Hi, good afternoon, everyone, and thank you for joining the Ocular Therapeutix session. It's our pleasure to be hosting President and CEO, Pravin Dugel, and I guess Chief Strategy Officer is not here, but anyway, Ocular has finished its pivotal SOL-1 trial and is awaiting completion of SOL-R. As the TKI race goes, I guess you could already be filing on the one trial guidelines of FDA or suggestion of the FDA. Before I go on and botch all of this, I'm just going to let you go ahead and tell us the strategy, and I'll go into questions.
Annabelle, first of all, it's great to see you again. It's been a long time. Thank you for having us here. I really appreciate the opportunity. The regulatory part of this obviously is extraordinarily important and very germane. If you'll allow me, let me delve into that a little bit and tell you where we are and tell you what has happened. Stepping back a little bit, let me state the obvious. I think we will all agree that my job, this company's job, primarily is to get this drug, AXPAXLI, approved by the U.S. FDA. I know that's stating the obvious, but I just want to say it because it's important. For that reason, I think it's very important also to state that we have to be completely and totally aligned with the FDA.
They seem very obvious, but those two things really are our guiding light. They're our North Star. Based on those two principles, let's go back to what the FDA has done. What the FDA has done in February of 2023, that date is really important to remember. It's February of 2023. They have issued very clear, specific formal guidelines, the guidelines are based on two things. First of all, they feel rightly that sham is not proper masking. The reason for that is because patients can see if the drug has been placed or not. We've known that for decades. Because we have a subjective endpoint, which is visual acuity, that may influence how hard the patients may or may not try. That's the first thing.
The second thing is the FDA stated clearly that they will not allow for a superiority track for a drug based on a label that nobody uses. We know that there's not a single human being in this planet who is chronically treated per label by EYLEA or LUCENTIS or by Vabysmo or EYLEA HD. Everybody does treat and extend it, which is not in any label. Based on those two principles, the FDA has issued very specific guidelines on how to conduct superiority and non-inferiority studies. What we have done is we followed their guidelines precisely, again, per the North Star that I stated earlier. Their guidelines, their reasoning is the following. They feel that this is a ultimate head-to-head study. That's our superiority study, the SOL1 study. It is. Scientifically, it is about as clear and clean as you can get.
It's a pure head-to-head study. Secondly, this may be a little controversial, but this is the FDA's point of view. They feel that this is a single cycle of treat and extend. This is what we do with treat and extend on a regular basis over and over again, which is that we inject the drug and we wait for the drug to lose effect. We do this over and over until we establish the proper cadence for that particular patient. That's treat and extend. They feel that what we're doing here is a single cycle of treat and extend where the patients are rescued. Now, the pushback appropriately may be, we don't wait for 15 letter loss, and that's appropriate, and they're right. What the FDA would say is that this is not a 15 letter loss.
This is at most a net of five letters because these patients have to gain 10 letters or get to 20/20 before they're randomized. The FDA will not budge from those 15 letters. That's a line in the sand that they will simply not budge from and haven't for at least five decades. The reason for that is 15 letters is a doubling of the visual angle, and that will not change, period. That's their reasoning. Our challenge has been to go ahead and provide information that satisfies the FDA as well as the clinician. Now, there's no doubt that we're completely aligned with the FDA. We have a SPA, which as you know, is the highest level of agreement that you can get with the FDA. In fact, we are the most FDA-aligned retina company there is. We're the only one that has a SPA.
Actually, we have two SPAs. The challenge has been how do we satisfy the FDA with the results? Now that we have the results, we have satisfied the FDA. We've met their evidentiary standard of a p-value of less than 0.001. As you know, with the SOL-1 results, the p-value is less than 0.0006. The second evidentiary standard is that of safety. We have a completely clean safety profile. We've met the FDA's challenges. Now, the clinician's challenges we've met with this study by showing two things. One is disease control and durability like they've never seen before. Disease control we measure by the OCT. That's the standard for measuring when a drug works and doesn't work and when the patient needs to be retreated.
What we've shown is that with a single injection at month nine, there's OCT stability within 30 microns, and that's unheard of in a majority of patients. That's absolutely unheard of. Clinicians look at that and say, "We've never seen this kind of disease control." As far as durability is concerned, you'll recall that at month 12, 2/3 of the patients are rescue-free with a single injection. Again, that's the best durability that nobody's seen before. What I would say is that, look, this study has been extremely efficient. I go back to the North Star and say we are completely aligned with the FDA. Our job is to get this approved per the FDA's guidelines. What I would say is that if there are any questions that anybody has with any company, including in our field, there's a simple question to ask any company, including us.
That simple question is: have you met formally with the FDA after February 2023 with a formal written documentation that looks at your study design vis-à-vis their guidelines? Not before February 2023, after February 2023. It's a very simple question, and clearly we have because we had a stop.
Got it. Okay. A lot of questions to come from there. One of them being that this trial and having been designed differently than a lot of others with a non-label comparator arm, although something that they're familiar with this treat and extend strategy. I guess, what does a retinal specialist take away from this study when they're trying to think about the different options to use in the marketplace? They are presented with a patient, and they're looking at your product versus other products that have been studied one way versus your product that's studied another way. Is it hard for them to compare one versus the other if they're completely different study designs, and how do they make a decision from there? I guess that's the question I would have. What kind of feedback have you been getting from the general community?
I'm thinking in more practical terms, how they approach your product that's been studied very differently than others.
It's an excellent question. Look, it's easy for me to answer that having practiced for 30 years. As you know, there's more retina expertise in our company per capita than probably any other company on the planet. We're a one-trick pony. We know retina inside out, and that's all we know, but we know it better than anybody else. It's really simple. Name me one drug in our field in retina that is used per label or per clinical trial. Just one drug. There isn't one.
No, I guess they're all.
There isn't one, right? That's exactly the point. There isn't one. The whole idea, and as far as my job here is to get this approved, and I've already said earlier on, we're perfectly and totally aligned with the FDA. We haven't yet talked about this, but this goes to what I'm sure you want to address and what I want to address, which is that we're more confident than ever that we will be approved. Again, we're more confident than ever that we will be approved with a single trial. We will be not only best in class, but first in class. Now, to answer your question directly, what do clinicians look for? It's really very simple. I understand that the primary endpoint is not necessarily what clinicians do, which is wait for a 15-letter loss.
However, that's what the FDA wants, and we satisfy that challenge. What the clinicians look for is very simple. Does this drug give me disease control? What is the durability, and is it safe? After that, they'll figure out how to use it, right? Clearly, we've shown that. I go back to saying we have never seen disease control to this degree ever within 30 microns. That's audacious. That's never been seen. We see durability clearly where 2/3 are rescue-free with a single injection at month 12. That's never been seen before. The safety profile is absolutely clean and acceptable. There's no question about that. As far as how it's being received is concerned with my colleagues, well, I think that people expect to have this in their hands. The question now is how will they use it?
Will they start immediately with a fixed every six-month regimen, or will they go ahead and use a treat and extend and continue to extend until they feel comfortable? That's really the discussion going on. I think everybody feels that they will have it fairly soon in their hands, again, with a single trial, and that's what we plan to do.
Yeah. I guess one of the things that we've heard is that a sweet spot, I guess from a physician perspective and a patient perspective. Okay. Patient perspective, of course, they want to go out as long as possible. The physician would like monitoring. Is there an expectation that it would automatically go into a six-month label, or do they just want to monitor? How do they get them back in the office after six months?
Let me just say again, there's not a single drug in my field that is used per clinical trial or per label. I'll challenge anybody to prove me wrong, okay? The point here is to get this to the physician's hands, and they'll figure out how to use it.
It's going to start happening.
It will be adopted immediately. It'll be adopted immediately because there's no change in the workflow. There's no added overhead. The experience is exactly the same. It's a self-sealing needle at 25 gauge. It'll be adopted immediately. Now, whether some physicians are going to go automatically to every six months or some physicians are going to go ahead and start with treat and extend, that I don't know. That's something that the community will decide. We're not going to die on the hill for that, and we haven't done a clinical trial to show that either way. If you're asking for my opinion as to what will ultimately happen, I think this is the ideal drug to be given the way that we all want to treat our patients with this, which is every six months. Let me explain that.
What we're doing with treat and extend right now is not something that has any kind of a scientific basis whatsoever. There is no study on treat and extend, and it's completely misaligned with what all of medicine does. Nobody waits for disease to come back before they figure out how to treat. No cancer doctor says, "Look, I'll wait for your bladder cancer to come back before I figure out how often to see you." No cardiologist says, "Let me just wait for your first heart attack before I figure out how to treat you." It's completely misaligned with what all of medicine does. The reason we do this is because we don't have the proper drug to do what we want to do, which is really to treat every six months. That's our comfort level. That's where patients feel comfortable because they want to see their doctors.
They don't want to not see their doctors for two or three years. Physicians feel comfortable seeing a patient with a chronic disease just in case something should happen that would be untoward. For a drug that's going to be appropriate for every six-month fixed treatment, that drug should last for 9- 10 months. The reason for that is in case the patients get ill or the physician is out of town, et cetera. This is the ideal drug for every six-month dosing. How physicians will get to that, whether it'll be immediately fixed dosing or whether it'll be extended treatment stint, is something that they will figure out. My job is to get this approved as quickly as possible and get it in their hands to have patients have a better outcome as quickly as possible. They'll figure out how to use it.
I guess, in terms of getting it approved as quickly as possible and having information there about retreatment, do you need SOL-R to be able to get a label with retreatment?
Hey, that's a great question. Let's talk about this comprehensively and talk about the single trial approval, okay? What I have said over and over again is to say that we have ongoing formal, and that's emphasized, formal discussions with the FDA. That's said deliberately. These are formal discussions. Every time I'm in one of these fireside chats or in one of these meetings that say we have ongoing formal discussions, please understand that if there wasn't a path forward, I wouldn't continue to say that, or I couldn't continue to say that. The fact that I'm saying that must mean that the FDA continues to engage us and must mean that there's a path forward. Why is there a path forward? Well, here's what we understand regarding a single trial approval. This has nothing to do with FDA commissioners, either present or past, whatsoever.
It doesn't. This is a standard that has existed since way back when. In fact, Dr. Boyd has recently pointed to an article from 2010 in the "New England Journal of Medicine." The standards have not changed. The evidentiary standards have not changed, and it's important for everybody to understand what those evidentiary standards are. There are two evidentiary standards prior to the Kefauver-Harris, and there are two evidentiary standards following the Kefauver-Harris. Prior to the Kefauver-Harris, number one, the study has to be well masked. It has to be properly masked. The fact that we don't have a sham fits that bill. The study has to be properly powered. We clearly fit both of those things because we have a SPA. Those boxes have already been checked. Those are the two evidentiary standards that have not changed prior to the Kefauver-Harris.
Post Kefauver-Harris, there are two other evidentiary standards. First, the P value has to be less than 0.001. Ours is less than 0.0006. Clearly we meet that. The second evidentiary standard is that there have to be at least 300 patients for safety purposes only that can be looked at at the same time as the submission. Clearly we meet that because we are doing nothing with SOL-R except that SOL-R is continuing as it is. We have a great deal of flexibility with SOL-R to provide those patients. It's not that this is something new, this one trial approval. The fact of it is that no other drug, no other clinical trial has met all four of those evidentiary standards. We have. That's why we have ongoing formal discussions.
In regards to the label and redosing, realize that we will discuss our labeling strategy when appropriate, but suffice it to say that there's a lot of redosing experience within SOL-1 and certainly with SOL-R. Remember that everybody in SOL-1 at week 52 has been redosed. Within SOL-R alone, there's a great deal of redosing experience. In SOL-R, obviously, there's a great deal of redosing experience. Our goal is to have a label that nobody else has, that has never been achieved before, which is a superiority label with flexibility of dosing every 6- 12 months with repeatability. Again, this will be the first and only drug, as far as we're concerned, that will have a superiority label, which will provide great advantages from a commercial point of view as well as from a pricing point of view.
Got it. I guess I'll ask another relatively controversial question. There's obviously two TKIs being developed, and if they're designed with different studies, again, how do physicians make a decision what to go with? When you don't have two studies that are designed in the same way, how does that physician make a decision? I'm only asking because I'm thinking from the practical perspective. I know your goal is to get approval, but the physician's goal is to choose the best treatment. How do they know what that is when the two studies were designed completely differently? I guess I'm thinking more from a practical perspective.
Yeah. Look, as you can appreciate, I'd rather talk about my own company than anybody else's company. In order for a physician to have a drug, it has to be approved first, right? Before you even go there, I think the first question to ask is: what are the guidelines for a drug being approved that is outside the FDA's guidelines? The FDA's guidelines are very clear. We have followed the guidelines of February 2023, and I think what you should ask every company is: have you had formal meetings with the FDA with formal documentation that evaluates your trial design vis-à-vis their guidelines following February 2023? Again, that's the most important question to ask every company, ours as well. Clearly, when we have an answer, a formal answer, it means that we have a spot.
Okay. Fair enough. Getting, I guess, questions about the Eylea arm and how it outperformed. It did better than expected. I guess the question is: was this treatment-naive population, I guess, a low bar given that they were so responsive to Eylea? Is it a representative population that was in the trial, I guess, is the question.
Yeah. Again, let me give you my thoughts on the trial results first. What surprised us and what didn't, let me talk about your second part, which is how will this drug be used in real life? Look, obviously, this trial has never been done before, and the control part, which is a single injection of EYLEA, has never been done before. This is all new things that all of us have learnt as a community, which is very valuable, right? The first thing I would say is let's just do an exercise where we just look at the treatment arm and forget about the control arm, just as a matter of exercise. I think anybody would agree that the drug completely outperformed any model in the treatment arm only. The thing that people get hitched up about is what the control arm did.
I'm perfectly fine with you saying the control arm outperformed, but I'm not really sure personally whether that's the accurate statement. I think what we learned from that is that it takes a heck of a long time to lose 15 letters of vision. By the way, that control arm is of academic value. It really has no practical value. Nobody's going to go ahead tomorrow and say, "Hey, look, I'm going to change the way that I use EYLEA based on this study." It takes a long time to lose 15 letters of vision. However, the way to look at the results are the way that the FDA would look at it and the way the clinicians would look at it, right? From the FDA point of view, look, we met the primary endpoint.
We're the first study ever to hit a superiority primary endpoint with a p-value of 0.0006, period, and an acceptable safety profile. From a clinician's point of view, yes, that endpoint may not be clinically relevant as much from their point of view because they don't wait for a 15 letter loss. They look at the OCT, and when they look at the OCT, they may see stability within 30 microns at month nine with a single injection. That's phenomenal. That's what they look at for disease control. They look at the fact that 2/3 of patients were rescue-free at month 12 with a single injection. That's durability. That's what they look at. Of course, they know how to use this. They'll use this immediately because it'll go right into their workflow with more than enough evidence. Now, how will it work?
Look, here's what I would tell you. Every single drug that I know of that I've studied in the last 30 years of being a PI has done worse in the community than in the phase III study. That's logical because you want to have the best patients possible for a phase III study, right? Every single drug. This will be the first drug ever that will do better in the community than in the clinical trial. The reason for that is because we specifically selected patients that were VEGF-dependent and were designed to lose vision in the clinical trial. That's not the case in the community. In the community, the bar for success will be much, much lower. Let me explain. If you go to a retina specialist office in a single day, they may see 50 patients.
Of those, maybe two may be new patients, right? The other 48 will be patients that are on chronic visits. The physician may look at Ms. Jones and say, "Ms. Jones, for the last three years, I've given you EYLEA every eight weeks. I know that you're frustrated. However, there's a new drug that I believe may last longer. Let me give that to you. It's called AXPAXLI. Come back in eight weeks because I want to see how you do." She comes back in eight weeks, and the physician will say, "Wow, you're doing great. Let's extend that to now to 12 weeks, on and on and on." The bar for success for a patient like that is extraordinarily low. It's just based on durability.
This drug will actually do far better when used in the community than it did in the select patient population in the clinical trial itself. Although in this clinical trial with this patient population, it hit a superiority primary endpoint with a very robust p-value that no one else has ever done before.
Got it. Let's move on to SOL-R because you completed enrollment, I guess, this past December and could have data, I guess, in the first quarter. What are you looking for in this trial, and what do you think the FDA will want to see or want to pull from this trial to be able to feel comfortable in the approval of one? Is there anything that they would pull from this trial?
Yes, a great question. The first thing I'll tell you is, look, we're not changing SOL-R at all. SOL-R is recruiting extremely efficiently, and we're executing SOL-R fantastically. Nothing is going to change with SOL-R. What I'll also tell you is that from an efficacy point of view, we've already met the evidentiary standards for the FDA with SOL-1 alone. I will repeat again, I know this is the third time that I've repeated this, I'll continue to repeat this as many times as you want, we intend to file on SOL-1 alone for approval. We are more confident than ever that we will not only be best in class but first in class. However, we're not changing SOL-R. The reason for that is because SOL-R is going to provide us with a great deal of flexibility as far as safety patients are concerned.
It will also provide us with a great amount of leverage from a commercial point of view. Remember, in SOL-R, we go head to head, although without statistical analysis, against EYLEA HD. That'll be very valuable from a commercial point of view. Also, SOL-R will be important for some outside U.S. regulatory agencies. Again, I want to repeat this, our intent is to file based on SOL-1 alone, and we're more confident than ever that we can do so.
Okay. Do you have any information at this point from SOL-R? Is there anything that you can gather from there? Do you have a sense of continuation, dropouts, anything like that? Is this completely blinded?
Well, Annabelle, as you know, look, the retention and the execution of SOL-1 was unprecedented. That was a study, as you recall, that people said we could never recruit, and if we did recruit, we could never execute because everybody would drop out or everybody would rescue off protocol, et cetera. The execution of that in terms of retention was phenomenal. We don't expect any less from SOL-R. We haven't guided you as to the numbers as yet. We will when appropriate. I think there's every reason to believe that our execution is going to be fabulous there as well.
I guess in the little time that we have here, can you talk about SOL-X that started? What kind of enrollment are you seeing from SOL-1 into SOL-X? Any reasons to enroll, reasons not to enroll? Can you just give us an idea of some of these components?
Well, there's no reason not to enroll. Obviously, it's a very easy study to enroll in, right? We're seeing that. Again, the execution, the retention is fantastic. Remember, there are two goals that we're trying to solve here. One is that of sustainability, which is what we spent 95% of the time talking about. The second is that of better long-term outcomes. We will show that in SOL-X because one of the many things that we look at, and one of the very important things, is the visual acuity of patients that cross over. They'll cross over after two years of pulsatile therapy. We don't think those patients will ever catch up because they'll get fibrosis and atrophy, which happens, is detectable as early as 90 days.
We believe that with SOL-X, we'll be able to show that not only will vision be maintained, but the chronic long-term outcome in regards to fibrosis and atrophy will be better than with any of the anti-VEGF long-term studies that we've seen so far.
That's great. Okay. In the two seconds we have left, any comments on the opportunity you have in diabetic retinopathy and even maybe DME? Is it moving into DME potentially or how do you expand from here?
We believe that we'll be successful in having a drug that you can give once a year, which is phenomenal, in a target that's three and a half times as big as wet macular degeneration for all of diabetic retinal disease. We believe that we will get a label that includes all of diabetic retinal disease. Remember, we're recruiting patients who also have non-center involving diabetic macular edema. The FDA historically, including in my last company, Iveric Bio, has given a label based on the disease, not based on a clinical trial and not based on the specifics of the patients that are recruited, but based on the disease. We believe that we'll get a very broad label for all of diabetic retinal disease, and we believe that we'll have a drug that one can give once a year.
If it duplicates what we saw in the original HELIOS study, it will reduce the risk of any vision-threatening complications literally to zero, which is absolutely phenomenal.
Okay. I think that's a good place to end it. Thank you for that and look forward to seeing how this all evolves.
Annabelle, thank you for the opportunity. It's wonderful to be with you again.
Thank you.