Okay, let's kick things off. Welcome, everyone, to the Piper Sandler Healthcare Conference. I'd like to introduce our next company. We have Ocular Therapeutix and their CEO, Pravin Dugel. Welcome, Pravin. You know, I know the company really well, but maybe for the audience and for those on the webcast, if you could maybe just provide an overview of Ocular, you know, focus on ophthalmology and, and maybe talk a little bit about AXPAXLI.
Absolutely. So, Bjorn, first of all, thank you for having us here. It's always wonderful to meet with you and to be in this terrific conference. So, Ocular Therapeutix is a company that's based in Bedford, Massachusetts. It is primarily focused on retina. What we have are two phase III studies. We have said that the readout of the first study, called SOL-1, will occur in the first quarter of 2026. The second study is called SOL-R, and this study will read out, and we've given ourselves a fair amount of leeway in the first half of 2027. What we're doing is putting a TKI on a platform that we believe is has great potential. It's a tunable hydrogel. There are two problems that we're trying to solve. One is fairly obvious, and one may not be quite as obvious. The one that's obvious is that of sustainability.
What we're doing is targeting a known target, which is VEGF. So we're not reinventing the wheel. We believe that that greatly de-risked the target site because it's a known target, known to work, in a number of retinal vascular diseases. So the first problem that we're trying to solve is, in terms of sustainability, is that despite having a treatment in this blinding disease after almost 35 years, to me, as a retina surgeon, it's unconscionable that 40% of people in this country alone are not getting treated and are dropping out, and going blind. So sustainability is one of the issues we're trying to solve. The second one is long-term outcomes, and this is the one that I think people tend to forget. Even those patients who are on treatment and can stay on treatment after two to five years inevitably get worse than baseline.
The reason they get worse than baseline is because of the pulsatile nature of the treatment, which causes the back of the eye to be thin and thick and thin and thick, tantamount to having concussions, and that leads to fibrosis and atrophy. Vision gradually gets worse, and we thoroughly believe that with sustained suppression, we will have better long-term outcomes. Sustainability and better long-term outcomes, those are the two problems that we're trying to solve.
So with AXPAXLI, you've got several phase III trials that are currently running. I think the first trial, SOL-1, started a while back.
Yep.
Close to completing. Can you just talk about timelines on completion, when we could expect data from that study, as well as what the objectives are of that trial, given it's a unique design to your second study, which is the SOL-R study?
Yeah, I think the thing to remember here, and we'll talk about wet macular degeneration and diabetic retinopathy and diabetic macular edema maybe separately, although there's a great deal of overlap, as you can imagine. What we have done very deliberately is to be as strategic as we can possibly be. There is a purpose to every single trial. Also, I think it's really important to realize that we probably have more SPAs per capita than pretty much any other company, on the planet, and the reason for that is very simple. We want to be completely aligned with the FDA, absolutely and completely aligned. We are not going to be doing any trials at regulatory risk whatsoever, so the purpose of SOL-1, going to wet macular degeneration, is very simple. The purpose of SOL-1 is to obtain a superiority label, period.
And we can discuss, you know, why that's important in just a bit. But clearly we have a trial that the FDA has validated with a SPA. It's a trial designed per the FDA, really. We follow the guidelines exactly, and we believe that we'll be on path to get a superiority label with the success of that trial. Now, the second trial, SOL-R, is primarily for clinical relevance. We believe that it's an absolutely clinically relevant trial. And remember, both of these trials are going to be looked at together. You need two successful phase III studies, for approval. And looked at together, these two trials are going to answer every question that the clinician, the patient, and the payer wants. We believe that we will potentially have a label that will be the best the industry has ever seen.
It will be a superiority label with the flexibility of dosing every six months to twelve months with repeatability. And remember, this is not going to be on the label, but this is for commercial leverage. In the masking arm of SOL-R, we're using high-dose EYLEA. So we will have information. This is for numeric analysis, not for statistical analysis, versus the second generation of anti-VEGFs, namely high-dose EYLEA as well. And from a commercial point of view, that will be very advantageous for us. So as a clinician, and I can say this as a clinician that's practiced for 30 years, what I would want to know is how long does this drug actually last? And with SOL-1, we'll have that information. We'll have data going all the way, alpha-protected data to twelve months, as you know. I'd want to know, can this drug be repeated?
We'll have that information with SOL-R. I'd want to know, how does this drug do against the standard of care, namely two milligrams EYLEA? I'll have that answer with SOL-R. Then I'd even want to know, how does this drug do against the second generation of anti-VEGFs? And we'll have the numeric analysis versus high-dose EYLEA. So once this drug comes to market, there will be more information for this drug than any other drug that I know, that I have known in the last 30 years in my field.
So with data across both trials, SOL-1 and SOL-R, what is your optimal target product profile for AXPAXLI? What would you like to see from both data sets that would inform you, all right, this is the target profile that would, you know, maximize market adoption?
Yeah, so there are three things that we're targeting here. We call this a triad that's related. One is the superiority label, and they should be talked about, all three should be talked about together. The second is the size of the market, and the third is the adoptability, right? So the first thing, superiority label, why is that important? As a clinician, I can tell you that, and I think you know this, I think I've famously said myself when I was on the other side, look, I never look at labels. It really doesn't mean anything to me. And if you ask your KOLs, that's what they'll tell you, as I used to say, and they're right. But that's not the right question, right?
The right question to ask as a clinician is, does it matter to you that you get to choose the drug that you want from day one? Does it matter to you that you're not forced to use a cheaper and inferior drug, watch your patient fail, and then petition for the drug that you want in the first place? Does it matter to you that the ASP is as high as possible in the drug that you've chosen? And who's not going to say yes to all of those questions? That's what a superiority label gets you. And that's one of the keys of adoption. The second one, very simply, is that nothing needs to change in terms of the workflow for the clinician. And as a clinician for the last 30 years, trust me, that matters a great deal.
There are no steroids involved, there is no going to surgery, there are no carcasses, there's nothing left behind. The physician simply reaches out his or her hands, gets a better drug, and simply has better results. There's not a single piece of new equipment to buy. So for those, and the experience is really the same. This is a self-sealing 25-gauge needle, and this is going to be the same experience that the clinician has had with EYLEA or LUCENTIS or any of the second-generation anti-VEGF. So adoptability will happen seamlessly, and I really think it will be used overnight.
Durability, is that, does that play into the target product profile as well in terms of how, what's the minimum durability that you would want to see with AXPAXLI?
We'll have a very good answer, Bjorn, as you know, with SOL-1, right? The primary endpoint is at month nine. It's about as clean from a scientific basis as you can possibly imagine. There's no extrapolation. We'll have the actual data, and we'll have alpha-protected data all the way to twelve months. We believe that we will have twelve months on the label. We are very, very excited about that. And to answer your question, look, as a clinician, we feel very comfortable seeing our patients with chronic diseases every six months, right? I don't think that anybody really feels comfortable with a chronic disease saying, come back in a year or come back in three years or whatever it is. It's every six months, and patients feel comfortable with that as well.
So for a drug that, for seeing patients every six months, you really want a drug that's going to last nine to ten months. You know, the patient may get sick, the doctor may be on vacation, who knows? So this is a perfect durability product profile for seeing a patient every six months.
Currently, what's the standard of care? How, what's the durability like with the current anti-VEGFs?
You know, it really is all over the place, right? I mean, we do something called Treat and Extend. And, you know, there's no one else in the field of medicine or no other discipline that uses something like Treat and Extend. Basically, we wait for the disease to come back, and then we try to figure out how often to see the patient. I mean, you don't go to your oncologist, and the oncologist would say, look, I'll wait for your bladder cancer to come back, and then I'll figure out how often to treat you. I mean, you don't go to your cardiologist and say, look, I'll wait for your third heart attack, and then I'll figure out how often to treat you. But yet, that's what we do.
The reason that we do that is because we don't have a reliable treatment that we can use on a regular basis that makes sense for the doctor and for the patient. That's why scheduling is a nightmare on both sides. As a clinician, I can tell you, scheduling Treat and Extend, you have no idea when these patients are going to come back, is a nightmare. For the patient, it's also a nightmare. Now, so if you can have a drug that is in tune with when you want to see the patient every six months, that's a huge advantage for both the clinician as well as for the patient.
You talked about the superiority label. What are efficacy expectations in SOL-1 across each arm for you to achieve that superiority label?
Yeah, it's a great question. So when we talk about the superiority label, it's important to look at two different audiences, right? I think that, you know, as a company evolves, you know, my audience also changes. And my audience is obviously you, the street as well. But my audience now is not just clinicians, but it's also strategics. From a strategic point of view, they completely understand the significance of a superiority label. I mean, instantly, right? That's really the Holy Grail for us. Nobody's achieved a superiority label versus an anti-VEGF. We'll be the first and we'll be the only. And it's not just a superiority label. We're backing it up with a couple of other things. Again, this is a triad. It's a superiority label. It's also data. It's also long-term data.
Remember, we announced that we have the long-term open label extension study that we call SOL-X. That will give us a lot of information. Probably the most important information are the crossover patients. So these patients are going to be crossed over after two years of pulsatile therapy. We don't think those patients will ever catch up, right? We know that fibrosis and atrophy can be detected as early as 90 days. And this is after two years. So we will have data with SOL-X showing that in order to get the best results, you have to start on this premium drug from the very beginning. The third part of the triad is our IP. As you may know, we've announced recently that our IP extension has been granted to 2044.
So that triad of a superiority label, as well as the data supporting long-term use, as well as the IP extension, is a really powerful triad that the strategics understand instantly. And I think the street is also beginning to understand. The superiority label from a clinician's point of view is exactly what I told you. The fact that there's potential to be immune from step therapy, the fact that the premium drug can be used immediately, the fact that the ASP will be as high as possible, all those things are very attractive to the clinician. And remember, we've also built a moat around this because now if somebody else wants to try and get a superiority label in the future, they'll have to go up against us, right? So again, that puts us strategically in a very, very attractive position.
Got it, got it. I guess the question on SOL-X, when could we start to see data from that trial? Clearly, the SOL-1 patients will have to go through the first twelve months, and then there's redosing at month twelve and month eighteen, and they would likely go into SOL-X at month twenty-four?
Yes, that is correct. So let me just kind of backtrack a little bit and tell you what we're trying to achieve there. I talked about the crossover patients, right? And I just want to spend a little bit of time discussing that. The tragedy of what we're doing right now is that we have a target that now for almost four decades has been validated, which is the VEGF target, right? There's no doubt that the results by inhibiting VEGF are nearly miraculous. And for an old guy like me, you know, look, when I was in training, we would watch patients lose vision. And the fact that Genentech and then Regeneron came in and showed us what inhibition of VEGF can do, in my mind, having lived through that, is nearly miraculous.
Yet the tragedy, as I said earlier on, is that 40% of patients in this country in the first year do not get the treatment. They all go blind. The other tragedy on the back end is that even those patients who are able to stay there and gut it out with the treatment, after two to five years, almost inevitably get worse than baseline. So there's a tragic front end and there's a tragic back end. And we're solving for both, right? And we firmly believe that if we have constant suppression of VEGF as opposed to this pulsatile suppression that's causing the fibrosis and atrophy, we'll have better results on the back end. And with SOL-X, to answer your question, that's exactly what we'll show.
I did want to touch on SOL-R. So clearly a different design than SOL-1, non-inferiority, head-to-head against EYLEA every eight weeks. But then you talked about the EYLEA HD arm as well. What was the importance of the EYLEA HD arm? Was it strictly around, you know, addressing the sham arm or lack thereof with FDA guidance, or was it also the fact that you could, you know, analyze head-to-head versus HD?
Really, it was both. It's a great question, and the answer is both. What we really should do also, and I'm very, very, very proud of this, and this I think, I talk about this all the time, although I don't think it'll ever be appreciated as much as it should be, and it's not credit to me, it's credit to my colleagues, is the amount of thought that has gone into de-risking the patient population, right? Remember that the way patients are selected in the clinical trials is very different in SOL-1 than SOL-R. In SOL-1, we specifically selected anti-VEGF dependent patients. These patients are designed to fail, right? Once, right? That's the whole idea behind the rescue. In SOL-R, it's almost the opposite. What we've done very, very carefully is to have the longest ramp that I know.
It's a six-month ramp with a two-period opportunity to observe patients for fluctuations. What we want in a non-inferiority study is absolute stability, and that's exactly what we've selected for, and I don't think any other company has been this thoughtful in de-risking patient selection for specific clinical trials in a bespoke manner. Now, getting to your question, what the FDA has clearly said, and this is about as clear as it can be, is that they do not consider a sham injection to be proper masking. Okay, let me just say what a sham injection is, and a lot of people don't realize this. A sham injection involves touching the outside part of the eye, the conjunctiva, the white part, with the hub of a syringe. That's it. There's no injection.
What we do when we numb the eye for an injection is we numb the outside part of the eye, the conjunctiva. We are not numbing the optic nerve. Okay, that's something that I think a lot of people don't understand. So your vision doesn't change one bit. If you can see a 300-nanometer floater, you can certainly see a whole bunch of liquid coming in. And that's the whole point. The whole point is that patients know, and we know this, we've known this for decades, when you're injecting something and when you're not injecting something. So if you have a subjective endpoint such as visual acuity, patients can certainly be biased to try harder or not try as hard. And the FDA knows that. And in their guidelines in 2023, they clearly stated that sham injections are not proper masking. Doesn't mean you can't do it.
You're just doing it at risk. That means that even if you hit the primary endpoint, because you're not properly masked, you may not get approved. So what we've done is taken no such risk. We've done exactly what the FDA wants and has stated over and over and over again in public as well as in written documents. And in order to not use a sham injection, you have to mask for your drug. And the requirement for the masking arm is that it has to have the same cadence and the same rescue criteria as your investigational drug. Now, you can use anything. The FDA doesn't restrict you. You can use water. I mean, it doesn't really matter. We chose to use high-dose EYLEA. Why did we do that? It's because we're that confident, right?
At most, the second generation anti-VEGFs may get you another week or two weeks. We're in a different orbit. We're talking about nine to 10 months. We have no problems going up against high-dose EYLEA. We welcome that. We are that confident. And yes, it'll provide us a huge amount of competitive advantage from a clinical point of view, from a commercial point of view. And I think it's only fair to provide doctors, patients, and payers with information saying, look, this is how good our drug does, and this is what it does against the second generation of anti-VEGF agents. And we'll have the numeric analysis of that data.
In SOL-R, you mentioned the lead-in phase with the potential for five anti-VEGF injections. You're looking at enrolling patients that have minimal variations on OCT. Talk about the rationale on selecting for these types of patients into SOL-R.
Yeah, you know, what most other companies do is to say, look, we want to recruit as quickly as possible. There's very, very little thought placed on patient selection. And we've already talked about Treat and Extend. And you know that the variability of this disease, as in many of our retinal vascular diseases, ranges from having to treat patients every two weeks to treat patients every six months. You have no idea who they are, right? There are no biomarkers. There are no genetic biomarkers. There are no anatomical biomarkers. What we've done is to say, okay, we're going to use the loading phases for both studies to super-select a patient population that is as de-risked as possible and bespoke for each trial. So yes, that's harder to recruit, obviously, although our recruitment has been extraordinarily efficient. We've done record-time recruitment for both studies.
Most importantly, we've also de-risked the patient population as thoughtfully as possible. Nobody's done this. You know, in the beginning, you could get away with this because if you look at ANCHOR and MARINA or VIEW 1 and VIEW 2 or HAWK and HARRIER, these are trials with thousands of patients. You could argue that this kind of variability can be overcome by increasing the numbers. That's true. However, we're not doing thousand patient studies, right, or two thousand patient studies. We're doing studies with, you know, 500, 300 patients. This kind of variability, as we've seen in some trials, can unintentionally really be risky for a trial and blindside the results. We believe that we've immunized ourselves from that by de-risking the patient population.
And I guess we've got a few minutes. I want to talk about the NPDR opportunity as well. You know, clearly a high unmet need, and anti-VEGFs are underutilized. Can you talk about the issues on why, even with FDA approval of EYLEA, LUCENTIS, and diabetic retinopathy, that these products are underused and where you think AXPAXLI could solve some of these issues?
Look, this is a no-brainer, and we're extremely excited about this. The fact of it is that what we saw in HELIOS was astonishing to us from a clinician point of view. Every single parameter, no matter how closely we checked every single parameter from the fluid difference to the DRSS, the Diabetic Retinopathy Severity Score to the perfusion, every single parameter favored the drug. And we really had no choice but to say, look, we would be irresponsible and we wouldn't be doing our fiduciary responsibility if we didn't go ahead and do this trial. And again, this is de-risked because it's a known target. You know, suppressing VEGF gives you results that are phenomenal. We know that. However, these patients are asymptomatic. They will be unable to come in every month or every other month.
And not only that, but if they miss their visits, there's a danger of a rebound effect. So you can actually make them worse. So LUCENTIS, EYLEA, et cetera, are not used at all. I mean, less than 1%. Although the rate of a blinding complication for these patients is 30%-40% year upon year, it's not insignificant. If we do what we believe we will do with AXPAXLI, this will require an injection once a year. And once a year, vision-threatening complications go from 30%-40% to literally zero if HELIOS is replicated. So the conversation with the patient will go like this: Ms. Smith, you've got a blinding disease. Although your vision is really good right now, your chance of developing a vision-threatening complication is about 30%-40% year upon year. And that's statistically proven data.
If you come to see me but once a year, like you go to a dentist for teeth cleaning, I can reduce that rate of vision-threatening complication literally to zero. I mean, think about the impact of that. Literally to zero. That's doable. That's impactful. That's sustainable. And that's millions and millions and millions of patients who are not getting treated right now. So we are absolutely excited about it. We've got a novel, fantastic endpoint, the ordinal endpoint. We believe that our chance of success is sky high, and as usual, it's also validated by SPA.
And so what was the rationale on the ordinal endpoint? Because traditionally, it's been a two-step, greater than two-step improvement on DRSS as a regulatory endpoint in this area.
Yeah, the two-step is really non-negotiable for the FDA. They want to see a difference of two steps in the Diabetic Retinopathy Severity Score. However, previously what they had said was to say, look, you get to pick one or the other. Is it two-step improvement or decrease of worsening? You don't get both. What we proposed is to say, look, in a blinding disease like this, it matters if the drug makes you better. It matters if the drug stops you from getting worse, and it matters if the drug maintains, and they agreed. There wasn't any back and forth. They simply agreed we have a spot for this new endpoint, and I believe that everybody that will ever do a diabetic retinopathy study will use this as the primary endpoint because it's clinically relevant and it makes complete sense from a clinical point of view.
These are objective endpoints. And I just want to go back as we end to what I said earlier on regarding sham. There is no problem using sham for an objective endpoint. So yes, we do have sham for our diabetic studies. And the reason for that is because it's a primary endpoint that's absolutely objective. It's photographic. So you can't try hard to change your photograph. It's very, very different than visual acuity as a primary endpoint where sham is done at risk.
Perfect. I think we're going to end there. A lot of exciting developments and looking forward to data in Q1.
Thank you for having us here. Thank you for including us in this great fireside chat.
Great. Thanks for being here.
Take care.