Welcome to the UBS Virtual Event. Eliana Merle, you may begin.
Hi, everyone. Good afternoon. I'm Eliana Merle, one of the biotech analysts at UBS. Very happy to have Ocular Therapeutix here with us today. And joining us from Ocular is Pravin Dugel, the Executive Chairman, President, and CEO. Pravin, thanks so much for joining us. Maybe, before we jump into the specific, can you tell us a little bit about when you joined Ocular and yeah, what you see as the vision for the company and the team that you've assembled?
Eli, first of all, and Samantha, thank you very much for having us, and I'm delighted and honored to be included. I will assure you that I had no plans to return. As much as I absolutely loved my time in Iveric Bio, I was very happily retired. This was such a unique opportunity where I knew there was a product from my time in Iveric Bio that absolutely worked, a platform that worked for sustained delivery, which, as a physician, I knew how important it was for my patients. And I saw a regulatory path that was about as clear as it could possibly be. There was a singular challenge in this company, and that the challenge was: Can you communicate well enough to recruit for this trial?
which was the first of its kind, but followed the FDA guidelines absolutely precisely. In retina, I was convinced that I could assemble what has been known now as really the dream team, to be able to communicate exactly the reasons the FDA wanted this trial design. I think we've been very successful in doing so, because our recruitment has been just, simply outstanding.
Great! Well, yeah, maybe you could give us an overview of some of the data that you've seen so far, both, you know, some of the extended duration, you know, details on your mechanism of action, and where you think this is differentiated in the wet AMD landscape?
This is a tyrosine kinase inhibitor, and as you know, the VEGF receptors are tyrosine kinase. This works. This is an intracellular pan-VEGF inhibitor. Very importantly, not all tyrosine kinases are the same. This one in particular is about 200 times more potent than others that are being developed. That, in combination with the platform, the platform being a hydrogel, gives us the advantage of having a very similar PK/PD, which means that when the drug is gone, the hydrogel is gone as well, so there's no stacking issues whatsoever. We know from studies done in Australia and in the US, we're very confident that this will last for at least 10 months or so.
So the trials are designed in a way to showcase that, as well as lead us to, I think, a great deal of commercial advantage. What you'll notice is the trial designs are not the same. One is a superiority study, the other is a non-inferiority study. This was done from a regulatory point of view to give the FDA a great deal of confidence that the results are indeed what they are. But it was also designed specifically to give us a very large, I believe, commercial advantage in potentially having a label that will have flexibility. In other words, dosing from six months to nine months, we'll have repeatability, as well as potentially the only drug in the market with a superiority label.
Mm-hmm. Yeah, that's exciting. Maybe we can go into that in a little bit more detail, specifically some of the FDA feedback that you got and the details of these designs.
Yeah. That's a really important question because I think there's a lot of confusion out there. What the FDA wants is really very, very clear. They have stated repeatedly, and this hasn't changed, you know, even as Dr. Chambers has now left the FDA, this really hasn't changed with the current administration at all. What they've said is to say, "Look, we want you to compare a drug to what is being done in reality, not to a label that's never used." And what's being done in reality is treat and extend. And what that means is that the drug is given, an anti-VEGF is given, and then one waits until it loses effectiveness, and then that's repeated in a different cadence until that particular cadence is found that's appropriate for the patient.
And that's really what this replicates, and that's what the FDA wants, which is a drug given head-to-head, and what we see is when that drug loses effectiveness, but just once. The patient is then rescued, and then the patient is on label Eylea for the rest of the trial. This is what the FDA guidelines dictate. This is exactly the way we designed the SOL-1 study, and it was validated with a SPA agreement. We're very confident in our regulatory pathway for SOL-1. We also designed SOL-R exactly according to the FDA guidelines for non-inferiority. The FDA has stated explicitly that they do not believe that sham is proper masking.
We have received a guidance Type C response that is written, so a written response from the current FDA stating the following in writing: First of all, they've stated that SOL-R, our non-inferiority study, is a registrational study. They've also stated that all we need is SOL-R and SOL-1 for approval. In other words, no other study is needed. And very importantly, they validated what we've been saying all along. They have stated, again, in writing, that they do not recommend sham injections. They do not believe that sham is proper masking. They've also said that if there are studies with sham injections, and of course, we don't have any, that will be at-risk under review. And again, this validates everything that we've been saying.
We've elected not to do any trials at risk, and therefore, given the SPA agreement for SOL-1, given the written Type C response for SOL-R, we are very, very confident in our regulatory path for both studies.
Great. And then maybe just talking a little bit about the data that you've seen so far, what gives you confidence, and success in both SOL-1 and SOL-R?
You know, first of all, there are several boxes to tick, right? The first one, most importantly, is safety. And let me talk about that. We know that Eylea and Lucentis are absolutely very, very safe drugs. They're superb drugs that we've had decades of history with. In order to succeed, in order to replace those drugs, one has to be at least as safe as those drugs, and I'm very confident that our safety profile is as good, if not better.
What actually gives me a great deal of confidence in that is not just the trials that we have done, the three in retina, which is, you know, one in Australia, one in the US, and a trial called HELIOS, which is a small diabetic retinopathy trial, but actually a glaucoma trial that's not all that well known with our glaucoma product called PAXTRAVA. And the reason I say that is because the hydrogel is exactly the same, and PAXTRAVA is placed in the angle in the eye right behind the corneal endothelium. If you were to pick a place in the eye to place a product to check for any kind of safety issue, it would be right there. Because if there's any inflammation, if there's any safety issue, the endothelial cells are the first to be damaged.
They do not regenerate, and that causes thickening of the cornea. There was absolutely no change in the corneal endothelium. There was no thickening of the cornea, and that should give us, as it gives me, a great deal of confidence in the safety of our product. As far as efficacy is concerned, we had excellent results in the trial from Australia. The take-home message there is that it's the first time that this product has been used, any sustained delivery TKI, for that matter, has been used as monotherapy in a treatment-naive patient population, and the response was what one would expect for commercial-grade anti-VEGFs, as far as the OCT and visual acuity is concerned. As far as the US study is concerned, here, AXPAXLI went up against Eylea.
Eylea was the control, and what we're able to show there is that at 10 months, 80% of patients were rescue-free, which gives us a great deal of confidence in the success of our primary endpoint at month 9 in SOL-1. And most recently, what we've seen are the results of the HELIOS study. Now, this is a small phase I study, a safety study, really, for diabetic retinopathy. It was not designed for efficacy. It was a small study designed only for safety. What we saw there was absolutely remarkable, which is that every single parameter for every single patient favored the drug, and that doesn't happen by accident. So with a single injection, I think there's very little doubt that at week 48, this drug is safe, active, effective in diabetic retinopathy.
So all those things should give us a great deal of confidence in the data that is to follow.
Mm-hmm. Great, and any color on the powering in each of the phase III studies and sort of the minimum threshold to hit superiority and non-inferiority, respectively?
Yeah. So, let me tell you about SOL-1. We haven't disclosed the powering in SOL-R as yet, as that study is just been recently disclosed. But in SOL-1, again, the primary endpoint is at month 9. The primary endpoint is the percentage of patients who maintain vision. And the criteria is an absolute loss of 15 letters of vision, which is a net loss of at most 5 letters of vision, because remember, these patients have to gain 10 letters of vision in order to qualify to be randomized. We believe, based on our internal modeling, as well as information publicly available, such as TALON, that Eylea, the control arm, that number at most will be 20%.
We believe, based on the US study, that for AXPAXLI, that number at nine months at least will be 70% of patients. So we have a delta of 50%, and we need statistically a delta of 15%, one, five, to be statistically successful. So, we're very, very confident in our powering. Again, we expect a delta at least of 50%, and what's needed is 15%, a one, five. The other thing that I would tell you also is that our SPA dictates that all rescues, whether they're on protocol or off protocol, be counted as failures and be tallied in the final result, in the primary analysis. In other words, even if patients are rescued off protocol, they're not censored.
They must be counted in the primary analysis, and again, we expect far more of those patients to be in the Eylea arm than in the AXPAXLI arm. So, as far as the rescues are concerned, on protocol or off protocol, that also is very much in our favor.
Mm-hmm. Makes sense. And any changes in the rescue criteria in phase III versus the other earlier trials?
The rescue criteria, as mentioned in SOL-1, is going to be a net loss of at most five letters of vision. The rescue criteria in SOL-R has not as yet been guided publicly. We expect the rescue guidelines to be different and much more in line with the non-inferiority studies that you have seen.
Mm-hmm. Makes sense. And so it seems like the enrollment has been accelerating and going well. Maybe just what are your timelines for completing enrollment in SOL-1 and SOL-R and the timelines to data?
We're absolutely thrilled with the recruitment and the enrollment. On June thirteenth, we had an investor day, and I think we what we announced was beyond anybody's expectations or imagination, which is that we announced that a hundred and fifty-one patients had been enrolled and were in various stages of loading and randomization. This was really eight weeks after this team got together, which is absolutely remarkable. That shows you that an idea behind sharing those numbers and sharing that data was to show people that this could be done, this was being done, that this dream team wasn't here just to be on the website, but they were here to do work, and they were actually achieving great results.
We have reached very shortly thereafter a point where the recruitment is not just linear, but exponential, and we're doing extraordinarily well. The other part that is also important is we announced then, as we will still maintain, that the screen failure rate is lower than we expected and lower than we modeled. So what that means to us is not only are we getting a lot of patients, we're getting really good patients, really high-quality patients as well. Since then, we haven't really given you any numbers or guidance. It hasn't been a long time. We're doing very, very well, and we've kept on saying that we're very happy. We still are. Our original guidance in terms of completion of enrollment has been the end of the first quarter of 2025 . We have not changed that.
We have said, however, that we expect our enrollment to be earlier than that, and when appropriate, we'll certainly give you more specific guidelines.
Mm. Exciting. Congrats on all the progress. In terms of the landscape, there's a lot in development, looking at extended duration, other TKIs, gene therapy. Maybe just where do you see AXPAXLI fitting in the context of this landscape?
Yeah. So I think it's important to step back and say, "What is it that's needed for any drug to replace the current anti-VEGFs that we have?" And I say that specifically, because I've been part of the entire anti-VEGF process when I was a practicing physician. Anti-VEGFs are extraordinarily good drugs. The boxes that need to be checked have a very, very high bar. The first one, and this has to be checked sequentially, the first one is safety. The safety of any drug has to at least match anti-VEGFs. You can't have an inflammation rate of 2% or 5% or 8%, and you certainly can't have inflammation where you don't know when the inflammation is going to occur, so the patient effectively has to be followed all the time.
You don't know if it's going to occur early, late, in the middle, et cetera. So if there's any drug or any strategy that doesn't check that first box of the anti-VEGF being safety, it simply is not going to go any further. The second box is that of efficacy. Anti-VEGFs are efficacious 100% of the time, now, unless you've got the wrong diagnosis. Now, they may not work as well as you want them to work, but they will show some sign of efficacy 100% of the time. So you can't have an efficacy rate that's going to be 50%, 60%, or 70%. It's got to match the anti-VEGFs. The third box is that of adoptability. You've got to have a drug or a strategy that will allow it to be placed in the current workflow.
It's illogical to think that doctors are going to close their office and change, you know, what they do economically, completely because of a drug. That's a very, very big ask. So at the end of the day, it really has to fit into the current workflow, and I believe that AXPAXLI checks all those boxes, and on top of that, adds the durability that I've mentioned of at least nine to 10 months. The other thing that I would also mention is that, which really isn't talked about much, is that, we know that most patients, almost all patients who get anti-VEGFs in the current manner, end up losing vision, not by rebleeding, but by fibrosis and atrophy.
And we have good evidence now that that happens because of the pulsatile nature of our treatment, where the back of the eye gets thick and thin and thick and thin. It's like having multiple concussions, and the result of that is going to be atrophy and fibrosis. So if suppression occurred in a way to decrease those oscillations so that there's a low level of suppression, but it's constant, then there's a really good possibility, and there's very good evidence for this, that there'll be less fibrosis, less atrophy, and the long-term outcomes will be better. So I think there are major advantages that AXPAXLI has, that others don't in different categories. And I think I'm very confident that once these studies are positive, that this drug will be used pretty much universal.
Mm-hmm. It makes sense. And what are your expectations in terms of the dosing interval? You have the flexibility in the design between, I think you said, six to 10 months dosing. So, yeah, what do you think you'll see in phase 3, and how this could potentially affect the commercial uptake?
Yeah, that's a great question, and what I would say is what we want in the label, again, it's obviously too early for labeling discussions at this point, but you can clearly see that given the way these two SOL-1 and SOL-R trials are designed, we have a clear strategy for our labeling discussions. What we want in the label, number one, is we want flexibility. We want the drug to be used as often as every six months, if necessary. Now, we don't think it's gonna be necessary in a whole bunch of patients, but in some it may, so that flexibility needs to be there, and it will be there, you know, based on our SOL-1 and SOL-R study. We want repeatability, obviously. That will be there based on the SOL-1 and SOL-R study.
We also want to label the only one of its kind, we believe, potentially, that has superiority in it, and we believe that that is a possibility based on SOL-1. The other question is, well, how will it be used commercially? I really believe that we'll continue to treat and extend, and the reason for that is that this is a variable disease. We, at this point, don't have genetic markers, we don't have biomarkers to tell us how patients will respond. So the only thing we really do have is what we're doing right now, which is trial and error, and personalizing our treatment according to that particular patient, trying to find the proper cadence of injecting the anti-VEGF or, in this case, the TKI. I believe that treat and extend strategy will continue. However, everything will be shifted to the right.
In other words, a patient that may have required, say, Eylea every two weeks, which is rare, but, I'm just using the extreme, may now require AXPAXLI every six months. A patient that required Eylea, you know, every 10 weeks may now be sufficed with giving AXPAXLI once every nine or 10 months. So everything will be shifted to the right, but I think that strategy of personalizing treatment and using treat and extend will continue.
Mm, makes sense. And just in a landscape with high-dose Eylea, Vabysmo, potentially gene therapies and other novel TKIs, as well as biosimilars, how do you think about where this would be used in terms of whether it switches naive patients, and what you think the opportunity would be, if you are able to extend the durability?
Yeah, well, look, with gene therapy, as I mentioned earlier on, I think there's so many challenges in terms of, of the overall safety, efficacy, adaptability, et cetera. I really don't consider that to be a competition at this point, at all. I think there are many barriers that they have to go through, at least in the treatment of chronic diseases. As far as the newer anti-VEGFs are concerned, if you look at Vabysmo, if you look at high-dose Eylea, we're talking about extending a couple of weeks. We're in a different orbit. You know, we're talking about not a couple of weeks. We're talking about nine to 10 months. So, we really have no concerns about competition there whatsoever.
In fact, if you look at our SOL-1 study, the third arm involves high-dose Eylea, right? So we're not afraid to go up against high-dose Eylea at all. The third arm is for masking purposes, not for statistical analysis, as you know. But again, I'll just repeat this, which is, we're not talking about extending a few weeks. We're talking about nine to ten months, so again, it's exponentially different.
Mm-hmm. Makes sense. That's helpful context, and beyond what AMD, I guess, what have you seen so far in terms of efficacy in diabetic retinopathy and, you know, your next steps there?
Look, the data, as I mentioned earlier on, the HELIOS study has been absolutely fantastic. We have, as I said earlier, every single parameter aligned in favor of the drug. Now, what does that mean? That means that it gives us a great deal of data-based confidence in the success of SOL-1 and SOL-R, based on what we see in HELIOS. It also means that we have a new target now, that apparently we have no competition for, which is diabetic retinopathy, which is an enormous market. Finally, what I would say is that every single drug of the anti-VEGFs that suppresses VEGF, that works in wet AMD, has worked in retinal vein occlusion, diabetic macular edema, diabetic retinopathy, et cetera, and all retinal vascular diseases.
There's no reason that AXPAXLI shouldn't follow the same path and work in all the other retinal vascular diseases as well. So the potential for this drug, not only in, in wet AMD, but also in the rest of the retinal vascular diseases, is enormous. And let me also add in wet AMD, anybody would say the wet AMD market is large, and they would say that based on the calculation of the sales of Eylea, Lucentis, and Avastin, if it wasn't Avastin, but Eylea or Lucentis, but that's only half the story. Remember, they're counting that number and describing that market size with a 50% dropout rate. With a more sustainable treatment, if that dropout rate is reduced by even 5% or 10%, that target patient population increases exponentially, and that doesn't even include the other retinal vascular diseases.
So again, the potential for this drug, I think, is enormous.
Mm-hmm. Yeah, no, absolutely, particularly on the increased compliance, and just so in terms of next steps, I guess, in diabetic retinopathy, what are your plans in terms of potential further trial starts?
Well, very honestly, Ellie, I mean, we're still a small company. We are a growing company, but we're a small company. So we've made it very clear that our priority is SOL-1 and SOL-R. Diabetic retinopathy comes after that. Our intention has always been with the study results that we saw from HELIOS, to put together a dossier, which we're putting together, and to have a formal meeting with the FDA to see what the path forward is in diabetic retinopathy. We absolutely intend to pursue diabetic retinopathy. We will have a discussion with the FDA and then determine our strategic course.
Mm-hmm. Would you potentially start that prior to the readout of SOL-1 and SOL-R, or would you wait for those results before starting another pivotal program?
Yeah, I don't know the answer to that yet. It just really depends on how quickly we can, you know, get our meeting and so forth. We're very fortunate because we are well-capitalized. We certainly have the capital to do these studies. But as I say, we still remain a fairly small company, and we wanna make sure that we don't lose our priority system. Our priority is still SOL-1 and SOL-R.
Mm-hmm. Awesome, makes sense. And I guess just taking a step back, what are the updates that we can expect from Ocular over the next twelve to eighteen months, whether it's data-related, enrollment-related, regulatory-related?
You can certainly expect to see more data from HELIOS. What I have committed to, you know, very early on, and I think I've kept that commitment, is to say, "We'll show you every single patient. We'll do all the analysis that we can possibly do to show you how effective this drug is," and we'll continue to show new data for HELIOS. You can also expect, when appropriate, you know, very transparent updates on our enrollment, which we're delighted to provide both on SOL-1 as well as SOL-R, when appropriate. I think, as I said, what we have said consistently, which is that we're delighted with the enrollment.
We're delighted not only in the number of patients we're getting, but we're delighted with the quality of patients we're getting, as witnessed by the low screen failure rate, which will be realized when we actually share the numbers with you.
Mm-hmm. Great, and one last question, just we talked about your interactions with the FDA, but what about the EMA and your interactions there?
This is certainly a global drug, and we've designed our trials with that in mind, that it will suffice for regulatory standards, not just in the US, but also outside the US. We are in discussions with the EMA. We will update you regarding that when appropriate, but we certainly expect a very collaborative, very supportive path with the EMA.
Mm-hmm. Awesome. Well, Pravin, thank you so much for joining us. It's great to see you again.
Thank you. Thank you for having us. It's an honor, a delight to be here and to see both of you again. Ellie, thank you, and Samantha, thank you for hosting us.
Great. Talk to you soon.
Take care.