Of the Citizens' Life Science conference for 2025. My name is John Wall, I've been an analyst here, and pleased to be kicking off with Ocular Therapeutix, a name we've been covering for quite some time. CEO Pravin Dugel joining us. And we're just going to have a light discussion here. We'll save some time for Q&A at the end from the audience, but hopefully something that we can all learn a little bit because this is a very exciting time. We're hearing developments in the ophthalmology space, you know, pretty much, you know, at least every month from people developing drugs for, you know, wet AMD, retina-specific conditions. But Pravin, maybe to kick off, and we can jump into some details, is, you know, what is your overall strategy and mission in Ocular Therapeutix?
Yeah, John, first of all, listen, thank you. Thank you for all the diligence that you do for us, and thank you for all your support, and thank you also for inviting us to this meeting. Really grateful for that. The mission is really simple. I mean, look, we wanted to, you know, when I came in here, obviously there are a lot of things that changed. The company, as you know, changed entirely, but one of the first things we wanted to do is to have an identity for the company and a mission for the company. This is a retina-focused company now. It's not a retina-only company. It's a retina-focused company. We have a drug in AXPAXLI, and the goal here is to have two different things that we do. There are two goals.
First, the one that is fairly obvious is we want to have a drug that's sustainable, as good, and the reason is really simple, as good as the anti-VEGFs are, right? They've been around for almost four decades, and they're phenomenal drugs. What is really tragic, I think, and should be unacceptable to us, is that because of the sustainability issues in this country alone, and it's just in this country, you know, the richest country on earth, really, from a medical point of view, 40% of patients drop out in the first year. I mean, just think about that. And those patients go blind. 40%. We have a known target. We have a known treatment, but yet it's not sustainable. So that's goal one.
Goal two is even the patients that are able to come back and come in on a regular basis, the rest that stay behind, what people do not realize is that even when they are able to come back, almost all of them inevitably, after two to five years, end up getting worse than baseline anyway. When we saw this, the obvious thing was we used to think, well, that is from rebleeding. It is not from rebleeding. It is from fibrosis. It is from scarring and atrophy. What we know now is the reason for the scarring and atrophy is that the way we give these medicines in a pulsatile manner, the back of the eye gets thick and thin and thick and thin. It is neural tissue. It is kind of like having multiple concussions, right? That is why it scars.
Those are the two things that we're trying to achieve, which is to get better sustainability, right, and more people who are treated and less people who go blind. There's great opportunity there. The second one is we're trying to get better long-term outcomes for these folks.
It's hard for me to keep track of time these days. How long ago was it when you joined the company?
Yeah, it's been, wow, it's been a year and a bit. It hasn't been all that long. It's a big change in the company. Again, I think what we've done now is to have an identity. We have a focus. We certainly have the personnel that we want, and it's all about executing. You know, that's what we're focused on. So far, as you know, we've been, I think, executing exceptionally well.
There was chatter a little over a year ago when you were not with the company where you would end up. You had a very successful career in the space, and people were wondering, well, what is next for Pravin? You chose Ocular Therapeutix, made a big splash. You know, how is the report card a year in? How were your priorities? What drew you to the company? What did you want to do? How has that been going so far?
Yeah, so John, I mean, honestly, I mean, I had no, I loved what I do. I love what I do now. I loved my previous company. I loved every second of the career change I made. I do not think there are a whole bunch of people that make the career change I made. Remember, for 30 years, you know, I was a practicing retina surgeon, right? And sort of came into Iveric Bio. I was very happily retired, making wine in Napa for all of three months, and I realized that, you know, my wines were not going to be ready until 2027, and I had to find something to do. Again, I was not looking, but this was an opportunity that was just phenomenal.
I, you know, as confident as I am in the product as I was then, I am even more confident today, and I'm sure you'll ask me seeing what I'm seeing. The reason is really simple. It's what I just mentioned to you, which is that this is a product that has, I mean, it's not something that is a high-risk product, I believe, because there's a known target, there's a known mechanism that's proven, and the regulatory pathway, which we'll talk about, I'm sure, is completely clear. We've done everything exactly according to what the FDA wants. To the credit of the team before us, they got a spot, the team before us, and they deserve all the credit.
When I saw the product, when I saw the opportunity, having practiced for 30 years before, knowing that this would fit in, you know, like that in the office and be adopted like that, and knowing the need, and knowing that with a SPA, there was an absolutely clear regulatory pathway forward, it was just an opportunity I couldn't pass up.
Can you talk a little bit about the landscape? You mentioned the anti-VEGFs. 40% of people stop, go blind eventually. We have newer drugs in the last couple of years, Eylea HD, Vabysmo. Vabysmo doing great, Eylea HD trying to catch up. What's going on in the landscape where we're seeing these longer duration products? You know, recently we just saw Eylea HD proposed to have a six-month label. FDA said, "No thanks." How important is the longer duration and, you know, what impact do you think that would have on commercial uptake?
Yeah, it's a great question. There are many, many layers to your question. It's a really profound question. First of all, let me just again emphasize that 40% number. That is in this country alone. That number is way higher outside the U.S. That 40% number is not just made up. It's been shown over and over and over again in real data. It's a verified number. To me, it's astonishing. 40% of people, I mean, that's, and if we can, with our product, increase the sustainability and decrease the dropout rate by even 10%, that's a quarter million more people in this country alone that will not go blind. The potential of the impact of this drug is just absolutely enormous. I think the main thing is to sort of look at that.
The other part also is the regulatory part, which I think is what you're getting to with Vabysmo and everything else. The CRL that Regeneron got is really important from the point of view of the statement that the FDA made. The FDA has made it very clear, these are regulatory guidelines that we want you to follow. If you want to do a superiority study, this is what you do. If you want to do a non-inferiority study, this is what you do. It couldn't be clearer. It doesn't mean that you can't go outside the guidelines. If you do, they're not going to stop you because it's not a safety issue at all. It's a risk issue, right? It's a proper masking issue. What that means is that you're doing a trial at risk.
What that also means is that even if you hit the primary endpoint, you may not be approved, or your bar for success may be much, much higher. We're doing none of that. We're taking no risk whatsoever. We have a SPA for the first study. We have a written type C validation for the second study. What the CRL shows you, the Regeneron CRL, is to say, look, if a study is not properly conducted and properly masked, we're not going to approve you. I think that actually portends very well for us because we've done everything by the books.
You know, if the bear is for Ocular Therapeutix, they point to you ran a small phase I study, not a lot of patients, but, you know, what gives you confidence that what you're doing now is, you know, supported by that data? Can you talk a little bit about that phase I data set?
Yeah, sure. John, look, that's a very fair and very appropriate question. Thanks for asking that. The reason is very simple. It's the results that you see, right? If you had, and not that this is an inherited retinal disease, but if you have an inherited disease where, you know, kids, you know, pass away at six years of age, say, and you've got, you know, I don't know, you know, 12 kids that have made it to 40, that's pretty convincing, right? Just like that, you know, in wet macular degeneration, what happens is that this disease, patients don't get better by themselves. When we saw what we saw in the phase I studies in the U.S. and in Australia, and we saw the results that we saw, that doesn't happen by accident. It's a binary event.
It's not like, say, in my previous company, in geographic atrophy, where you can say, well, you need large numbers there because the changes are micrometers, right? It can go either way based on patient selection and so on and so forth. That's not the case here. Either it works or it doesn't work. It's really a binary decision. You can see that right away. More importantly, the way the studies were conducted and what the studies show is really, really important. The first study was a dose-ranging study, and the significant, and this is the one in Australia, and the significance of that is that it's the only time that I know, the only study that I know, and this is really important, where sustained delivery medication was used as monotherapy in a treatment naive patient population. Our competitors haven't done that.
They've always combined that with a commercially available anti-VEGF. It is hard to tell which one is having what impact. Here, this was entirely naked. It was used by itself in a treatment naive patient population. What I would say is the results that we got were what you would expect for commercially available anti-VEGFs. That does not happen by accident. You know, that is not something that just happens by chance. When we did the study, which was a controlled study in the U.S., what we saw were the rescue rates, which were very, very convincing to us versus Eylea. I think that is when we made the decision to say, look, this is enough evidence for us to go to a phase III study. That is really the reason.
When we look at the data across kind of the class, the tyrosine kinase inhibitors, it gets difficult. You know, there's different patients, different criteria, different study designs. What, you know, to your point that you're the only ones who have shown this data, if we don't see the data, it's hard to guess, but what is it about AXPAXLI that could be different than the others in the class?
Yeah, so I think, again, great question. I think there are two ways that I'd like to answer that. First is the product itself, and the other is the study design and patient selection. As far as the product itself is concerned, the TKI is a well-known TKI, known to be the most selective, most potent TKI. The ELUTYX technology, again, is not something that is new at all. It's been used, approved by the FDA, and over 5 million patients have used it, not just, obviously, not just in the eye, but elsewhere as well. It's been used in neurosurgery, urological surgery, elsewhere. We have an approved format, which is ELUTYX technology, an FDA-approved format, and we have an approved TKI.
We're very, very content and confident that these two products, the way we put them together, are going to work exactly the way we want them to work. In fact, what we're seeing under masking now, which we'll talk about in just a little bit, validates what I'm saying right now. Let me switch to the next one, which is to say, how are these studies conducted? I think one of the most important things that's missed in our field, and this is sort of my biggest talking point that I can give you, is the single most important thing that anybody can ask me is something that very few people, nobody's really ever asked me directly, which is to say, tell me what you have done in your clinical trial design to de-risk the patient population and increase the chance of success. That is the most important thing t hat was on the list.
That was on the list. I saw, yeah, it was on the list, and that was you.
The reason is really simple. If I sat here with you and said, John, I've got a great drug for colon cancer, you wouldn't let me get away with that, right? You'd say, what do you mean colon cancer? What kind of colon cancer? What stage? What grade? I'm here to tell you that wet macular degeneration is no less variable than any of the other oncologic diseases that you know, be it colon cancer, bladder cancer, breast cancer, lung cancer, all those things. The problem is we are 50-80 years behind oncology. We have no genetic marker. We have no anatomic biomarker. We have no idea how patients are going to behave. That's why we do something called treat and extend.
Treat and extend really is, let's play it by ear. Let's see how you respond. There are some patients that will require treatment every two weeks. There are others that may require treatment every six months.
That's being a doctor.
Yes, but there's no way to know.
Yeah.
Which is fine, being a doctor. If you're doing a clinical trial, hard, right? If you, and this has happened, by the way, and I won't mention names, but in other trials where they failed, if you happen to have unintended, this group of patients that may be totally VEGF dependent or whatever, it doesn't need very many, you can completely bias your trial unintentionally and leave a good drug on the table.
I think this is a good segue, and you alluded to this, your two phase III trials, SOL-1 and SOL-R. It's kind of hard to unpack as, you know, one identity, but you guys designed these so they flow into each other. Maybe if you could just talk at a high level between the two, and then we can talk about each separately.
Absolutely. Let me just talk about the patient selection and how the two are designed. The first trial is a superiority trial, right? It's called SOL-1. Again, both of these are exactly according to the FDA guidelines. In a superiority trial, what you want to do is you want to select patients that have the most amount of VEGF receptors and are most VEGF dependent, load them up, and allow them to fail once. That's what was required, right? We selected not patients with poor vision, because there you get fibrosis and atrophy, as I said, but patients with exceptionally good vision, 20/80 or better, and most amount of VEGF receptors. We tested the VEGF receptors to make sure they functioned because those patients were required to improve by 10 letters or more or gain 20/20.
Perfect patient selection to go ahead and load them up and then allow them to fail once, right? That's the patient selection for a superiority study. That is very, very different than a non-inferiority study, which is the second study, which is called SOL-R. The non-inferiority study, that's not the patient selection you want. What you want in a non-inferiority study is absolute stability by definition, because stability wins. Here what we have is we have three loading doses of Eylea, and then we have two opportunities to observe. Now, what are we observing for? We're observing for those VEGF dependent patients that will fluctuate. We have two opportunities to weed them out. We have two more loading doses, and then we randomize. In each case, we're super selecting patients, enriching our patient population in a bespoke manner appropriate for each study.
Now, that's the patient selection part. Why did we decide to have these two studies the way we did? The knee-jerk reaction that everybody has and others are doing as well is to design the same study twice, right? It's the same thing twice. You need two studies for approval. We didn't do that. When you think about it, that is terribly inefficient. I mean, it doesn't require much brain power, but it's terribly inefficient because the second study really provides no additional information, just confirmation, right? We wanted to have two studies that complement each other and provide all the information that's needed so that we have a logistic, regulatory, as well as commercial advantage. Let me talk about each. Logistically, we required that everybody go into SOL-1 first. Those that screen fail SOL-1 in the beginning ended up in SOL-R.
We didn't lose any patients. That worked perfectly. Once SOL-1 was fully randomized, we took patients from the outside for SOL-R. It is the most efficient logistic complementary study design that you can have. That worked really well. From a commercial point of view, look, we have the potential of having the best label ever in this field, a label that is a superiority label based on SOL-1, only one, right? The first and only one, a label that has the flexibility of dosing of every six months based on SOL-R to every 12 months based on SOL-1, and repeatability based on SOL-R. From a commercial point of view, it's worked out beautifully. We have the numeric analysis. Remember, we talked about the second generation of anti-VEGFs. We will be going up against high-dose Eylea.
Not for, again, this is not for statistical analysis. This is for numeric analysis and SOL-R as a masking arm, but that's going to be very, very valuable commercial advantage for us. Finally, from a regulatory point of view, and this has not been recognized as much as it should, remember, no regulatory agency will see either of these studies in isolation. You'll always see it together. For instance, when somebody looks at a regulator and one of the agencies looks at the number of rescues, say, in SOL-R, which is the non-inferiority study, they will look at the rescues in context of SOL-1, knowing that this drug lasts for 9-12 months. That's a huge amount of power that we have in terms of information distribution between these two studies. They work in a perfect complementary fashion. They've worked perfectly well so far.
I really do believe that this kind of design for its efficiency is going to be the standard for the more thoughtful sponsors in the future.
With SOL-1, can you talk a little bit about that superiority endpoint, the primary endpoint, your powering, and what gives you confidence that, you know, some of these Eylea patients won't go all the way to nine months?
I mean, again, the modeling that we've talked about is really based on previous studies, as well as internal modeling. For Eylea, what I can point to, for instance, is the Talon study. That was in a non-super selected patient population. Even then, when patients were treated and extended, meaning the drug was on board, the anti-VEGF was on board, even then, only 20% or so of patients, or less than 20% actually, made it to that endpoint. We are very confident that in a super selected patient population that's selected to fail, that number is a very conservative number. For us, we know from the U.S. study, we are very confident that over 70% of patients for AXPAXLI will be rescue free. The biggest thing, though, is not those numbers. The biggest thing is the delta, right?
We need a 15%, 1.5, 15% delta to be statistically significant. We are very confident that we are going to be well above that. What I will also tell you is the reason that I said, John, earlier on that today I am more confident than I have ever been, as confident as I was before, is because of what we are seeing under masking. Now, it is very important to say that we are masked, right? We are masked. We can look at three things. We look at this obsessively for trial conduct, which is the most important thing in this company, is trial conduct of SOL-1. We look at the number of rescues. We look at the cadence of the rescues, the profile of the rescues, and we look to see if those rescues are on protocol or not, all under masking.
As far as the number of rescues are concerned, if we've selected the patients properly to fail, we should be seeing a robust number of rescues. That's exactly what we're seeing. The second part is the cadence of the profile of the rescues. We expect a certain cadence, knowing how Eylea behaves. What we're seeing, the timing of the rescues, we're thrilled with. We're very, very, very happy with that cadence. That's number two. Number three is whether we're seeing those rescues on protocol or not. What I've said earlier on and repeated many times is that the vast, vast, vast, and I've said it 3x , the vast, vast, vast number of rescues that we're seeing are absolutely on protocol. Given all that, under masking, again, I'm going to repeat, this is all under masking, I feel more confident today than ever.
You guys recently amended that trial design. Can you talk a little bit about what you did and why you did it?
Yeah. This is actually, thank you for bringing that up. This is actually really important. Let me just tell you what happens. There's a good historical background here. There are three things that are really important. The first one is the team before us, as I mentioned, and they deserve the credit, actually got the spot, which was fantastic for SOL-1, the superiority study. The way it was designed is the primary endpoint is at month nine, and the study ended. There was nothing else after that, right? The FDA requires a certain number of patients to have at least a two-year follow-up for safety only, not for efficacy, but for safety. In order to satisfy the FDA requirements, we had to put all those patients and overload the second study, SOL-R, so originally had 825 patients.
Not because we needed them for powering, but we needed them to satisfy the FDA second-year requirement because SOL-1 ended at month nine. Our investigators came to us and said, "Hey, look, you're putting us in a really difficult position because once the study ends and the study is positive, we've got to go to these patients who volunteered to be in the study and say, "Hey, look, there's nothing for you until the drug is approved." That's a really difficult conversation. They're right. I mean, having done this for 30 years, it's not a great conversation to have. That's number one. Number two is we saw what happened to Vabysmo. Vabysmo got a four-month label, and there are very few patients that actually made it to that mark.
The threshold for getting something on the label, the number of patients to make it there, is actually quite low. We were confident, we are confident, that there will be quite a number of patients with AXPAXLI that they'll be able to easily make it past the primary endpoint to the 12-month mark. It would be great to have the opportunity to get 12 months on the label. That's number two. Number three, and this is the gating factor, people ask, "Why did we wait this long?" This is the reason. Many of us have done more clinical trials than anybody else. I'm very proud of the people that we have here. This is the best of the best of the best in terms of the retina talent we have.
None of us, none of us have ever seen patient retention as good as we're seeing right now. We've just never seen it. Putting that all together, we said, "Look, let's just go to the FDA and see if we can extend SOL-1 into the second year." They said, "Okay." Now we can have the maximum amount of exposure in the second year to satisfy their safety requirements. If that's the case, we can drastically reduce the recruitment for SOL-R. We reduce it from 825 patients to 555 patients. What that does is the recruitment for SOL-R, remember, you need both studies, is going to happen much faster, much more efficiently.
The bottom line of all this is we're going to get to the finish line much faster, much cheaper, and potentially with a much better label that has the flexibility, a potential superiority label with a flexibility of six months to 12 months of dosing.
In the last minute, that'll be a perfect button. Can you talk about timing of Calus over the next, let's call it 12.4 months? Like, what should investors be keeping an eye on?
I think there are a number of things that are really exciting on board here. You know, obviously, the completion of SOL-R will be updating you as appropriate.
Do you have any guidance on SOL-R?
You know, not as yet from the last time. You know, in January, we said we had enrolled 311 patients. Remember, now it's going to be much faster because the number is going to be 555 patients as opposed to 825. All of that is going to happen a lot faster. You know, when appropriate, we'll guide you. Remember, when we give you guidance, we make sure that we do an accurate job and so forth, and we will. You'll also, I think, hear about our interaction with the FDA regarding diabetic retinopathy and diabetic macular edema, which we're thrilled with. We've made a commitment to go after that target. We have no competition. Our results of the HELIOS study have been absolutely fantastic. We're really encouraged. You'll hear about that.
Finally, obviously, what everybody's waiting for, which we're very confident about, is the card turn for SOL-1, which will going to be in the first quarter of 2026.
Okay. Perfect. I guess that wraps up the time we had. We covered a lot of ground. We're looking forward to tracking the progress. This is one of the more compelling stories, I think, in the space. Obviously, there's a lot of commotion, so it's a fun time to be covering it. Thanks again, Pravin, for joining us.
John, thank you again. Thank you for having us here and for all your diligence and support. Thank you.
Thanks.
Thanks.