Okay.
All right, we're going to get started with our next session. Thank you, everybody, for joining us at the Leerink Global Healthcare Conference. I'm Marc Goodman, one of the biopharma analysts, and we're lucky to have Ocular Therapeutix with us, Pravin Dugel, who's the CEO. Thank you for joining us. Maybe I'll let you just make a quick, just opening comment. It's been just a lot going on over the past year and, you know, joining the company and just give us a sense of, you know, why this company. You know, I guess you could have done a lot of different things, and it's always an interesting question to kind of kickstart.
Marc, first of all, thanks for having us here. It's really an honor and a delight to be here. When you ask an open-ended question like that, unless you pull the plug on me, I may keep going for the entire half hour.
I'll stop you.
It's really simple. You know, look, as a person that practiced for 30 years, to me, it's absolutely tragic that we have a treatment that we know works, a target that we know is valid. Yet in this country, and in this country alone, in the first year, 40% of patients are dropping out of treatment because it's not sustainable. 40% of patients that drop out are going blind. To me, it's just absolutely tragic and it's solvable. The other part also that's solvable is that even in patients who stay, after about two to five years, inevitably end up losing vision anyway, even with this treatment. The reason for that, now we understand it, is because of the way we treat, which also makes it not sustainable, causes oscillations in the back of the eye.
Because we treat in a pulsatile way, t he back of the eye, which is nerve cells, end up getting thicker and thinner and thicker and thicker and thinner. It's like having multiple concussions, and they end up having fibrosis and atrophy and going blind. What we're doing in this company with AXPAXLI is solving two problems: the obvious one, which is that of a sustainable treatment, but the other one, which may not be quite as obvious but is equally important, which is better long-term outcomes by reducing the amount of fibrosis.
Right, right, right. Okay. Just high level for a second, just to explain the goal of the product for a second before we jump into it, because I don't want to get into the details too much without at least the high-level overview.
With AXPAXLI right now, we're in two phase three studies, so two registrational studies. One is a superiority study called SOL-1. The other is a non-inferiority study called SOL-R. You'll notice immediately that what we're not doing is we're not repeating the same study twice, which is what most people do. This is very deliberate, and we believe it's quite revolutionary in a positive way, which adds even more information. Having two different studies, a superiority study and a non-inferiority study, reach the same conclusion. We're targeting wet age-related macular degeneration with a product called AXPAXLI, which is a TKI, a tyrosine kinase inhibitor. We've also said publicly that our plan sometime in this calendar year is also to target non-proliferative diabetic retinopathy, for which there is really, effectively, no used treatment at this point.
Okay, good. Thank you. During the earnings call, there were some changes to the study and stuff. Take us through, here's what we were doing and here's what we changed, and here's why we're doing this.
Yeah, the bottom line of what we, the change, which is an amendment to the SPA, is that it allows us to get to the finish line much faster, much cheaper, and with a better label. Let me explain that. What we had in the superiority study, the SOL-1 study, was a primary endpoint at month nine. We did not have anything else after that. As you know, what the FDA requires is a certain number of patients to be followed for two years for safety reasons. We had to overpower our second study named SOL-R in order to satisfy that FDA requirement. What we did was we requested an amendment that was approved to extend SOL-1 to satisfy the FDA's requirement. We also could now reduce the size of SOL-R.
Effectively, what we did was to reduce that delta between the card turn of SOL-1 and SOL-R. Remember, we need both studies to be positive before we can submit to the FDA. Effectively, we can now submit to the FDA with two positive studies a lot faster than we could have without the amendment. By the way, I'm sorry, Marc, we gave up absolutely nothing. That's the really important part. We gave up absolutely nothing. The primary endpoint remains exactly the same, which is nine months in SOL-1, and the statistics have not changed. Again, recapping the end result of this, we'll get to the finish line a lot faster, a lot cheaper, and with a much better label.
It's basically numbers of patients is what we're talking about.
We shifted from every, all the safety follow-up being in the second study to some being in the first study. Therefore, we could reduce the size of the second study.
Why now?
Yeah, that's a great question. You know, that's been asked of me often, which is to say, look, why'd you do it now? If you knew that, why do it now? Why not do it in the very beginning? The answer is very simple. In this, what I'm very proud of and what we did in this company is to have what we call an all-planet team. We've got a whole bunch of people here that have been doing clinical trials for 20- 30 years. In our experience in retina and doing clinical trials, what we noticed, under masking, of course, is retention rates like we've never seen before. The best retention rates that we've ever seen, which has been phenomenal. We've got fantastic retention in SOL-1.
Without having fantastic retention, we would have never proposed this amendment because we needed to have the confidence of saying, we absolutely will get that number of patients to the finish line in two years. Why now is because we needed to see that retention number.
I see. Okay, that makes sense. Maybe it's a good time to talk about what the market needs, which is kind of where you started, which is this duration issue. Talk about how you think the product will be used in the real world. Also talk about, you know, there's some other TKIs we didn't talk about. It's a TKI, but talk about, you know, well, we have a TKI, there's some other TKIs, and how you differentiate your product from the others in the market.
Okay, there are a lot of questions there, but let me just answer the first one first in terms of how it will be used. First of all, one of the really important things is that it'll be adopted the very next day after it's approved. There's going to be a very simple and very quick and very seamless adoption. That's because of logistics, and it's also because of economics. The logistic part is very simple. Nothing needs to change for the doctor. There's not a single piece of new equipment. There's absolutely nothing that needs to change. The patient flow doesn't need to change. The doctor simply reaches out and gets a better medicine without having to change one thing in his or her office whatsoever. It'll be very, very easily and seamlessly adopted.
The whole experience for the doctor and the patient is going to be no different than injecting EYLEA or LUCENTIS. It's just a better drug with a better outcome that lasts longer. Now, from an economic point of view, it's a win-win-win for everybody involved. As I said, let's talk about payers first. As I said earlier on, 40% of patients in this country alone are actually dropping out of treatment. Those patients don't drop out of the payers' insurance policy. Those patients are going blind. Having been in boards of payers, they're one of the costliest types of patients. I know this sounds very cold, are blind patients. They use an enormous amount of resources, have all kinds of accidents, things like that.
To be able to reduce that by even 10% means, because now we have more sustainable treatment, that there are about 250,000 more patients that are being treated in this country alone. That's a huge cost savings for payers and much better for patients, obviously. The payers will love this. That means that we'll be able to certainly be eligible for premium pricing. That also means that the ASP will be higher. The doctors will get paid more per injection. From an economics point of view, it makes complete sense. Doctors oftentimes don't know economics as well as they should. If you ask a lot of them, they'll say, you know, it's a better drug. It's going to be much better for patients. But, you know, I make my money by injecting, and I may be injecting less. That's absolutely not true.
They'll actually be injecting a heck of a lot more. Not the same patients, but the attachment of patients will be much greater because the dropout, we're convinced, will be less. Again, even if the dropout is reduced by 10%, that's 250,000 more patients in this country. They'll be eligible for treatment. They can inject all they want. They'll inject with a better drug. They get paid more. They potentially will have other targets for which there is no injection at this point, which is non-proliferative diabetic retinopathy.
Just so everybody understands, how are the docs making money? And how's that changed? I mean.
The ASP changes because the higher the price of a drug, any drug.
What is the ASP?
That's the actual pricing.
No, no, what is it plus now, though? It's ASP plus.
Right now it's 2%.
2%. It used to be higher.
Yeah, exactly. Because the pricing will be higher.
Yeah. I'm just saying that it used to be ASP plus 6, and now it's ASP plus.
It's used down to 2.5, I believe.
Right. I'm saying they like the fact that the drug could be higher priced. Because on an absolute basis, that's what they're.
Correct.
Yeah, yeah, yeah. Okay, let's come back to how you see this product in the real world. It's launched. It's okay.
Yeah.
How's it going to be used?
It'll be adopted very quickly for the reasons that I've mentioned. I think the way that it will be used in the very beginning is what we call treat and extend. For those of you who are not familiar with treat and extend, what we do is to go ahead and treat a patient with, say, EYLEA, LUCENTIS, what have you, VABYSMO. For every patient, we wait to see when that drug loses effectiveness. For some patients, it may be after a month. For some, maybe after two months or three months. We go ahead and keep doing essentially trial and error until we find the proper cadence for that particular patient. That's treat and extend. I think that's exactly what we'll do with this drug. The reason for that is very simple. We're used to doing it.
We're very familiar with it. However, the treat and extend will be moved. The needle will be moved very much to the right. What I mean by that is if there's a patient that requires EYLEA, say, every month, that patient may now require AXPAXLI every six months. If somebody requires EYLEA every two months, it may be every 10 months with AXPAXLI. I think it still will be treat and extend, but it'll be moved very much to the right. My prediction, and this is just my prediction, is that after a little bit of time, I think we'll all move to fixed treatment. The reason for that is, again, quite simple. It's because treat and extend, as useful as it is now, is very, very difficult on the patient and scheduling for the doctor.
It's a lot of experimentation.
It's a lot of, exactly. Scheduling-wise, it's a nightmare for both. I think what people realize is to say, look, this is a great drug, and it lasts for this long a period of time. It's perfectly safe, and it's very effective. Most of us like to see patients with chronic diseases every six months. I think they'll come in every six months. The burden is coming in. It's not the injection, right? They'll already have taken the burden of coming in. I think they'll be just treated every six months on a fixed basis. The scheduling will be easier for the doctor, and it'll be easier for the patient as well.
Today, not just, obviously, what you're talking about, the treat and extend. The goal here is maybe someone's been on EYLEA for a certain amount of time. They've had the loading dose. They're comfortable with this one month or two months or whatever it is that they're comfortable on in year one. Then why not bring your product in? Kind of, is that how you see this? Like later in year one, or is it year two, or even out of the gate? Why not just, how do you?
Marc, quite honestly, I do believe that, I think what you're asking me is, is this a first-line drug, or is this a maintenance drug?
Yeah, I think that's the question.
It's a fair question. What I would say is really simple. I mean, my flippant answer is, you know, why would I care? Because if somebody has to use EYLEA once or twice and then uses AXPAXLI for the next 20 years, it's still going to be the most impactful drug. That's the worst-case scenario. However, I firmly believe that this is the only drug that will be needed. I believe it is a first-line drug. Why do I say that? It's simple. You know, one is because we've got great studies to show that steady state is established within 24 hours. We have patients in our study in Australia where this drug was used as monotherapy in treatment-naive patients. The only thing that was used.
What we saw were responses that were akin to what you'd expect to see with commercial-grade EYLEA or LUCENTIS.
As quickly as-
As quickly.
What they're getting.
Exactly.
There's no reason to even wait.
That's what I think. Now, having said that, even the worst-case scenario, if it wasn't, this still will be by far the most impactful drug in our field. You know, somebody will do that study. Maybe it'll be us. Maybe it'll be others. I believe that this will be the only drug that will be required.
Yeah. I think a frequently asked question, I'm sure as well, you know, you have competition kind of going after your space a little bit as well, doing with the same, we'll call it the same business model, same six-month. Talk about just the differences, you know, between your product and their product.
Look, people ask me about the biosimilars for the anti-VEGFs and VABYSMO and so on and so forth. As far as the anti-VEGFs are concerned, we're agnostic to that. It really doesn't matter because we're in a different orbit. You know, when we talk about a VABYSMO or high-dose EYLEA, we're talking about adding another two weeks, what have you. By the way, we will have data that we will have, that's not non-statistical data because there is a masking arm versus high-dose EYLEA in the SOL-R trial, the third arm. It's non-statistic numeric data that we'll have. Nonetheless, again, these drugs add another couple of weeks. We're talking about a different orbit where we're talking about, you know, 9-12 months. We're not worried about that fight whatsoever. As far as other TKIs are concerned, look, we're very different.
Our TKI, in what is known to be the most potent by 200-fold or so, the most selective by about 100-fold. Our data is completely different than others. And very importantly, the format is completely different. We have a tunable hydrogel. There are no carcasses floating around. There's nothing left behind. When the drug is gone, the hydrogel is gone. It is an entirely different product.
What about the clinical studies that everybody's pursuing? Like, this is the part that I didn't quite understand, the sham versus the not sham. Can you just explain to people?
Yeah, absolutely. What people don't realize is that when you numb the eye to give an injection, you just numb the skin of the eye, what we call the conjunctiva. That's all you numb. You don't numb the optic nerve. The consequence of that is the vision doesn't change at all. You can imagine people notice tiny, tiny floaters. They certainly notice when a huge amount of water or drug is coming in. Typically in clinical trials, and this happens all the time, patients would say, "Oh, I saw it come in. I see the drug come in." They see a whole bunch of stuff coming in because the optic nerve, again, functions just as well as it always did. In sham, what you do is you touch the skin of the eye with the hub of the syringe.
There's nothing going in at all. Patients can easily, you know, say, "Look, doc, you didn't do anything. I don't see anything." Or they'll say, "Oh, you injected. I can see the whole thing coming in." The FDA knew this all along and said, "Look, sham is not proper masking." Period. They set very clear guidelines in what they want. If you want to go down a regulatory pathway that is risk-free, this is what you do for non-inferiority. This is what you do for superiority. We followed the guidelines exactly. We were rewarded with a SPA with the SOL-1 study and written Type C letter for SOL-R. We're doing exactly what the FDA wants us to do. We believe that our path for regulatory approval is completely de-risked.
Right. You nailed both studies. You're there.
Right.
Let's talk about SOL-1. Looking at the percent of patients who make it out to this nine months, you know, without rescue, I think, you know, this would be interesting. There's no rescues. I guess this is kind of a, you know, an interesting question, right? Because you worry about, you know, I guess, what's the right word? Off-protocol rescues? Is that the right word? Just somebody who's just because it's the right thing for the, I mean, how does that work here in this study?
Let me talk about the statistics and the powering, and then we'll talk about what we see right now. As far as the powering is concerned, with very good modeling as well as with studies that are publicly available, such as TALON, for instance, we believe that with a single injection of EYLEA, at most 20% of patients will get to that nine-month mark. Remember, the primary endpoint remains at nine months, and it's the percentage of patients who maintain vision, right? We believe that most with EYLEA, that's going to be 20%. Based on our U.S. study, we believe that that's going to be at least 70% with the AXPAXLI group. So the delta is 50%. And all we need is a 15% delta to be statistically significant. So we're quite well-powered as far as that's concerned.
On top of that, per our SPA, what the FDA has said is that as far as rescues are concerned, nobody will be censored. That's really important. Every rescue, whether on protocol or off protocol, has to be counted for the primary analysis. That is very much in our favor because there will be many more of those in the EYLEA arm.
Does that work in your favor?
Yeah.
Is that even fair?
We're happy to have that. You know, there'll be many more in the EYLEA arm than in the AXPAXLI arm. Clearly, as far as the powering is concerned and the statistics are concerned, we're very much favored, I believe. We're in very good shape. What I have said publicly is, obviously, with SOL-1, we're masked. Our number one priority in this company is the conduct of the trials. The way we look at the conduct of the trials is by looking at the number of rescues, the cadence of the rescues, and whether the rescues are on protocol or not. What I've said publicly is when we look at those three parameters, we couldn't be happier. We're absolutely thrilled. I've also said publicly that the vast, vast, vast majority of rescues, and I've said that three vasts, are absolutely on protocol.
Interesting. Okay. Just remind us, like, where are we in enrollment with these studies, both of them?
With SOL-1, we have completed randomization in December. We announced that publicly. With SOL-R, we have not guided you as to the most recent updates. What we did say at the time of JPM, which was in January, is that we had 311 patients who were enrolled in various stages of loading and randomization. Now, obviously, with a third of the patients now being reduced, right, because we have gone from 825 patients to 555 patients in SOL-R based on the recent amendment, we believe that that randomization, the completion of SOL-R, is going to be much faster.
Right. Okay. The timing now of when we're going to get data for these studies is what?
Again, it's a little bit too early to say for SOL-R. We'll guide you when appropriate, but we haven't done so as yet.
Okay. And SOL-1?
SOL-1, what we've said, because of the amendment, remember, we need to remain masked in order to get the 12-month data. Now what we will have is the card turn in the first quarter of 2026.
In a sense, SOL-1 is going to take a little longer and SOL-R is going to take a little shorter. At the end of the game, it does not really matter because they both have to be done to file.
Not quite. SOL-R, because remember, we have to keep masking, right, is going to be, instead of being in the fourth quarter of 2025, in the first quarter of 2026. A very slight delay.
SOL-1.
That's SOL-1.
SOL-1.
SOL-1.
Right, right.
Whereas SOL-R now will be reduced in size and will be a lot faster. We haven't got it as to when that'll be. However, we need both studies to be able to apply to the FDA. The application process, because SOL-R now is going to be so much faster, is also going to be a lot faster.
Yeah. Okay. Good. Good, good, good. NPDR.
Yep.
Talk about that program and just a little bit of the saga with it and, you know, big picture, and then kind of come down to your program and where we are.
Non-proliferative diabetic retinopathy is a huge unmet need. There are about 6.5 million patients in this country. What we know with that is that these are patients that are asymptomatic, are working age typically. However, the risk of vision-threatening complications is about 30%-40% year upon year. There is a very effective treatment that's never used, which is the anti-VEGF. That has to be given every month to every other month. Less than 1% of patients are being treated, less than 1%. There is a humongous need. There is a well-known target. And, you know, unfortunately, patients continue to go blind.
They're not getting VEGF because it's not approved.
It is approved.
Then why?
Patients just can't come in every month. I mean, these are asymptomatic patients, and they're not going to be, you know, leaving their work to come in every month or every other month. Effectively, nobody's getting treated, although there's a very well-known target, right? It's a fantastic opportunity. What we did was a study called HELIOS, which is primarily a safety study. What we saw there at week 48 was that in the control arm, 37.5% of patients developed what we call vision-threatening complications, right? This is diabetic macular edema or proliferative diabetic retinopathy, which is right in line with the natural history. I said 30%-40%. However, what to me was absolutely remarkable was that in the AXPAXLI arm, with a single injection of AXPAXLI at week 48, 0% of patients, 0% of patients had vision-threatening complications. I mean, that is remarkable.
As a physician, I can sit there with a patient and say, "If you come in to see me once a year, like you go to your dentist for teeth cleaning, I can reduce your chance of having a potentially blinding condition from 30%-40% to absolutely zero." I mean, that is remarkable. We absolutely will go after non-proliferative diabetic retinopathy and diabetic macular edema. I say and diabetic macular edema because every patient who was enrolled, every single patient who had diabetic macular edema with a single injection improved at week 48. What we've done is to show you not just every single patient, we've shown you every single eye. The more we analyze this, the better and better and better that data gets.
As you saw maybe in the Angiogenesis presentation, which was a few weeks ago, when we looked at different layers of fluid, there was clearly a separation in favor of AXPAXLI. We will go after non-proliferative diabetic retinopathy and diabetic macular edema. We will meet with the FDA in the first half of this year. We've said we'll do that, and we'll guide you as to the study when appropriate. It's a clear and open target for us, and there's clearly a huge need as well.
There was confusion. You had the 40-week data, and then you showed the 48-week data.
That's right.
Right? What was the confusion?
Yeah. I don't know there was much confusion.
What was the debate? What was the question?
Yeah. You know, we unmasked the trial at week 40, right? Because the primary endpoint was reached. It was a safety study, and there were absolutely no safety issues, and there've never been safety issues. The data was so good, we said, "Look, let's try and follow the patients as much as we can." The most, once you unmask the trial, it's difficult to follow the patients, right? We went ahead and followed the patients up to week 48, and we showed everything.
Right. That's the data that you were just talking about.
Yes.
The week 48.
Yes. I mean, the week 40 is just as good as well. The week 48 gets even better.
Yeah. It's just interesting how, like, I don't know, I guess the response was different, I suppose, in people understanding the data better.
Oh, I think what you're talking about is the share price, right?
Yeah.
That's what you're talking about. Okay. That's the confusion. Yeah. What ended up happening is very simple. This was a safety study, right? The patient population was really not controlled and was not super selected. I think what people did was to look at that and say they compared it to what's called a PANORAMA study where EYLEA was given every month or every other month, and they looked at something called a two-step difference, right, which is an arbitrary profile that we have in terms of response. They looked at that and they said, "Wow, yours is different. Yours is not as good as PANORAMA's." It wasn't because of a safety study. It wasn't designed for that. It was a small safety study.
Now, if patients were selected specifically for that, we're convinced with the data that we have that we can go ahead and be as good. Again, it wasn't selected for that. One should really look at the effect of a single injection over 48 weeks and the vision-threatening complications, as well as if you look at the DRSS changes, everything also there is in favor of the drug.
Yeah. Let's come back to SOL-1 and SOL-R. Obviously, you need both studies to be successful to file whatever. You know, talk about, okay, the first one comes out, how do we think about the second one with respect to de-risking.
Yeah, that's a great question.
How far is the success? Yeah.
We are convinced with a lot of work internally that with a positive SOL-1 study, the chance of SOL-R being successful is through the roof. We are absolutely confident of that. There are many reasons why, but what it really boils down to is if the drug is going to last for 9 to 12 months, why would it not last for 6 months? That is really what it is, is repeating every 6 months in SOL-R. We are very confident that with a positive SOL-1, we will have a positive SOL-R.
Yeah. I guess right now you're thinking the second study will be when again? Because the first study will get the data, as you said.
The first study, SOL-1, will have the card turn in the first quarter of 2026.
The first quarter, right.
The second study, SOL-R, we haven't guided you to.
It'll be in 2026, though.
We haven't guided you to that as yet, but we certainly feel it'll be much faster now with the amendment.
Right. Okay. Got it, got it, got it. What have we not hit on in our last couple of minutes? What else?
I think the most, I feel the most, you know, misunderstood or not understood part of our trial designs is the patient selection. You know, what we do not do in retina is we don't talk about patient selection all that much, but we do realize that we have in wet macular degeneration an extremely variable, diverse disease population. Some patients are treated, you know, every month. Some patients are treated every 6 months. We do something called treat and extend. When you're doing massive studies like we used to do with 2,000-3,000 patients, you know, it comes a wash. When you're doing studies of our size, it's extraordinarily important to pick the proper patients to allow the best chance of success in your study. I think that's what we've done with a great deal of thought and in a bespoke manner for each study.
In a superiority study, what we've done is pick patients with very good vision who have the most amount of VEGF receptors. We've tested those receptors to make sure they function by requiring an improvement of 10 letters or visual acuity of 20/20. It's the perfect patient population to go ahead and load up and allow the drug to fail once, right? It's perfectly selected for that. It's very different than SOL-R, which is a non-inferiority study. Here, what you want is absolute stability. What we have is three loading doses, and then we've put in something that nobody else has, which is two opportunities to observe the patient. What are we observing for? We're observing for fluctuations because we want stability. We have two opportunities to weed out unstable patients. We have two more injections of loading, and then we randomize.
It's much harder to go through that kind of patient selection. It's much easier to just let everybody come in. What we've done, and what I hope people understand, is that we've reduced all these variabilities painstakingly, de-risked the patient population, and increased the chance of success of the study in a bespoke manner for each study.
Yeah. I'm glad you brought that up. Lastly, just give us the cash position just so we understand.
What we've said in our earnings call is that we're well capitalized into 2028. Certainly the completion of both studies.
The completion of these studies.
Yeah.
Okay. Good. Thank you. Thanks for joining us.
Thank you, Marc. It's been great. Thank you for the opportunity.
Fantastic stuff.
Thank you so much.
Yeah. Good to see you.
Good to see you.