Welcome to the UBS virtual event. I would now like to pass the call over to Eliana Merle.
Hey, guys. Thanks so much for joining us. I'm happy to have EyePoint here with us, here for a fireside chat. Joining us from EyePoint is Jay Duker, President and Chief Executive Officer, as well as George Elston, Chief Financial Officer. Thank you, guys, for making the time. Maybe just to kick it off, can you tell us a bit about EyePoint's platform and your technology that differentiates your approach?
Sure, and thanks for having us, Ellie. So EyePoint, what we really do at our heart is drug delivery to the back of the eye, and our platform to do that is called Durasert. Durasert has been in four FDA-approved products in a non-erodible form. Our lead product, which was formerly known as EYP-1901, is now being called Duravyu. That also is in Durasert, but it's in Durasert E for erodible. The previous iterations of the product had a non-erodible polyamide shell. That was not necessary for Duravyu, so we removed the shell, making the entire insert bioerodible. So the nice part about what we're doing is that we have four FDA-approved products with essentially the same platform.
The matrix that we use to hold the drug together in the insert has been used in tens of thousands of patients, so there's a long safety history that's quite positive for this technology. The technology is shipped and stored at room temperature and comes in a prepackaged, well-tested injector system that's sterile, so there's no mixing that the physicians need to do.
Makes sense. Can you elaborate a little bit on how the Durasert technology works, and why sustained delivery is so important in the context of wet AMD?
Sure. So, first of all, what we're using in Durasert is vorolanib, which is a small molecule tyrosine kinase inhibitor. And if one were to inject a small molecule into the eye intravitreally, like for how we treat wet AMD, without a delivery system, it would be gone in days. So in order to make a small molecule last longer, you need a delivery system. And the second part of the equation is that what's lacking right now in wet AMD care is durability. We have plenty of good options that are short-acting options that are safe and effective, but none of them really last very long.
By using a combination of a small molecule TKI, vorolanib, with our Durasert E technology, we're able to deliver therapeutic levels of drug for at least six months, and perhaps up to nine months in humans with a single injection, and that's really our advantage. The big advantage of Duravyu over other approaches is longevity.
Makes sense. And yeah, I guess starting with wet AMD and your phase II results, can you walk us through the design of the phase 2 DAVIO-2 trial, and what your considerations were for making the design choices that you did?
Sure. So that's really an easy answer, because I'll just go back historically. Very early on in the development of EYP-1901, we recognized that our advantage was longevity, in that we decided that we were going to go for a label of maintenance therapy in wet AMD for either previously treated or naive patients after a load with anti-VEGF. So that was the part of the TPP that we had decided on long ago. After we got positive phase I data, internally, there was a discussion about whether to take this program directly to phase III. And so we went to the FDA in twenty twenty-two with a Type C meeting, laid out a phase III program. They commented, we made some changes, and at the end, they had given it its blessing. So we had a phase III design in 2022 .
Internally, we then decided, it made more sense to do more of a traditional, drug development approach and do a phase II trial. But we designed the phase II trial, the DAVIO-2 trial, around what the FDA had told us. Now, there were a few changes. For example, the phase II trial did not involve re-injection of our drug. The Phase IIIs will. The phase II trial had a primary endpoint of combined 28 and 32 weeks, so around eight months. The phase III trials, the FDA had discussed with us, and we agreed, would have a one-year endpoint, combined 50 and 56 weeks. But overall, other than that, the phase II design, was very similar to what the FDA had agreed upon. And so we executed that trial, and as I think you know, and we reported back in December, very good top-line results.
We hit the primary endpoint of non-inferiority change in visual acuity against an Eylea on-label control, with a change in difference in letters at the end of eight months of less than half a letter. And more recently, we reported twelve-month data, which, even without a re-injection of our drug, continued to show excellent visual stability in the Duravyu-treated eyes. Safety has not been a concern in any of the trials. In DAVIO-2, we had no ocular or systemic SAEs attributable to our drug or to the insert, and that's been true across all the trials that we've done. We've now treated about 191 patients with Duravyu, and we've had no ocular or systemic SAEs. And so safety is really important in the retina space, as I'm sure you and others who follow it know.
And so while that's not the primary endpoint, you can call it primary endpoint one point one. You have to have safety, and we've really shown that. And I want to add, one of the other interesting things about vorolanib is it was studied as an oral agent in wet AMD several years ago, and that we have a database of about 150 patients who took it orally with no ocular SAEs related to vorolanib. So we have a very large safety base right now of patients treated with vorolanib. We also, the secondary endpoints, we hit them all. We reduced the treatment burden by about 80%, whether you looked at it prospectively against the Eylea control or you looked at it retrospectively against history.
We had two-thirds of the patients able to go up to six months after Duravyu went in without a supplement. In the anatomic data, that's the measurement of the retinal thickness that we do on optical coherence tomography or OCT, that looked really good, too. There was no significant difference between the Eylea arm in either of the Duravyu arms. So overall, the phase II really hit the top line in the secondary endpoints really to a T.
Mm-hmm. Makes sense. It's exciting data. In terms of your phase III and design and your registrational strategy, I guess you have two pivotal trials about to start in wet AMD. Can you give us an overview of these trial designs and your rationale?
Sure. So first, the rationale behind non-inferiority trial designs is well-established with the FDA. The last five approvals for wet AMD drugs have been non-inferiority, and in order to do a non-inferiority trial, you need a non-inferiority margin, and that margin has been designated as 4.5 letters, so that the lower limit of the confidence interval when you do the statistics at the end of the trial can't cross minus 4.5 letters. I want to go back to our results in DAVIO-2 just for a moment, because the non-inferiority confidence interval didn't cross 2.6 letters in DAVIO-2, so that we were, from a visual acuity perspective, miles away from the non-inferiority margin in DAVIO-2, which gives us great confidence for the pivotals. So that's the overall design, non-inferiority, against a standard Eylea control.
We're going to use one dose of our drug. That dose is 2.7 milligrams. That dose is achieved by injecting two inserts simultaneously in our injection system. We can actually inject up to three inserts with a single injection with our injection system. So that 2.7 mimics about the 3-milligram high dose that we used in phase II. All of the patients in the trial will get loaded with Eylea. What that means is, day one, everyone gets an Eylea. They get randomized to day one. Week four, everyone gets Eylea. Week eight, everyone gets Eylea, and then thirty minutes later, they either get their first dose of Duravyu, or if they're randomized to the Eylea arm, they get a sham. They then come in monthly. Every other month, the Eylea arm gets another Eylea.
In the Duravyu arm, every other month will get a sham, except at month eight, they'll get another Duravyu. So there's no early rescue with Duravyu. It's an every-six-month drug. And that will continue. The primary endpoint for efficacy is a combined visual acuity 52-56 weeks combined. But the study will go on for two years for safety, and that's important because, you know, the FDA made it clear, and you can see with other programs as well, to get a label for continued re-injection, you have to show safety over that two years. And so we're excited to be perhaps the only program that's got two pivotal trials in sustained release with re-injection.
And again, from the perspective of what the patients want and what the physicians want, re-injection is important, because it gives the physicians more control over the long-term treatment of their patients. Other highlights of the trial, just like in DAVIO-2, in the pivotal trials, there will be a masked physician who determines if a rescue criteria is met, and therefore, theoretically, and frankly, practically, the Eylea arm can also receive a rescue. And that actually happened in DAVIO-2. By month eight, 6% of the Eylea arm had gotten a rescue treatment, despite the fact that they had gotten every other month Eylea. What that tells you is that we enrolled a very tough-to-treat population, because even every other month Eylea didn't keep them under control. And I think that number, by month 12, expanded to 13% had been rescued.
So when we look at the pivotal trial, there'll be rescues in the pivotal, too. We hope and expect the numbers to be less in the Duravyu arms for several reasons. But we're also going to be compared to the rescue number in the Eylea arm, not just in the Duravyu arm, which, from a statistical perspective, we believe will be helpful. So the rescue criteria or supplement criteria, the major one that we're using is the same major one we used in phase II. No different. Five-letter loss from best on study with 75 microns of new fluid due to wet AMD. There'll also be a mandated rescue for hemorrhage if it's confirmed by an independent retina specialist. And that's really the extent of the supplements criteria that were used in the phase III.
One of the other things to note is in the phase II, 20% of the supplements given in the Duravyu arms did not meet criteria. We gave the phase II investigators leeway to rescue if they thought it was in the patient's best interest, and we're really going to ask them to stick to the protocol for the phase III, because we'd like to see fewer rescues. So on to another change is we're enrolling both previously treated and naive patients into the pivotal trials, where we'd only enrolled previously treated before. There are several reasons why we're doing that.
The first reason is that when we evaluated the patients who did best in DAVIO-2, the patients who didn't need many rescues, it appeared that the eyes that had been recently diagnosed actually did better than the group as a whole, with 80% of them making it through eight months without a supplement. The second reason is we enrolled a really tough-to-treat population in DAVIO-2. How do we know that? First of all, historically. Historically, the population we enrolled had an average of 10 injections leading into the trial. That's a lot, 'cause in the real world, it's about six injections or less. The second way we know it is we had rescues in the Eylea arm, which I mentioned.
The third way you can tell is if you look at our data from the phase 2, and you look at the OCT data from the Eylea arm. What you'll notice is every two months, the OCTs got wetter in the Eylea arm. That tells you that every other month, Eylea was not controlling all those patients, and they were tough to treat. So let's go back to why naive patients? Well, naive patients, depends who you ask, but anywhere from 20-25%, maybe up to 30% of the naive population probably can get by with less than every other month Eylea. Well, that, I think, where our drug should do very well with those patients, the ones who are not really dependent that much on anti-VEGFs frequently.
In which case, we think that our results in that full population should be even better than what we saw in DAVIO-2. So we are re-enrolling naive and previously treated. I think that also gives us an enrollment advantage because most of the wet AMD trials just enroll naive patients. So overall, those are the major changes from DAVIO-2. Again, the changes are things that we knew about ahead of time because we had discussed with the FDA and aligned with what they were. For example, the re-injection is okay with them in the one-year endpoint. But also, using naive, I think that that's actually gonna help us.
Mm-hmm. Great! That's a very helpful overview. And just in terms of, like, the status of initiating these trials and given the, you know, many trials ongoing in this space, what is your perspective on how long it will take to enroll the phase III program?
So, let me start out first by saying that, there's a lot of reasons I'm glad we ran a phase II and didn't go right to pivotal. But one of them is we learned a lot about how to recruit these trials. In our phase II trial, we enrolled a hundred and sixty patients in about eight months using seventy centers. Most of those patients were enrolled in the last three months of the trial because there were lessons that we learned in the first few months that we're gonna be able to apply to, the pivotal trials, and we already are. We have, right now, over a hundred and forty sites that have agreed, and we want them to be in the trial. We've started activating those sites.
And what we expect is when we get the first patient randomized dosed, that's the same day, obviously. We're not just gonna have one or two centers up and running. We hope to have a dozen centers up and running, with another, you know, 50 or 60 coming online in the next few weeks. So we're really gonna do a very quick ramp-up of the sites. There's always really been competition for wet AMD trials when you go back. There are a few that are open, some of which we're not directly competing with because the inclusion criteria is a little bit different.
And others that, you know, companies have reported that they'll be starting up in the Q1 or Q2 of next year, where we hope to have a really good number of patients already in our trial or trials, I should say, since the second trial is expected to start within the first few months of the first. So, we are doing a lot of things to ensure that our trials are on the top of investigators' minds. But I think equally importantly, our trial is very easy for investigators to understand because they've run non-inferiority trials before. We have a fixed interval for both drugs, and everybody's getting treated, and there is the opportunity to rescue if anyone's getting undertreated. I think it's a very easy trial for patients to understand, and that makes it recruiting easier as well.
So there's a lot of things that we're doing, you know, sometimes are just basic walking and tackling things that make it easier for the sites to bring patients in. But having a lot of sites, and having great communication, and listening to the sites about what they want and how to make it easier for them to enroll, those are many of the lessons that we learned in DAVIO-2. So onto the timing, I think you can look at other wet AMD trials and see how long they take to enroll. Generally, they're a year or less, and we are quite optimistic we can meet or beat that.
What I can say, and this is certainly not guidance, and it's low probability, but if we enroll the phase IIIs at the same pace that we enrolled at the end of DAVIO-2, we could enroll this trial much faster. So that's what we're going for. Can't say we're gonna be there, but, we're optimistic that we can enroll both trials in less than a year.
... Mm-hmm, exciting! Turning for a moment to DME, what should we expect to see from the phase II DME data in the first quarter next year? And I guess, what would you view as encouraging or good data?
Yeah, so I wish I knew what to expect, because I have ESP and win the lottery. But I'll tell you what we think is likely is that, first of all, DME, like wet AMD, is an exudative disease. There are leaking blood vessels that are primarily mediated by VEGF. And vorolanib is a very good blocker of VEGF working at the receptor level. And we know we're many fold times the IC50 with our inserts, so we're optimistic that we're going to be able to shut down the VEGF in this disease. We also, again, our you know first principle that I mentioned from the start, is that we're maintenance therapy.
So we believe that after a load of Eylea or any other anti-VEGF, that using Duravyu in DME is likely to maintain the gains of vision and anatomy that were achieved with the load. So once again, we don't have to be better, and we don't have to be just for hard-to-treat patients. Because the pivotal trials will be non-inferiority, we just have to match it with, hopefully, our, you know, our longer durability. So what we hope to see that would be encouraging to take us into pivotal, would be some improvement in the visual acuity in the Duravyu treated eyes. So the study is structured, it's all, previously treated DME, but they have to be active. They had to have fluid going into the trial and decreased vision.
They were then randomized to either 2.7 milligrams of our drug, 1.3 milligrams of our drug, or Eylea control. Everybody got one injection of Eylea at day one, and then 30 minutes later, got our drug or sham. Then it's essentially a PRN trial, meaning there was no other mandated injections, but the patients are watched for the need for rescue. The rescue was based on the same type of criteria we used in wet AMD. However, because they have active fluid, we also said if by 12 weeks there hasn't been a 10% reduction in the thickness, they would get rescued. Knowing that against a PRN Eylea, we'd like to see our drug perform better, meaning visual acuity-wise, because that would give us quite hope and optimism that in a non-inferiority trial to on-label Eylea, we could tie them.
Obviously, we want to see continued safety, and there's been no issues with that. We'd like to show the anatomy follows the vision. And what I mean by that is, if you do get a visual improvement, you want it to be shown that it's because the anatomy is at least slightly better than the control group is doing. So that, to us, as, as a company, that's what we're looking for to really say, "Yes, this drug is going to work in DME as well," we hope, and there is every indication that it would, and that we're going to go forward with pivotal trials in DME. Because that opens up, obviously, a whole other large market for us.
Absolutely, and taking a step back in terms of the broader landscape, I mean, there are a lot of novel approaches in development across gene therapy, TKIs. Where do you see Duravyu fitting in, and how do you think it compares to others in the space in terms of efficacy and safety?
Yeah. So, taking even a step back further, what you're seeing now is, you know, after 15 years of anti-VEGF, anti-VEGF therapy, you're seeing the investigations go in one of two directions: new mechanisms of action, which many of them are still unproven, or longer durability. I think we're in the lead for longer durability. Why? We have the most robust phase 2 data set of any of the TKIs, or I would say, the gene therapies. As I mentioned already, we are going for a label of every six months, so we're repeatable, and therefore controllable by the patient and the doctor, should they want to repeat. We have very good safety data, extensive safety data, as I already mentioned. We have a pathway to approval that's the same type of pathway that's been used multiple times before.
It's a pathway also that doctors can understand. Quite simply, the type of label we'd like to see, if we can get approval, would be maintenance therapy in wet AMD, treatment-naïve or previously treated, after three injections of an anti-VEGF. The way I think docs will think about it is, if we're twice a year, that would be maintenance therapy of six injections of Eylea. You can replace three injections with Eylea with one of us. It's kinda quite simple. The other important point to make here about the sustained-release is, when we talk about supplements, you know, we like to keep the supplement rate down, but remember, a supplement treatment for us is not a failure. Patients will probably need supplements, but doctors don't mind giving injections, but what they want is fewer injections.
They want to be able to safely and effectively take some of their wet AMD patients out longer than they are now. I think the one of the problems gene therapy has, is that the promise of gene therapy is one and done. That's why your doctors, and payers, and patients would go through the cost and the risk of gene therapy. But if they're not really one and done in a large number of patients, then it's hard to see what the value is there, versus again, something like us. And, you know, you don't have to work in everybody. This is over a $10 billion market right now, probably $15 billion in five years. But, if a patient or doctor doesn't like Duravyu, just wait, it's going to go away. They don't have to use it again....
Which again, gene therapy, a little bit different. So I think we're very well-positioned with, I think, the most de-risked program, and am confident that we can enroll these trials fastest, and hopefully therefore, be first to market. We think that that's still likely, and we'll have, I think, a label in an MOA that physicians will appreciate and understand.
Great. And could you give us a little bit more color on some of the regulatory discussions that you had, in designing the phase III program?
I think at a high level, they're fairly straightforward. You know, the way you kind of ask the FDA questions, and they say, "We agree," or, "We don't agree." It all started again in 2022. We'd like to do a non-inferiority trial. Sure. Non-inferiority margin of 4.5. Sure. Previously treated patients or naive? Okay. Obviously, I'm paraphrasing, but you know, this is the gist of it. What we said, you know, nine-month trial, they said one-year trial. Can we load everybody? "Yes, but you have to do a one-year trial." Those are the kind of interactions that we've had, both in 2022, and I would say at the end of the phase II meeting, that you know, led to the design.
I guess one more thing, 'cause this keeps getting brought up, although less and less now, is sham formatting fine. The FDA told us that in twenty twenty-two. They reiterated at the end of phase 2 meeting, in depth. While there is still a little bit of noise out there that you can't do sham, you can do sham formatting.
Awesome. Well, I think we're coming up on time, but thank you so much for joining us, and we look forward to hearing all the updates.
Great. Thanks, Ellie.
Thanks. Bye.
Bye-bye.