place for anti-VEGF? Is it a replacement, or is it a treat and extend tool?
Yeah, so, you know, I guess, and it's a great question. It's an appropriate question. We just look, do you see this as a first-line drug, an initiation drug, or do you see this as a maintenance drug? I think my flippant answer, and I'm not going to give you a flippant answer, but my flippant answer would be, you know, why do I care? At the end of the day, even if it's a maintenance drug, this is going to be the most impactful, biggest drug that our industry has ever seen. That's true. However, I believe that this will be a first-line agent. Why do I say that? Because of two reasons. We've got great evidence that's now been published, and you can see it in some of our presentations with non-human primates, that steady state is established within 24 hours.
We have human evidence. We have patients that we saw in our study in Australia where this drug was used as monotherapy in a treatment-naive patient population. The results are akin to what you would expect to see with commercial-grade anti-VEGFs. I firmly believe that this drug is all that you will need, that we will need as an initiation drug as well as a maintenance drug. Even if I'm wrong, at the worst-case scenario, if it's a maintenance drug with two injections of Eylea and then AXPAXLI for the next 20 years, this will still be the most impactful drug in our field, without a doubt. I do want to tell you that we are using loading doses in both studies.
The reason we're using loading doses is not because I think that we biologically need them, although that's not what we're out to prove or disprove. The reason we're using loading doses is, toward your other questions that I'm sure you'll have, for patient selection. Patient selection is absolutely key and is the most underrated element in my mind in terms of clinical trial design and the chances of success of clinical trials in our field. The loading that we're using in a bespoke manner that I think is extremely thoughtful is entirely because we want to select the proper patients for the proper studies. I hope we go into detail regarding that.
Let's go into detail regarding that right now. What is that proper patient? What is that patient selection you're looking for? How is it different from other potential programs? Are they finding the right patient? What do you think is the right patient?
I'm so glad that you asked this because this is one thing that I think is most poorly understood and is absolutely crucial. Let me back up a little bit. You know, I'm a one-trick pony. All I know is retina and nothing else. You deal with things in oncology and immunology and rheumatology all the time. If I were to come to you and say, "Hey, you know, I've got a drug for colon cancer," you wouldn't let me get away with that, right? You would say, "What do you mean colon cancer? What kind of colon cancer? What stage? What grade?" All those things. Wet macular degeneration and for that matter, all our retinal vascular diseases are no less variable than colon cancer.
You know this because if you talk to your KOLs, they'll tell you, even now, look, there are some patients, and these are exceptional, obviously, that I have to absolutely treat every two weeks. There are other patients that I can get away with treating every six months. We have no way of knowing who those patients are. We're 50 years behind oncology because we have no genetic marker. We have no anatomic biomarker. They all look the same. By the way, that's why we do treat and extend. The reason we do treat and extend is because we have no idea how a patient is going to behave. Now, in the real world, we can get away with doing treat and extend.
In clinical trials, we have gotten away with this and not addressing this because the studies that have been done by companies like Novartis and Genentech and others have been massive studies with 2,000, 3,000 patients. You can say that with numbers that are that large, these things get mitigated and equalized. When you're doing studies that are less than 1,000 patients, you better be darn sure that you've got the right patients in order to not screw up your studies. This has been done. Studies have been upended, and without naming names, by improper patient selection or lack of patient selection. What we have done is to put a huge amount of thought to proper patient selection to go ahead and super-enhance and de-risk our patients.
In the first trial, which is a superiority study, what we have done is specifically selected patients without fibrosis with the most amount of VEGF receptors, and we've tested them to make sure that those VEGF receptors respond. So these are patients with good vision, not previously treated, treatment naive. We've tested the VEGF receptors by requiring that they improve by 10 letters or get to 20/20. A perfect superiority patient selection to allow them to go ahead and be loaded up and allow them to fail once. This is in contrast to our second study, which is a non-inferiority study. Here, that's not what we want. We want stability because stability is king in a non-inferiority study. Here, we've got three loading doses, and then we've got something that nobody else has ever instituted, which is two opportunities to observe the patient. And what are we observing for?
We're observing for fluctuations. Those anti-VEGF addicts that are unstable, we weed them out, and then we have two more loading doses, and only then do we go ahead and randomize. Perfectly selected for a non-inferiority study for absolute stability. Again, there's a huge amount of thought that has been put into this. This makes the recruitment a lot more challenging, but on the other hand, it also thoroughly de-risked our studies in a very bespoke manner and an appropriate manner for each study.
Okay. That was a lot, but I'm going to ask you one more straightforward question. Many would argue that your first study being a superiority study is, you know, not necessarily de-risking. It's unconventional, and it's unconventional having gone from just phase I studies into the superiority studies. What was it in the phase I that allowed your predecessors to be able to leap to that phase III registrational study? You know, that's highly unusual. You would think that you'd have a phase II dose finding, dose exploration, find what the right dose is, optimize it, and move forward. Are you working with something? I guess one could argue that you could have scrapped that and started at phase II, or you could work with what you have. You know, what got you comfortable working with what you have and then optimizing that?
Annabel, do you remember when we spoke in my previous company? We spoke in Iveric Bio. Remember the first study?
Mm-hmm.
It was not a phase III study, and the same questions were asked of me. Wait a minute, this is a phase II study, isn't it? And guess what? The drug is approved. My point is that the FDA doesn't care what you call the study. You can call it a phase 1000 or a phase zero. It simply has to be properly masked, and it has to be statistically significant. In many ways, let's go back to the SOL-1 and SOL-R studies. One would argue that those studies were really not designed by us. They were really designed by the FDA. As you know, what happened was that in February of 2023, everything changed because the FDA came out with guidelines that they very specifically wanted people to follow if they were going to do trials without regulatory risk.
They said, this is how you design a superiority study. This is how you design a non-inferiority study. The most important aspect of that, where they made it very clear that sham is not proper masking. Why is that not proper masking? It is because when we numb the eye and give an injection, we numb the skin of the eye, what we call the conjunctiva. We do not numb the optic nerve. The patients can see just fine. The vision does not change. If you can see tiny little floaters with old people like me, you can sure as heck see a whole bunch of fluid coming in. Patients would know. They would say, you just injected me, or you did not inject me because the sham was touching the outside of the eye with the hub of the syringe.
The FDA said, look, sham is not proper masking. It does not mean that they are going to prevent you from doing a study with sham, but they are going to say, look, you are not properly masked. Even if you go ahead and hit your primary endpoint, we may not approve you because you are not properly masked, or your barrier for success may be far higher. We were not willing to take such risks. Sure enough, we were rewarded with a SPA. Clearly, the FDA approves of what we are doing from a regulatory point of view in both studies. We are very, very comfortable that we have a clear regulatory pathway where we have taken no regulatory risks. Although the study design may look unconventional to you, the fact of it is that it is validated by a SPA, and it is exactly what the FDA wants.
The second part of your question is, what gave me this amount of confidence? It's very simple. It's the data, the quality of the data, and the consistency of the data. Let me explain. The quality of the data is such that these patients in this disease do not get better by themselves. It's not one of those things where the disease fluctuates. If you don't have proper treatment, these patients go blind. In these studies, this drug was used as monotherapy. It wasn't used as combination therapy in addition to an already known anti-VEGF that works. It's very difficult to decipher which drug is actually having an effect. In fact, as I told you earlier, there were patients in the Australian study where this drug was used as monotherapy in treatment naive patients.
What we're seeing as far as the data is concerned is the drug by itself, unaided by anything else. These patients do not get better by themselves. That's the quality of the data. The consistency of the data is the following. In the history of this planet, every single drug that inhibits VEGF and works in wet macular degeneration has also worked in diabetic retinopathy as well as diabetic macular edema. If this drug had not worked in diabetic retinopathy in our Helio study, I'd be sitting here trying to tell you why that disease is somehow weirdly different when every other drug has worked. Luckily, I don't have to do such a thing. This drug has been absolutely consistent in all the targets where it's been investigated, including wet macular degeneration, including diabetic retinopathy, including diabetic macular edema.
The quality of the data and the consistency of the data gives me an enormous amount of confidence in the success of this drug.
Okay. That was helpful. Maybe you can talk about some of the changes that you made to both of these trials. Can you just detail them and explain why you implemented them this far into the study?
Yeah. This is the beauty of having two studies that are complementary that are actually not the same study twice. I know that's what's traditionally done, which is to knee-jerk repeat the study. What that does is make it a very simple design of study, obviously. The second study really is a missed opportunity in my mind because it really doesn't provide any new information. In our case, when you take these two studies together, it provides all the information that a physician would need in order to go ahead and have confidence in this drug and for us potentially to get the best label in the market, which is a superiority label with the flexibility of dosing of 6-12 months and repeatability. To answer your question, here's what happened. The team before us deserves the credit for getting the spot.
However, the study stopped at month nine when the primary endpoint was reached. What that meant was that the FDA's requirement of having a certain number of patients hit the two-year mark, not for efficacy, only for safety, not efficacy, would have to be the burden would have to be borne by the second study. It absolutely overloaded the SOL-R study with 825 patients, not for powering, but just to meet this requirement. It also meant that our PIs came to us and said, "Hey, you know, once the study is positive at month nine, I have nothing for the patients." That is a difficult argument to have. They were right because we've had those discussions before in our previous lives.
The second reason is because we saw the label approval for Vabysmo and realized that they got a four-month label with very few patients having crossed the four-month barrier. The threshold was very low, and we were certain and are certain that more than those patients would actually cross the barrier at 12 months with AXPAXLI. The third thing, and this was the gating factor, and this is why we did not do it immediately, is because all of us who collectively have had hundreds of years of experience in clinical trials sat together and said, "We have never seen patient retention this good in the 20 or 30 years we've been doing clinical trials." Think about that. Think about what that speaks to in terms of the quality of patients we're recruiting.
Based on all those things, we went to the FDA and said, "Hey, we do not want to jeopardize the spot, but what we'd like to ask you is whether we can go ahead and have a second year where we dose every six months and if that can be counted along with SOL-R for your safety." They said, "Yes." We said, "If we can do that, we can reduce the number of patients in SOL-R by a third." They said, "Fine." We also said, "Look, if we can keep it masked for 12 months, we have the potential of getting 12 months on the label." There are two take-home messages from this. The bottom line is that's a total win for us. We gave up nothing. The primary endpoint remains the same at month nine. The powering remains the same.
What we got in return was the ability to get to the finish line faster and cheaper. The second thing that it tells you is the kind of relationship and collaboration we have with the FDA. This is a total win for us thanks to the cooperation of the FDA. I believe the reason for that is we've done everything exactly according to what they wanted us to do and taken no risk from a regulatory point of view whatsoever.
Okay. Just on the retention question, I know we're running out of time, but I mean, this is a longer duration drug. The idea is that you're injecting a drug once. Is it by default you're going to retain them because they haven't needed to take a second shot yet? When you talk about retention, can you tell us at what point you're counting that retention?
Yeah, up to the point of the study right now.
Have you had patients taken multiple injections already?
What we have not done is we have not disclosed, you know, what patients are in what stage in that level of granularity. Let me give you the context of this. Remember, this was a study that everybody said could never be recruited. They also said, "If you can recruit it, it is a no-brainer to succeed." They said that this study could never be recruited, and we recruited well ahead of schedule. They said, "Even if you could recruit it, doctors are not going to follow protocol. They are going to go ahead and rescue whenever they want." We said over and over and over again, the vast, vast, vast majority of patients that we are seeing under masking are being rescued per protocol.
The third thing they said was, "Even if those two things happen, patients are just going to drop out whenever the heck they want." We are saying right now, we've never seen retention this good. What does this all mean? For us, it gives us even more confidence in the success of SOL-1. It gives us great confidence. The second thing that it does is that it validates the quality of the sites that we've picked and validates the quality of the patients that those sites have picked.
Okay, great. I mean, we are out of time, but I do want to make sure I hear that correctly. When you read out on SOL-R, what will that tell us for SOL-1? Is it a drug? Do we know how the drug will behave from SOL-R that we can read into SOL-1 and be confident that the SOL-1 is going to get us to where we want?
I think it's the other way around you're asking, right? Because remember, SOL-1 is going to read out. I think.
Oh, yes. I'm sorry. I got it backwards.
I think what you're saying is, with a positive SOL-1, can you give us confidence in SOL-R being positive? The answer is yes, we'll supply that. Here's the easy answer. The easy answer is really very, very simple, which is to say, look, once SOL-1 is positive, the superiority study at month nine, right? That means that this drug can last for 9 to 12 months, right? Month nine being the primary endpoint. The simple extrapolation of that is, look, if the drug lasts for nine months, why would it not last for six months in SOL-R, particularly when we have a non-inferior margin of 4.5 letters? Again, if the drug lasts for nine months, why would it not last for six months? Yeah. Remember, this is also in a very, very selective patient population that I've described.
This is not your regular patients coming off the street, right? That's what most trials do. This is a patient population that has been super selected with a total of five loading doses and two opportunities to observe for absolute stability. In that patient population, in that super selected, super enriched, de-risk patient population, if you know a drug already lasts nine months, why would it not last six months?
Yeah. Good point. We unfortunately are out of time, and I didn't even get a chance to touch on DR, but is that trial starting? When did that start? Is it starting? Where are we? What's the timeline on that?
We have had fantastic discussions with the FDA. We are thrilled with the results. We will update you when appropriate. We believe that our regulatory pathway is absolutely clear. The only thing that is giving us a little bit of pause is the general macro environment that we cannot control. We want to be absolutely fiscally completely disciplined and responsible. That is what is giving us a little bit of pause, nothing else. You know, once there is a little bit more stability in the world, we will go forth. We really are not under any competition whatsoever. There is no competition. Others have thrown in the towel already. As I say, we have a clear regulatory path forward. This is a humongous market. We are thrilled with our HELIOS results. We will absolutely do the study, and we will absolutely own that market.
Great. Thank you for your time. I appreciate it and look forward to seeing the outcomes.
Fantastic. Annabel, thank you again. We're so grateful that you've had us here. Any chance that we have to tell our story, we're extremely grateful for it. Thank you.
Fantastic. Thanks.