Great. I'd like to welcome everyone to the Piper Sandler healthcare conference. We have our next company, Ocular Therapeutix. I'd like to thank, you know, Pravin Dugel, introduce him, Executive Chairman, President, and CEO of Ocular Therapeutix, so welcome, Pravin.
Very, thank you.
Great to have you. So I guess, you know, you, maybe just start off, for those that are unfamiliar with Ocular, just give us maybe an overview of, you know, what, you're focused on as far as, you know, the pipeline as it relates to, you know, retinal therapeutics.
Thank you. First of all, thank you for having us here. It's been a wonderful meeting, and our meetings have been fantastic. I really want to thank you and your colleagues for including us. Ocular Therapeutix is a company that's been around for a while and has undergone fairly major change recently. What we've done, we hope, is to have an identity of who we are and what we intend to do and a focus to achieve that. We believe that we have a superb hydrogel technology. This is a completely bioresorbable hydrogel holding a TKI that we believe is the most potent TKI available. We're trying to solve two problems in wet macular degeneration. One may seem fairly obvious, and the other may be not quite as obvious.
And the obvious one is that we're trying to solve the problem of sustainability. What we do know is that with the anti-VEGFs, you've heard of Lucentis and Eylea, these drugs are nearly miraculous for an old guy like me where we had nothing to treat wet AMD with as I was in training and early in practice. To have anti-VEGFs where you can actually not just treat patients in terms of maintaining vision but actually improve vision with Eylea and Lucentis is just absolutely miraculous. That's the good side. The unfortunate side is that as large as that market is, and that market is humongous, what you have to realize is that you're only seeing 50% of that market because 50% of the patients are actually dropping out because the treatment is simply not sustainable.
So 50% of people that shouldn't go blind are going blind, as good as the treatment is, because the treatment is simply not sustainable. So that's the one problem that we're trying to solve that is obvious. The other part that's not obvious is that even in those patients who are able to come in, the 50% who are able to come in religiously, what ends up happening, happening rather unexpectedly but inevitably is that after five years, their vision actually gets worse than baseline. So even if they come back after five years, they end up losing vision. And remarkably, this happens not because of recurrent hemorrhage, which is what we expected, but because of fibrosis.
And what we think is happening is that because of our pulsatile nature of injections where the back of the eye gets thick and thin and thick and thin as we inject on a monthly or bi-monthly basis, it's akin to having multiple concussions in the eye, and the eye undergoes fibrosis or the nerve cells undergo fibrosis. So we think that with AXPAXLI, with a long-term sustained release without those oscillations in the back of the eye, that the outcomes will be better. So again, we're trying to solve the problem of sustainability as well as give better chronic visual outcomes.
Got it. And so I guess, you know, from the standpoint of, you know, you talked about, you know, the unmet need and how you potentially fit that. But, you know, the treatment landscape's clearly evolving. We've got, you know, biosimilars coming into the landscape. How do you think AXPAXLI's gonna play into that, into that type of evolving market landscape?
So the answer, Biren, quite honestly, is we're completely agnostic to biosimilars or whoever comes in. And let me answer in a different way. People also ask me, what is the medical need for that, and what is the thirst for this? If you look, for instance, at Lucentis, a miraculous drug with a seven-year head start that Genentech had, and then after seven years comes Eylea from Regeneron, a company at that time that nobody had heard of. And perhaps Eylea gave you not better safety outcomes, not better efficacy, but perhaps, and very arguably, one extra week, and it absolutely took over the market. And the same thing is happening now with high-dose Eylea and Vabysmo with maybe an extra two weeks. But the bottom line is there's such a need and a thirst for increased sustainability.
We're giving 10 months, nine to 10 months. Now, whatever comes in front of that in terms of biosimilars, you know, anything else really is not gonna be comparable to the product that we're delivering. So we're completely agnostic to biosimilars or whatever other products are out there for the anti-VEGFs because of the long durability that we have.
You know, so AXPAXLI's currently in two phase III trials, SOL-1 and SOL-R. For SOL-1, I think you could probably agree it's a non-traditional design. Can you maybe talk a little bit about that design? What led you to, you know, move forward with the SOL-1? Because no company within the retina space has done a trial like this, you know, before you. So kind of, you know, what are, what were the drivers for that, and what's the objective of the trial?
The driver's really the FDA and doing good science and having a very clear regulatory pathway. I mean, it's as simple as this. The FDA said very clearly, it's in their website, they said, "Look, here are the guidelines for doing a superiority study, and here are the guidelines for doing a non-inferiority study." It's very, very, very clear. And they also said, "We don't want you using sham. We don't recommend sham, because sham is not proper masking." And a lot of people don't realize why it's not proper masking. You know, when we do these injections, we don't numb the optic nerve. So the vision never gets bad. The vision is as good as it is right now.
So when you put the hub of a syringe and pretend to inject and nothing comes out, patients will look at you, and this happened, has happened to me while I was, you know, PI for 30 years and said, "Doctor, you didn't do anything." On the other hand, when you go ahead and inject, they can see a swish of water or fluid coming in, they'll go, "Oh, I saw it." And the FDA recognizes this and knows that sham isn't proper masking. So what we did was to follow the superiority guideline that the FDA laid out for us as clearly as we possibly could with the SOL-1 study, and we were rewarded with a SPA agreement. In SOL-R, we didn't repeat SOL-1. We didn't do a SOL-2 for very good reason that we can discuss.
These two studies go together in a complementary fashion as well as anything. It's the most thoughtful two studies that I've ever been part of. But in SOL-R, which is now a non-inferiority study, we also looked at the FDA guidelines and followed that exactly and were validated with a written Type C response that clearly states SOL-R is a registrational study, that all we need is SOL-1 and SOL-R for approval. It again restates that the FDA does not recommend sham because sham is not proper masking. Of course, we don't have sham in either of our studies.
And so for SOL-1, congrats on completing enrollment. You know, the press release yesterday announced that, you know, you had more than 300 patients enrolled, and I think ahead of your, you know, timelines as well as I think investor expectations. Talk a little bit about, you know, fast forward Q4, you know, a year from now when we're about to get data. You know, what does, you know, statistical significance look like? What does clinical relevance look like from a trial like that?
Yeah. So the first thing, continuing with this idea of how well-designed these two studies are to fit into each other, it's not just that SOL-1 is now completely randomized. It's that there's also, and it should be said in the same sentence, there's a large bolus of patients that will be immediately transferred from SOL-1 to SOL-R. And that is unique. It's very thoughtful. It's never been done before. And what usually happens in two registrational studies is the same study is repeated. So the study is recruiting, and then it slows down and stops, and the other study starts. Here, it just goes on and on. It's just like a rocket ship that just kinda keeps going. All those patients are seamlessly transferred to SOL-R. So SOL-R already has a huge head start.
As you know, so that really should be recognized. As far as the outcomes are concerned in terms of when these two studies will conclude, look, our job is to make that delta as short as possible. It's a little bit too early to give guidance at this point, but we have said that our expectation is that the readout of SOL-1 will be a year or so from now, which is the fourth quarter of 2025.
So from a, you know, so you're looking at rescue-free rate at nine months as the primary endpoint.
Right.
and what's considered to be a statistically significant treatment delta benefit, and what would be clinically relevant?
Yeah. A great question. So what the primary endpoint in SOL-1 is at nine months is the percentage of patients that maintain vision. We believe that in our calculations that the Eylea arm that will be about 20% or so. We believe that with our AXPAXLI arm that will be about 70%. So the delta is about 50%. We need a 15% delta, 1.5, to be statistically significant. So we're very confident in the statistics. We're very confident in the design as well. If you're asking appropriately, what will the clinicians think? It's really important to take both studies together. That's why they were designed. And I believe that one of the strengths that we have of that is that it answers every question that the clinicians may want and gives them all the information that they could possibly need.
If clinicians look at both studies, they'll, what they'll see and what they'll be asking is to say, "How long does this drug last?" Well, that'll be answered really by SOL-1, right? At least nine, nine months or so in this proportion of patients. The clinicians may be asking, "Can I use this drug repeatedly?" They'll get the answer in SOL-R. "What's the flexibility of dosing?" They'll get the answer in SOL-1 and SOL-R between six months and nine months. And remember, in SOL-R, we're actually going up against high-dose Eylea. So they'll get an answer as to what happens with high-dose Eylea. Now, the high-dose Eylea arm is for masking purposes only. It's not for statistical analysis, but from a commercial point of view, we'll have a huge advantage in going up against high-dose Eylea.
This also sets us up for a potential labeling discussion that'll be very beneficial for us, right? You can imagine that what we're hoping to get is a label as the first one of its kind that shows superiority 'cause no other label ever has, that shows flexibility in dosing from six months to nine months, and that shows repeatability. The combination of these two studies is, I think, perfectly set up for us to be strategically superior, commercially as well.
And so you, I guess, you know, the 70% assumption in the phase three for SOL-1. That's derived from the phase one U.S. trial.
Right.
What's your confidence level in terms of the translatability of the U.S. phase one trial into SOL-1?
Yeah. It's really important to remember that the phase one studies in general, and I've done hundreds of them, are first of a kind, studies where the drug or the device or anything else that's used in phase one was ever used in a human being, right? Patients aren't properly necessarily selected. The only thing that you're trying to answer is, "Is this safe? And does this show a biological signal?" That's very, very different than phase three because by that time, you've already answered those questions. In phase three, what we are doing is we are putting all our effort into proper patient selection, and that is so, so important, and that's what gives me the confidence to answer your question. Patients have been selected very thoughtfully and appropriately in a bespoke manner for each trial.
Let me just explain this because this is really important to understand. If you look at SOL-1, it's a superiority study, right? And here, what happens in a neovascular membrane is you get a big stimulus. All these VEGF receptors pop up. The membrane starts growing, and here the vision is still good. The membrane grows and grows, and the VEGF receptors will involute. You get fibrosis receptors, bFGF, FGF. The membrane now is large. The vision is not so good. The membrane atrophies and fibroses and goes away. Most studies recruit here. We're recruiting here when the vision is good and the VEGF receptors are at their max. And not only are we doing that, we're testing them and challenging them to make sure that they're functional.
We're giving two loading injections, and we only will randomize patients if they improve to 20/20 or improve by at least 10 letters of vision. So it's not just that there are a lot of VEGF receptors. We're ensuring that they're responsive. So we're loading them up and letting them fail once, right? And that, that's the perfect selection for a superiority study. That is in contrast to SOL-R, which is a non-inferiority study. And here, what you want is absolute stability, right? Because it's not an inferiority. So what we're doing here is we're giving three loading injections, and then we've put in something that no one else has, which is two opportunities to observe the patient. And what are we observing for? We're observing for instability. Those anti-VEGF addicts that will fluctuate, right? Because we want stability.
So we have two chances to weed them out, and then we have two more loading doses, and then we randomize. So the importance of this, the thoughtfulness of this is that in each trial, the patient selection is absolutely appropriate and bespoke for that particular trial. And all those things never can happen in a phase one study. So that's what gives me a great deal of confidence, the patient selection and the results that we have from before in both of these trials. And just realize how much thought has been put in a bespoke manner to select these patients appropriately for each study.
And so I guess SOL-1, the patients enrolled were mainly U.S. and some Latin America.
Correct.
How does that compare in terms of site overlap to SOL-R where, you know, you commented that, you know, you've got now a bolus of patients that are able to go into SOL-R now that SOL-1's completed?
Yep. So obviously, SOL-1, 300 patients, SOL-R, 825 patients. So a much larger trial. Now, supposedly, SOL-1 was the one that was impossible to recruit, and SOL-R, anyone would say, would be a much easier trial to recruit because it's more close to the traditional non-inferiority study, but without a sham, right? There is no bad arm in SOL-R, right? The patients will either get AXPAXLI, get 2 milligram, Eylea, or get high-dose Eylea. There really is no bad arm at all. So we think that SOL-R is eminently recruitable. There's a great deal of overlap, certainly with the high, enrolling sites, in the U.S. We're continuing to activate more and more sites outside the U.S. We think we will be able to enroll SOL-R very efficiently. It's still early, but certainly that bolus of patients that are being transferred helps with that as well.
So how many more sites would you have in SOL-R?
Yeah. So I don't know that we've disclosed that here in the U.S. yet, but we're activating certainly a lot more sites, particularly outside the U.S.
Got it. So, you know, if I were to put on my analyst hat and try to, like, make some assumptions, maybe by, like, second half next year, you would have SOL-R?
Yeah. It's a great try, and you know, I'm old enough that I'm not gonna fall for that bait. But what I'll tell you is that my job is to make sure that that delta is shrunk as much as possible.
Got it. Okay. Now, I guess from a design standpoint for SOL-R, you've got three arms.
Yeah.
Right? Non-inferiority against Eylea, two milligrams every eight weeks. Well, you're going up against you know, I mean, essentially what was the market leader for a long time there. And what gives you confidence that you're gonna be able to achieve non-inferiority with every 24-week dosing of AXPAXLI?
Yeah. So, you know, look, we could have. It's important to state that the randomization ratio is two, two, and one, right? The high-dose Eylea is for masking purposes only. It's not for statistical analysis. But it gives us a huge amount of commercial advantage. And we're, you know, perfectly happy to go up against high-dose Eylea. High-dose Eylea, as with Vabysmo, may buy you another couple of weeks here and there. We're talking about nine to 10 months. So we're, we really believe we're in a completely different orbit, and it will provide really useful information to the physicians, and that's what we want for better care of the patients.
Are patients, in the AXPAXLI arm, or I guess in all three arms, they're allowed retreatment? I would assume?
Yes. So we have not guided you as the retreatment criteria as yet. But obviously, the rescue criteria is gonna be very different than SOL-1, right? The rescue criteria in SOL-R, because it's a non-inferiority study, is gonna be more akin to the non-inferiority studies that you're used to traditionally.
Got it. And then, you know, you mentioned that the Eylea HD arm within SOL-R is strictly for masking purposes. Is there gonna be any comparisons that could be made to Eylea HD every 24 weeks?
Yeah. So, you know, we haven't disclosed our statistical analyses and other analyses that we're gonna do yet. What I would say is because of the ratio, it clearly is not for statistical analysis, the HD Eylea arm. But that's data that can be very valuable for us from a commercial point of view. And certainly, we will look at that very, very carefully.
So there would be some sort of like a clinical comparison?
There certainly can be. That data is certainly available for that. Again, it's not something that the FDA necessarily is concerned about other than the masking part. We specifically chose high-dose Eylea for a very good reason. That reason was to give us commercial advantage, and we intend to use that leverage.
And so, you know, one could say that, you know, Eylea HD is dosed every 12-16 weeks. So could you have an advantage there potentially in terms of showing, you know, superior vision outcomes?
Look, if we weren't confident, we wouldn't do it, right? We certainly are very, very confident in that. But I think what I would do is to step back and say that as a physician, and a lot of the people in the team are physicians who've been practicing for a long time, so we think like physicians 'cause we are physicians. We have certain questions that we wanna answer before we treat a patient. And one of the questions is, how do you do against what is most commonly used, which is two milligram Eylea historically? How do you do against the best version of the drug that's most commonly used, which is presumably high-dose Eylea? How long do you last? Are you repeatable? Are you superior? All those questions will be answered.
Our aim is to make sure that every one of those questions are answered so that this will be the dominant drug.
You know, traditionally, retinal studies have followed patients for two years. Primary endpoint tends to be year one, and then you have longer follow-up up to year two. Is that something that's planned for SOL-R?
We haven't disclosed the second year plans and analyses as yet. We will be more than satisfying the safety requirements. They're followed for two years, as you know, for safety requirements. But it's important to emphasize that the primary endpoint for SOL-1 is at month nine. The two years the safety part, and the primary endpoint for SOL-R is at month 12.
Got it. And so after post that, there's no other additional, you know, follow-up or patient treatment at year two for SOL-R?
No, we haven't said that, or we said we just haven't guided you to that, but whatever we'll be doing after that will certainly satisfy the safety requirements, and whatever we do will be for commercial advantage.
Right.
That's the important part.
Okay. That's fair.
It's not a requirement by the FDA. It's for commercial advantage.
Agreed. Agreed. I guess what are the next indications? You've, you know, disclosed data in NPDR earlier this year from a phase one study. You know, what are your thoughts there? You know, you also, I think, had a few patients that had diabetic macular edema in that trial, so you showed some benefits. What are your plans for either indication?
I mean, I've gotta tell you, I think the HELIOS study, which is not a large study but a small study, which probably makes it even more important, is that the data is just spectacular. I mean, every single parameter was aligned in favor of the drug at week 48 with a single injection. Every single parameter. We showed every patient. I mean, I don't think anybody else has shown every single patient of the study. And everybody that improved had the drug. Everybody that didn't improve didn't have the drug. Everybody who had diabetic macular edema got better on the drug. Everybody who had diabetic macular edema that was not on the drug got worse. It's not just that we can treat non-proliferative diabetic retinopathy. Clearly, we can also treat diabetic macular edema with a single injection at week 48.
Perhaps from a clinical point of view, the most relevant thing is that these patients who are asymptomatic have a sort of a ticking time bomb in their eye. We know from natural history studies that the risk of vision-threatening complications is 20%-30% year upon year upon year. And indeed, in our control arm in HELIOS, vision-threatening complications occurred in 38% of patients in the control arm. In the treatment arm, with a single injection, it was literally zero. And to me, that's the most important point. Literally zero. So if these data are duplicated, that means that I can sit with a patient.
The patient may be a banker, maybe an analyst, maybe a mailman, maybe a taxi driver, anybody who's asymptomatic but has a 20%-30% risk year upon year of having a vision-threatening complication and say, "If you come to see me once a year, like you go to your dentist for your teeth cleaning, your chance of going blind can literally be zero." I mean, that is incredibly powerful, and nobody else can say that. And we literally have no competition. And our intention is to absolutely go into the non-proliferative diabetic retinopathy market. The only reason we haven't done that yet is because SOL-1 and SOL-R are our priorities. But that is our intent to talk about diabetic retinopathy quite a bit, in the next calendar year.
Have you started to have discussions with FDA around trial design?
We haven't disclosed any formal discussions as yet. We will go to the FDA when appropriate. We will disclose to you what the formal discussion, the outcome of the formal discussions are. Our intent is to have a strategic plan of developing AXPAXLI for non-proliferative diabetic retinopathy.
Perfect. I think, we're about out of time, and thank you for attending the Piper Sandler healthcare conference.
Baron, thank you so much, and thank you for including us in this wonderful meeting.
Great. Thanks.
Thanks.