Morning, everybody. Welcome to EyePoint's R&D Day 2024. We're really glad you could join us. We're very excited to discuss not only our phase III plans for DURAVYU and wet AMD, but our terrific 12-month data from the phase II DAVIO 2 trial. I'm Jay Duker, President and CEO of EyePoint. We're gonna be making some forward-looking statements today, and if you want more details about that, you can go to our website. I'm gonna start with some introductions, and then go over our agenda. I already introduced myself, but, for background purposes, I'm CEO. I've been CEO for about a year now. I was chief operating officer prior to that, and in my former life, I was the chair of ophthalmology at Tufts for 21 years. I'm trained as a retina specialist and actually still practice a half a day a week.
Joining me from the executive team is George Elston, our Executive Vice President and Chief Financial Officer. I think most of you know George. George has been in biotech for over 25 years. Extensive experience, especially in oncology and ophthalmology, and George has been with EyePoint for about five years. Our newest member of the executive team is Ramiro Ribeiro, MD, PhD. Ramiro joined us from Apellis about three months ago, Ramiro? It feels like three years to you, I'm sure, but it's only been three months. But Ramiro has just been a terrific addition to the team. He is also trained as a retina specialist, which is terrific for me because he and I get to spar together over various theories as to why things are occurring, and most of the time, he's actually winning the discussions at this point.
Ramiro has also extensive experience in biotech for the last 15 years, exclusively in ophthalmology, and he has run pivotal trials in retinal indications, both in the US and globally. Also joining us this morning are really two terrific key opinion leaders. Carl Regillo is, again, a guy probably, if you follow ophthalmology, needs no introduction. Carl is the head of the retina service at Wills Eye Hospital. He's also a member of one of the largest and most prestigious retina groups in the country, Mid Atlantic Retina. And Carl has worked with literally dozens and dozens of companies down through the last three decades, helping products get approved. And Carl's really is... When people talk about a key opinion leader, his opinions are really, really held in high esteem.
Also joining us from right down the street is Yasha Modi. Yasha's at NYU, also practicing retina specialist. Yasha also does uveitis, which means he's a glutton for punishment, for those of you who know that field. I used to describe Yasha as an up-and-comer, but he's an up-and-here-er. He, while young, has really made a terrific name for himself, as a KOL and as a clinician and as a surgeon. So following the introductions, I'm gonna give you a company overview. I'm then gonna describe our lead asset, DURAVYU, which is vorolanib intravitreal insert, formerly known as EYP-1901. Yasha is then gonna come up, and he's gonna review the top-line data. Eight-month was the primary endpoint for the phase II DAVIO 2 trial for DURAVYU and wet AMD.
Following that, Carl is gonna give the first public presentation of the 12-month data from the phase II DAVIO 2 trial, and I think you're gonna be very impressed with what you see. Ramiro and I will then talk about the pivotal programs. We have 2 pivotal phase III trials planned, and we will describe the details around those pivotal programs. I'll briefly update you on the early pipeline, and then I'll ask Carl and Yasha to come up, and we're gonna have what should be called a roundtable discussion, but it looks like it's gonna be a rectangular table discussion about interesting topics concentrating on wet AMD. We will have time for Q&A at the end, and I promise to get you out of here on time before 9:30. So company overview.
EyePoint is committed to improving people's lives with serious retinal diseases through improved therapeutics. But at our essence, we are a drug delivery company to the back of the eye. We have patented drug release formulations that allow us to improve the outcomes in the intervals of treatment. Our lead asset, again, DURAVYU, we'll be talking about in detail this morning. We're p hase III clinical stage company at this point, and DURAVYU, the lead asset, that is a potential of a multi-billion dollar market opportunity, along with a pipeline, which, again, if it comes to fruition, could be a second drug of a multi-billion dollar market opportunity. This is based around the Durasert technology.
Durasert has been around for several decades, and I think as most of you know, there are four FDA-approved products that have Durasert delivery technology. What we're using in DURAVYU, EYP-1901, is Durasert E, which is fully bioerodible. We have a strong balance sheet, and as of the end of this month, we predict we'll be at least $280 million of cash, which gives us a cash runway in well into 2026. Now, here's our pipeline. Wet AMD really is what this company is all about right now, entering phase III with DURAVYU. As you know, and as you'll see, Yasha will present really, really strong phase II data.
Despite a relatively small study of only 160 patients, we were statistically non-inferior to the standard of care, which is 2 milligrams Eylea. We also have a program in non-proliferative diabetic retinopathy. We reported top-line data about a month ago, and that data showed a biological effect for our drug, and a very impressive continued safety profile. But based on the results at this point, there's no plans to go forward with any continued studies of NPDR. We will have 12-month data for NPDR later on this summer. I'd also like to announce this morning that our DME trial, the VERONA trial, is now fully enrolled. We've enrolled 27 patients in that trial, randomized to either an Eylea control versus 1.3 milligrams of DURAVYU or 2.7 milligrams of DURAVYU.
We're on target to deliver top-line results from that trial the first quarter of next year. EYP-2301, which is razuprotafib in Durasert E, that's a Tie2 agonist. Tie2's important in VEGF-mediated diseases. You don't want to block Tie2, because if you block Tie2, you upregulate angiopoietin-2 , and angiopoietin-2 leads to vascular instability. So there's a balance between Ang-1 and Ang -2. You want Ang-1 , you don't want Ang -2, and by agonizing Tie2, you keep that in balance. And we have a very potent molecule that can do that, and we've been able to formulate it into Durasert E to last at least six months with a single injection. We're also studying the potential of complement inhibition in sustained release, and we are still in that preclinical phase of that study.
So this is a picture of a Durasert insert next to a pencil. You can see they're tiny. It's delivered in a standard in-office intravitreal injection. Nothing to, like to say, really difficult about it, but for most retinal specialists, it's something they do 40 or 50 times a day. A Durasert comes in a self-sterile package. The physician simply opens it, takes out the syringe injector, takes away a tab, pulls off a cap, and injects it. And what's nice about this technology compared to all the other sustained release technologies out there is we're shipped and stored in ambient temperature. No refrigerator space, and unlike gene therapy, doesn't have to be frozen at -60. The inserts provide a constant release of drug via what's called zero-order kinetics.
What zero-order kinetics essentially means is, after the small initial burst of drug that's on the surface of the inserts, you maintain a steady drug level, and in animals for at least nine months, and we believe perhaps a little shorter in humans. But that steady drug level applies constant pressure on the receptor, and this allows essentially microdosing, where you might think if you had a drug, whether you were giving intravitreal as an injection or orally, you have to get a big Cmax to make it last long. It's irrelevant with zero-order kinetics because of that constant release. So the drug is embedded in a bioerodible matrix, and they're designed so that the matrix holds the drug together through the lifetime of drug release. And that's important because you want to be able to control drug release with this insert.
You don't want to have your matrix go away before the drug is gone, because then you have free drug in the eye. And with free drug in the eye, you really don't know what type of dose you're getting, and the potential, if you had a free drug in the eye, that the drug could be mobile and perhaps even block the vision. So there's no dispersion of the drug with these inserts. So on to DURAVYU. We believe we have the best and most advanced sustained release program out there, and here are the reasons why. First of all, we've had great safety from our DURAVYU inserts, across now four clinical trials. We'll talk about that in a little more detail, but we've had no ocular or systemic SAEs related to the drug.
And this is really important, as those of you who follow the retinal space, that safety is really, really paramount to physicians, and we have the best safety track record of any of the sustained release out there. We now have aligned with the FDA on a non-inferiority pathway, non-inferiority for our pivotal trials. That's the pathway that, frankly, the last five drugs have been approved with, and, we're comfortable and highly confident in this non-inferiority approach. We have the most robust data set. I already talked briefly about the 160 patients in the phase II trial, but we've had, along with that, the other phase IIs and phase I, so the largest data set out there for sustained release.
And with back to the phase III trial design, we're the only company that's looking at redosing, and that's really important to patients and physicians, the ability to redose the drug on an interval that is better than perhaps than what they're getting now. This both aligns with the FDA, but it also aligns with, again, clinical practice. The phase III trials really have to show the physicians how to use the drug, and our non-inferior trial design against the standard of care, 2 milligrams Eylea, will be able to do that. And finally, our molecule, vorolanib, patented, very important. It's patented out to 2037. New mechanisms of action, we work at the receptor level, and really, again, best-in-class delivery system with those four FDA-approved products. So vorolanib is a small molecule tyrosine kinase inhibitor. It's highly selective, it blocks all the VEGF receptors, and it blocks PDGF.
By blocking all the VEGF receptors, we should block all isoforms of VEGF, VEGF A, B, and C, and by blocking PDGF, theoretically, you'll have reduced fibrosis. We'd like to be able to show that in a pivotal trial, and that's one of the things we'll be looking for, is the ability to reduce fibrosis with our drug. We've demonstrated, in a preclinical model, neuroprotection. This is a preclinical rodent model of retinal detachment, and the rodents that got vorolanib had less damage to their outer retina and had better visual function, with vorolanib in this model. Again, this is something we'll be looking for in the phase III trial to show, perhaps, we hope, additional benefits to not just the anti-VEGF and longevity of our DURAVYU. And we do not inhibit Tie2.
I think at everybody's table, you've got a paper, reprint, that is just about to be published, if it hasn't already, where we looked at the several different TKIs that are being developed or haven't developed for the back of the eye, and at the doses that we're using, vorolanib does not block Tie2. Again, something that's important. Vorolanib, interestingly, was studied in both a phase I and a phase II trial orally. At the time, it was called X-82. The idea is that you could give an oral drug once a day and control wet macular degeneration.
What you're seeing here, these are OCT images from the phase I trial, where patients. They were treatment naive, they were newly diagnosed with wet AMD, and they received only oral vorolanib, and you can see there is a really terrific anatomic response and visual response as well from oral vorolanib. Now, the drug wasn't taken forward past phase II because it had systemic toxicity, but there was no ocular toxicity reported. About 150 patients were dosed with oral vorolanib, and that again adds to our safety database, which makes us even more confident of the safety around vorolanib. The other interesting thing about this trial is that many of the eyes in the trial had wet AMD in just one eye, and they were receiving an oral medication, so naturally, the other eye would have received some vorolanib.
During the length of the trial, the eyes that received vorolanib, there was only 1% that converted the fellow eye to wet AMD. The eyes that were under control, it was a 12% conversion rate, again, showing the ability of vorolanib to actually block conversion of wet AMD and showing really excellent biological activity. This is an image of one of the inserts. These inserts are cylinders. They look yellow because that's the color of vorolanib. They're heavier than water, which means they sink down to the bottom of the vitreous cavity, and they basically stay there. We can inject multiple inserts with a single injection. We can inject up to 3, and we did that in several of the phase II trials.
But as you'll see in the phase III trials, the number of inserts we're gonna be using is two inserts to get the dose that we need. Controlled release for at least six months. Again, in animals, it's about nine months. We think it's a little bit quicker in humans. You don't see any free-floating drug, done as a, again, routine in-office injection and shipped and stored at ambient temperature. Each of these inserts is actually just 1/5,000 of the vitreous cavity, so they take up very little space in the eye. I wanna go into a little detail about safety now. I mentioned the excellent safety track record that we have, and these list the four trials for which DURAVYU was delivered. And we've given it to 191 patients with a minimum of 1-month follow-up.
We have a little bit more than that in the Verona trial now, but the other trials, at least 10 months follow-up, and some trials longer than that, and there are no ocular systemic SAEs associated with our drug. So really, really good safety record, both orally and delivered intravitreally. I'm gonna now ask my colleague, Yasha Modi, to come up, and Yasha is going to review the results of top line of the phase II trial, the 8-month data. Yasha?
Yes. Thank you so much. Oh, go ahead.
... All right. Good morning, everyone. Thank you for being here. Just as a background, I am a pure clinician and a clinical researcher. So, if there's anything that I say that is sort of not clear, please feel free to interrupt me, and I'm happy to sort of answer any questions. You know, actually, to Jay's point, we do a ton of injections every single week in clinical practice. And where we are in the landscape of AMD is, we're blessed to have incredible performing anti-VEGF medications, what we call probably second, some call third generation anti-VEGF medications. And I've been treating patients for up to eight years now, and the stalwart patients who continue to show up always ask me two questions: Can we extend the interval, and can we potentially stop the treatment?
I think the latter question is pretty clear that we can't, but obviously, extension of the interval becomes important. When we think about where we are, when patients miss visits, that's when we lose vision. And Rishi Singh, at the Cleveland Clinic, had demonstrated in his patients that patients who went larger than—longer than five weeks lost vision, and some of those patients lost vision irrevocably. So certainly, there's a need to get consistent therapy in these patients, and in comes TKIs and the promise, potentially, of longer-acting medications. Now, these are really designed to get a much more durable effect, but not necessarily replace anti-VEGF medications. So the DAVIO 2 phase trial, clinical trial was randomized, it was double-masked, and aflibercept was the control arm. So there are three total arms.
You have DURAVYU 2 milligrams, that's basically two inserts given by one injection, DURAVYU 3 milligrams, three inserts given by one injection, versus aflibercept control. All of these patients were heavily pretreated. In the year prior to treatment, the average number of injections was about 10, and the average time of macular degeneration of conversion to exudative disease was over 2 years for these patients. So intensively treated patients throughout the clinical study, very different from our treatment-naïve clinical studies. At day 1, at randomization, they receive an aflibercept loading injection. At week 4, they receive another one, and then at week 8, they receive another one. So 3 loading doses, just to get all of these treatment, previously treated patients on the same page.
Thirty minutes later, the DURAVYU 2 milligram and 3 milligram inserts are implanted or inserted into the eye, and then every 8 weeks, they're given sham injections to maintain the masking of the phase II study. These patients are followed monthly, so if there is a need to re-treatment, they can get retreated every month, if need be. And so the blended primary endpoint was at week 28 and week 32, effectively six months at the insertion of the DURAVYU implant, per the FDA guidance. Now, remember, we're going to be talking about three things. We're going to be talking about vision, we're going to be talking about reduction of, supplemental therapy, and then we're going to be talking about anatomy. And when we think about these patients, these patients should have all theoretically plateaued.
They've all received their treatment, and what we really want is to demonstrate stable visual acuity, stable anatomy, and a reduction of supplemental therapy. So on the y-axis here, what I'm showing is change in ETDRS letters, change in visual acuity. And what we see is after the loading dose, which is sort of where they get the DURAVYU implants, at month 2, we see incredible stability of their visual acuity all the way out through month 8. And so you can see as they sort of fluctuate a little bit, but they're all within a couple of lines of a couple of letters of each other, indicating incredible stability. If I were to test probably anyone in the audience here on ETDRS charting, we're all going to be probably within a 2- or 3-letter variation of one another as we get tested out in the absence of pathology.
Now, when you think about reductions in clinical treatment burden, we can do this in one of two ways. You can look back and say, "Well, what was the sort of number of injections people were receiving before they ended up getting into the clinical trial?" And if you look at the mean number of injections six months prior to screening, on average, patients receive 5 injections. Now, if you look at the mean number of injections after they get the DURAVYU implants, either 2 milligrams or 3 milligrams, the number of supplemental therapies is less than 1. So you take that numerator on the top, divide that by the denominator, and you get the reduction in treatment burden of around 85%-89%. Now, you could say, "Well, maybe that's not fair.
Maybe you're looking at data before they enroll in a protocol-specified way, and you're looking at what clinicians did in practice rather than in a protocol-driven way." But you can also do this analysis using the control arm within the protocol. So now let's add in the aflibercept arm. So these patients have to get injections every eight weeks, and the mandate, the minimum number of injections, is going to be 3. What you see is that number is 3.28, meaning that patients are also rescued in the aflibercept arm, needing injections every month, potentially. And so the numbers of the DURAVYU implants are the same. So the reduction in the treatment burden within the clinical trial going out to 32 weeks is 78% in the 3 milligram arm and 83% in the 2 milligram arm.
I think this curve really shows it nicely, where after they get the DURAVYU implant, naturally, in a population of individuals, you're going to see that patients over time are going to need more supplemental therapy. But what's really remarkable is when you get out to month 8, 60% of these patients, 63% of these patients did not require any supplemental therapy. Now, that's incredible because we do not have any drugs on the market that will allow us to get 6 months out. And if you look at the aflibercept arm, notice they're getting injections. They're getting injections at month 4, month 6, and month 8, and 6% of those patients also needed rescue treatment.
So no matter which arm we're in, of course, naturally, the most intensive arm is the aflibercept arm, but all of these patients at some level will need rescue treatment. And I love looking at the swim lanes. The swim lanes, I think, kind of give you the most visually impressive way of looking at data in a phase II study. What you're seeing here on the left, all those black dots represent the number of injections that people are receiving before they're enrolled in the clinical study. You can see some are getting very intensive treatment, some are relatively sort of like almost treatment naive, only have received two or three injections, and then there is going to be the run-up. And so the blue dots represent the aflibercept loading doses, and the pink represents those who are receiving aflibercept and two milligrams of DURAVYU.
What's abundantly obvious is the reduction in the number of supplemental treatments. So now, I think as a clinician, I always like to look at very specific patients and say sort of what happened. So if you look at patients 32, 33, those patients received a ton of injections beforehand, and then after they get the DURAVYU implant, they really don't receive anything. But then you can take a look at the last patient. Look at the last swim lane, number 53. This is a patient who's received a ton of injections, but then still needs supplemental treatment every 8 weeks. Now, certainly, we don't understand why some people will require that treatment, but even then, they still receive. Patient 53 received less supplemental therapy after they received the DURAVYU 2 mg implant relative to beforehand.
This is the 3 milligram data, also looks very similar, a lot of injections beforehand and less injections subsequently after they get the DURAVYU implant. Now, let's talk about anatomy. Again, remember that concept, these patients are fully treated. Their anatomy should be remarkably stable throughout the window of this study, and at the time in which they get the DURAVYU implant, what you see, or insert, I should say, what you see is that the, CST, it starts to look like maybe it's starting to creep up, but then there's incredible stability all the way out through month 8. And if you look at the aflibercept arm, it's sort of, kind of moving like this. Again, the, the amount of fluctuation, you have to understand the Y-axis. It's less than 25 microns.
So when you think about the retreatment criteria, if you look at Yosemite and Rhine, or if you look at Tenaya and Lucerne, the studies that approved faricimab, if you look at PULSAR, the studies that approved 8-milligram Eylea, you had to be somewhere between 50, at the most conservative, to 75 microns of fluid fluctuation in order to get retreatment. So this demonstrates, within 25 microns, incredible stability across these arms. And I want to show you some cases. I don't know how many of you are accustomed to seeing OCTs, but this is the world that Carl and Jay, we live in. And when we look at OCTs, this is the qualitative way in which we determine retreatments. Now, this is a patient who's had a lot of injections before they get treatment.
They have no fluid at the time of their screening or the time in which they get their day 1 injection, but they have clearly what looks like... There's a separation between the RPE and Bruch's membrane, so that's a classic or a sort of a, what we call a type 1 neovascularization. And throughout the entirety of the study, after they get the DURAVYU implant, they do not require treatment. This is a different patient. They look nearly identical to one another, but this patient has persistent amounts of subretinal fluid, even after their loading aflibercept injections, and after the DURAVYU implant, they maintain that small, persistent amounts of subretinal fluid. Now, retinal physicians, through something called a fluid study, are learning to basically tolerate some small amounts of subretinal fluid.
What's incredible here is that the CST is not rising, and the vision is not falling. Here's a patient who did require retreatment. So here, this patient gets the DURAVYU implant, and then when we get out to week 16, you can see that the amount of fluid is drastically worse. That triggers a retreatment, and what we would normally expect is if there's no therapeutic effect of the drug, then that patient should be getting injections every 8 weeks, similar to that of the control arm, but ultimately, doesn't require injections out to week 32. So in summary, the phase II DAVIO trial hit its primary endpoint, which was non-inferior change in best-corrected visual acuity. It had a favorable safety profile, as Jay had mentioned. And when we think about what's most clinically relevant to our patients is the reduction in treatment burden.
You can look at the six months before relative to the window in the study, and you can also look at it intra-study, within the study, looking at the aflibercept control arm, and there's a drastic reduction in the number of treatment burden. And what's most impressive to me as a clinician is 63% of these patients went supplemental-free at six, at six months. So, before we move on, I want to talk a little bit about what would happen if you get rid of all of the supplemental therapy. So in other words, let's say you take all of the patients who never required aflibercept, because aflibercept, we already know, it's an excellent drug. It can prop up the results in terms of your visual acuity, in terms of your CSTs.
So let's take all of those patients out, and let's see what happens for those who never require supplemental therapy. So what we were looking at is change in ETDRS letters again, and we can see that the curves are essentially all overlapping with some various changes throughout the window. At the primary endpoint, there is less than a 1-letter difference, showing incredible visual acuity stability, as well as this is CST data. Essentially, what we see is incredible stability in the patients who received the DURAVYU. And of course, if you imagine aflibercept, remember, we're dosing them every 8 weeks. What you're starting to see is a little bit of sawtoothing, kind of at the subclinical level, probably not clinically meaningful to most retinal physicians, but certainly doesn't have that stability that we see in the DURAVYU arm.
So I want to turn this over back to Jay.
... Yasha, don't go for a sec, 'cause I want to ask you one question. That was great, but that sawtooth thing that we're seeing in the aflibercept arm-
Mm-hmm.
What does that mean to you about the cohort that we enrolled?
Yeah, I think it basically shows that there's incredible disease activity, right? Because if you imagine, like, let's go and say you're taking patients that are effectively quiescent. Maybe they're just getting treated for the sort of conservative nature of maintaining stability. Well, then you would see that their sort of CSTs would be identical. There should be no increase in fluid, and here what you're seeing is that in the time in which they're not getting an injection, they have an increase in fluid, then they get the injection, and then the CST declines. Just tells you about disease activity.
This was a group of patients that needed a lot of treatment.
You can certainly see that through that data.
Right.
Yeah.
Thank you.
Mm-hmm.
So Carl Regillo is now gonna come up and present for the first time the 12-month data from the DAVIO 2 trial.
Thank you. Thank you. Thank you. Good morning. It is a privilege to be here. Before I get started, I want to say a few words about Jay. Jay and I go way back. Jay was a retina fellow when I was a resident at Wills Eye Hospital, so he's a little older. But I'm gonna say I've looked up to Jay my entire career. Jay is very humble and will not tell you on the podium here that he's probably among the most respected, most accomplished retina specialists internationally. And we're very proud at Wills. We only regret we weren't able to keep him or get him back to Wills Eye Hospital, but equally proud of all the work he's doing now with EyePoint.
I also want to say, in preparation for this meeting, Jay and Ramiro said, "Hey, how about presenting the 12-month data?" And I said, "Well, that's a great privilege. Thank you. I'd love to." My first question is this: "How does it look?" Because, through my career, I've been asked to present first to podium before, and it's not always great data. In fact, I've presented my share of failed studies. Lamplizumab, probably the most notable, and most recently, KSI-301 phase III. So, and it's always hard to dance around poor data, but that's not the case here, I'm glad to say. So we'll dive right into it. You've seen this, of course. Yasha did a great job presenting to you, the 8-month data. Here is 4 more months.
12 months, so that represents 10 months after the last dosing or the only dose of DURAVYU and the last dose of aflibercept in the load. And so what you're seeing here is ongoing, excellent, in fact, identical BCVA in all three arms, as shown here, to within 1 letter at 12 months. Again, 10 months from the DURAVYU insert. So impressive. That's necessary. In fact, as you can see, ultimately, for phase III, we're using a non-inferiority study design, and this is what has to be shown. And exactly what you would expect, these patients started with relatively good vision, because they've been mostly previously treated here, right? And they end with good vision. I've spent my career talking about optimizing disease control and getting the best long-term vision outcomes in wet AMD.
This also is reminiscent of the superb visual outcomes in disease control that we saw with the port delivery system, sustained delivery of anti-VEGF at an adequate level to control disease across the board. But here, of course, we don't deal with a surgery or device. We're dealing with an office-based bioerodible insert. So very impressive. And also very impressive here is very clinically meaningful supplement- free rates that continue on. You saw the 8 months. I'm showing you 4 more months to month 12. We're seeing now, 10 months after DURAVYU, half of the patients going supplement- free. So we're really seeing durability that's quite impressive. We sort of think of it as 6 months, but really quite a bit longer. Also notice, as Yasha pointed out, that we have a very active group of wet AMD patients here. How can I say that?
Because when you look at all three arms could be supplemented, and that includes the standard of care every other month, aflibercept. So we're seeing 5 more aflibercept injections after the loading phase. Month 12, we're seeing 22% supplemental injection rate in the control arm. So every other month, dosing with aflibercept, which is considered sort of gold standard, standard of care, and that's every control group going forward in our and going back, I should say, in our recent pivotal studies, and that's with faricimab, that's with brolucizumab. We're still seeing lack of complete disease control with every other-month aflibercept in this patient population. So that's, I think, particularly impressive. And then, also a word about Jay. Jay is one of the world leader in OCT. In fact, him and the other OCT experts call OCT VEGF-O-meter, right? And, 'cause it really...
There's been studies that really well correlate disease control with VEGF suppression and what we're seeing in OCT, and that's what we're seeing here. As Yasha pointed out, ongoing sort of flatline here, and in fact, a little bit of a dose response here, too. The higher dose DURAVYU controlled disease as well as, in fact, identical to aflibercept, despite that little sawtooth, which continues on. Again, indicative of active disease in our patient population here, and even the low dose to within 10 microns, which is essentially equivalent. And all this with regards to disease control and good outcomes with an excellent safety profile. So ongoing good safety. So now, again, over the course of 12 months and the 4 additional months that I'm now presenting, no new SAEs or AEs of any significance. The safety profile looks the same.
There has yet to be an SAE attributable to DURAVYU, and now with a pretty good size phase II, and as Jay said, the totality of all the studies and data that you're seeing here. There's always the potential when we do an insert, because we see it with the Ozurdex, dexamethasone implant, potential for anterior segment migration, which may or may not be a problem. It is with the, with the dex implant, but, probably not here, but we're not seeing it at all in general here, so that's good. In particular, safety is paramount. As mentioned before, we don't sacrifice safety for durability. That's why brolucizumab was a failure. That drug was a better drug.
brolucizumab was a better anti-VEGF in terms of drying and a variety of measures and outcomes in the clinical studies, but it's not as safe because it led to cases of excessive inflammation, vasculitis, and vascular occlusions. We had that issue to some degree also, which has suppressed the use of SYFOVRE in practice, but here there have been no cases of retinal vasculitis or vascular occlusions to date with this drug. Then more so, especially in a small study, the impact could be great if there's high rates of discontinuation, which discontinuation rates in this study remain low all the way out through one year, and no discontinuations have occurred related to DURAVYU. So in summary, this has been an easy presentation because the data is strong. I didn't have to dance around anything uncomfortable here. 12-month DAVIO 2 data looks excellent.
Ongoing maintenance, excellent stability of visual acuity, very strong anatomical control, disease control as shown here, and we're seeing half of the patients going supplemental-free out to 12 months or 10 months after the DURAVYU injection in both doses, and safety remains excellent. Jay?
Thanks, Carl. I'm gonna, before you go down, I'm gonna ask you a variation, rather, of the same question I asked Yasha.
Sure.
When you look at this data and you look at the sawtoothing pattern, and you look at the number of rescues in the Eylea arm-
Mm-hmm.
What do you think about the severity of disease that we enrolled?
Well, actually, the sawtooth in the excursions of about 12-15 microns is actually identical to what we saw in DAVIO 1, 2, and all the phase III registration studies with the anti-VEGFs have been treatment-naive patient populations. So to me, it's reminiscent and reflects a similar patient population. There's always the concern, and it, whether it's port delivery, whether it's gene therapy, all these sort of maintenance phase approaches, making sure that we recruit patients that are the types of patients we would want to use this drug in clinical practice.
Mm-hmm. Great. Thank you. Excellent. Ramiro, come on up, and we're gonna now talk about our phase III program.
Thanks, Jay, and good morning, everybody. I just want to first start with saying how privileged I feel about joining EyePoint. It has been great first three months. So I'm gonna give you an overview of our phase III program, and I wanna emphasize that the objective of the phase III program is very clear: it should gain global regulatory approval, have a successful commercial launch, and make sure we get the patients, the drug to patient and physicians as soon as possible. Our phase III program was informed by multiple interactions with the FDA. We had a Type C meeting in 2022 to discuss key components of the pivotal study. We had a phase III...
the phase II results for DAVIO 2 in 2023, and as you know, recently we had the end-of-phase II meeting with the FDA, where we presented the results of our phase II study and the details of the phase III program. Our phase III trials, the LUGANO and LUCIA, are gonna be global, randomized, double-masked, aflibercept control studies that are gonna evaluate the DURAVYU when given every six months, achieving a similar visual outcomes to on-label aflibercept while reducing the treatment burden. These two studies are designed as non-inferiority trials. We will enroll approximately 400 patients per trial, and we are gonna have two treatment arms, DURAVYU 2.7 milligrams and aflibercept as the active control. The primary endpoint is the difference in mean change in BCVA from day one to the blended week 52 and 56 compared to Eylea.
Secondary endpoints are safety, reduction in treatment burden, proportion of eyes supplemental-free, and anatomical stability. The secondary endpoints are very important for clinicians and patients.... Here are the key elements for the phase III program. First, as Jay mentioned, this is going to be the only sustained-release wet AMD program that is going to evaluate re-injections for label purpose. We will enroll patients with active AMD, meaning that those patients would have fluid in the retina and vision loss because of wet AMD. These are going to be either previously treated patients or treatment-naive. Every single patient at the beginning of this study will receive 3 loading dose of aflibercept. We are using sham injections for masking purpose, and as I mentioned, the primary endpoint is going to be at month 12, which will serve as the basis for the NDA submission.
Both studies are going to last for 2 years, and that's for proper safety monitoring. EyePoint is on track to be the first sustained-release wet AMD program, with two pivotal trials that enable the NDA submission to the FDA. Here's just a schematic of the phase III program. Patients are going to be screened. If they're eligible, they come in day 1, and they get three loading dose, day 1, week 4, and week 8. At that point, they would have their disease under control. At week 8, after aflibercept, patients on DURAVYU get the DURAVYU injection, two inserts, and patients on aflibercept arm get a sham injection. DURAVYU is going to be given every 6 months with sham injections between, aflibercept every 2 months, and the primary endpoint measured at month 12. Throughout the study, investigators are going to assess if the patient need supplemental therapy with anti-VEGF.
Now, we feel it's very important and we're very optimistic about having a very broad patient population in our study. This enrich the trial to have more supplement-free eyes, which had better outcome in DAVIO 2, and I'll go into that in the next slide. It also ensures a broad label and global reimbursement. A broad patient population will speed enrollment, and I'm happy to share that we already have selected more than 80 sites to be part of our phase III studies. The data that is going to be generated by a broad patient population is going to be very helpful for physicians and patients so that they know how to use the drug in the real-world setting. Again, to remind yourself, we're going to have at the beginning of this study, three loading dose of aflibercept.
So once patient gets to review, they will have their disease under control. Now, why do we believe that treatment-naive patients are also ideal for our phase III program? This comes from our phase II data, the DAVIO 2, which is the largest wet AMD TKI to date. In that study, as shown by Dr. Modi and Dr. Regillo, those patients were patients tough to treat. They had on average, 10 injections before being enrolled into the study. And a typical naive patient, they get between 6 and 8 injections in the first few years, and a third of those patients get even less of those injections. Also, the phenomena of tough to treat was observed on the aflibercept arm, where approximately 25% of them needed rescue therapy, supplemental therapy, even getting aflibercept every two months. And as Dr.
Modi presented, supplement- free eyes in the DAVIO 2 were the ones that has the best visual outcomes, and patients on DURAVYU did numerically better than those on aflibercept arm. We also have data on what we call the pseudo-naive patients in the DAVIO 2 data. So those are patients that had a diagnosis of wet AMD less than 1 year and received 2 anti-VEGF or less injections. So those are the pseudo-naive patients, and those patients had fewer supplemental injections compared to the overall cohort. We believe that the inclusion of treatment-naive patients not only expands the potential population, but also increase the probability of success. Again, to summarize, the purpose of the phase III program is to ensure we have global regulatory approval. With that, I'll pass to Jay for other preparations for the phase III study.
Thanks, Romao. Again, just to again reiterate, back to the points about enrolling naive patients. The main issue, of course, is after 3 injections of aflibercept, when DURAVYU goes in, they're not naive anymore. It's very clear that the supplement-free eyes do the best, and so we want to get more patients into the pivotal trial who are likely to be supplement-free, which means the broadest population of wet AMD. I'm really excited about this other project that we've been doing, which is our manufacturing facility. We're planning for success, and in order to successfully commercialize this drug, we're going to need to make a lot of inserts.
Right now, we make the clinical inserts in our headquarters in Watertown, which is fine for the pivotal trials, but we need to increase the ability to make the inserts for commercial success. So this facility is being built to our specifications in Northbridge, Massachusetts, which is about 45 minutes west of Watertown. It's a greenfield build. The developer and the landlord are building it exactly to what we want, and the deal that we have with the landlord is we don't pay anything for the building until we take occupancy, which should be probably later this year. This will be built to both FDA and EMA standards, and it's about a 40,000 sq ft building. Just a quick word on the early pipeline now. EYP-2301, which is razuprotafib and Durasert E.
This is a Tie2 agonist. It actually works through blocking another receptor called VE-PTP, and when you block VE-PTP, you antagonize Tie2. I'm sorry, you agonize Tie2. That upregulates Ang-1, downregulates Ang-2, and leads to vascular stability. This drug, razuprotafib, was formerly known as AKB-9778, and you may be aware that it was tested as a subcutaneous injection in diabetic eye disease. As a solo therapy, it actually did pretty well, especially anatomically. As a combined therapy, it was modest visual improvement, but we believe the ability to sustain release with zero-order kinetics will improve the ability to get better visual outcomes and better durability than when delivered subcutaneously.
So for the next part, I'm gonna invite Carl and Yasha to come back up, and we're gonna have a little bit of a discussion about some of the topics we just covered. You both have really given us a nice background in your clinical practice, but Yasha, why don't we start with you and tell us how you treat wet AMD patients? How are you gonna treat them this afternoon when you get back to your office?
Yes, I think there's a number of different ways that we can treat them. There's something called, like, a mandated injection schedule, a treat and extend schedule, where we sort of treat them every time but extend the time between visits and then as-needed basis or PRN basis. So I basically do... You know, I don't think we all have one size fits all, but probably 90% of my patients are on treat and extends to try and sort of maximize the efficacy but also give them the most freedom away from our practice.
Carl, I know you're a treat and extend guy, too, right? You've written all the papers on it.
I've spent my career, and I'm so glad you said you do that.
Yeah.
I've spent my career validating the treat-and-extend approach as the best way to balance efficacy and burden. There's PRN, which, when you look at the CATT study, actually didn't measure up 'cause it's reactive. You wait till disease recurrence to inject. So if you were to follow a patient monthly with wet AMD and inject only when you saw signs of recurrent exudation, ultimately it nibbles away at the vision over time. So the notion of continuous VEGF blockade by determining a specific patient's disease-free or exudative-free interval is the best way to maintain vision, and it's now been validated, prospectively controlled, including against gold standard monthly ranibizumab. So that's why in the United States, Yasha and all of our colleagues pretty much do treat-and-extend across the board, and even worldwide.
I remember early on, when I was talking about this and publishing on results, our international colleagues were still doing a whole hodgepodge of different things, but now the vast majority of retina specialists all over the world, that's what they do. And we know exactly how long our drugs last, because when we do the treat-and-extend, you can then look at the distribution of intervals, how many patients get it every 4 weeks, 6 weeks, 10 weeks, 12 weeks. And in the first-generation drugs, on average, they last about 8 weeks in the maintenance phase. That's why aflibercept's dosed 8, every 8 weeks. But there's a range of 4-12 weeks. Very few can go more than 12 weeks.
With the second-generation anti-VEGFs, which we've started to incorporate quite a bit in practice, I have to say that by study design, it exaggerates the durability of those drugs. You might see presentations that say, "Oh, look, some of these drugs, Eylea HD, whatever, can go 16 weeks or 20 weeks." In practice, that won't happen. They're a little more durable for sure, but not to that degree.
Give us the range. Let's start with 2-milligram Eylea.
Mm-hmm.
How many patients would you say have to still be treated every 4-5 weeks on 2-milligram Eylea?
I can tell you because I did a prospective study-
Yes, you did.
to measure that. But it's about 25%-28% of patients were being dosed more frequently than every eight weeks.
Yeah. So do you find it coincidental that 22% of our eyes required rescue in the Eylea arm?
It's exactly what you would predict.
What did you predict from it?
Based on something I published, I don't know, now 6-8 years ago.
Yeah. How many in your practice or in your studies went three months and did well at a three-month interval with 2-milligram Eylea?
37%.
Let's be exact. So one of the points we made earlier in the discussion is we had very few patients in DAVIO 2 who came into the study being dosed every three months. Makes sense. If you're already being dosed every three months, and your doctor says, "Hey, you wanna be in a study where you have to come in monthly?" Most patients are gonna say no.
No.
We got a few of them, and those patients actually did really, really well. No surprise, supplement-free. And so what we wanna do, again, is get more of those patients into the pivotal trial to make our results even better than what we got in the phase II. So Yasha, let's move on to the new drugs.
Yeah.
Eylea and Vabysmo. Incremental improvement, game changer? How, how do you feel about them, and what's the evidence?
Yeah, I think. So I use a fair amount of faricimab. I use less aflibercept 8 milligram. With faricimab, I think there certainly is an efficacy benefit over that of aflibercept. And then when you look at the duration of the drug, I think, you know, what's really important to realize when you're looking at TENAYA-LUCERNE or YOSEMITE and RHINE, those were effectively treatment naive. In TENAYA-LUCERNE, they were completely treatment naive. In YOSEMITE and RHINE, there had to be a 3-month washout of the patients that were previously treated, so effectively, they're all treatment naive. And so that's how you get these results of patients going out to 16 weeks. Now, you know, the Retina Consultants of America, it's a large private equity-owned practice, something like 250 retina specialists, and actually, I think it was Arshad?
They presented essentially all of their faricimab switch patients or those who were getting faricimab by treatment naive. 90% of the patients ultimately ended up being switched rather than being treatment naive. And when you look at the incremental duration in neovascular AMD, how much extra time do you get between injections? It was, I think, about, like, just over 8 days. So you know, that number is really important because in clinical practice, I was always sort of saying, like: "Oh, I maybe we'll switch you over to faricimab. We'll get you out another couple weeks." And the reality is, you don't even get out a couple of weeks on average. It's. And so that paper is actually, I believe it's a presentation. It's not published data yet, but because it's a presentation, it's publicly available.
I gonna state the obvious, I hope you both agree, that there's still room for additional ability of sustained-release medications out there to lengthen treatment intervals.
Yeah.
So-
What's amazing is that this is a previously treated population of individuals. A lot of the recent FDA approvals for what we call third-generation anti-VEGFs were effectively treatment naive. I love the fact that this study, the DAVIO 2 study, is taking on some of our most difficult to treat patients.
Right. And so, Carl, I'll get right to that question for you. We're jumping around a little bit, but do you have a problem enrolling a naive patient, given the data that you just saw? How are we gonna do with naive patients in a pivotal trial?
No, no, actually, I think this is a very easy study to enroll, 'cause patients are highly motivated to wanna... You know, we say injections are well-tolerated, and they are. Very low risk, very well-tolerated, but no one likes them. So in my experience with the port delivery system, for example, and that's even with going to the OR and with the device in their eye, it was pretty easy to recruit because patients would rather come in monthly and not have to get an injection, and be monitored, because they like this notion of sustained delivery and disease control, of a, of six months or so. And so although that was previously treated, it was recently diagnosed, so it was like a, it was like a treatment-naive patient population.
So in other words, I had a patient with new-onset wet AMD. I'd say, "Hey, we're gonna start regular treatment, and after 2 injections, we have the option to go into this port delivery system trial." And it's gonna be very similar here.
Mm.
Patient presents to me. I'm gonna say: Hey, we're gonna get you started on standard of care, standard injections, well-proven, well-tolerated, and then you have the option to continue on in that way, get good outcome, or the option to get a new product that's had a tremendous safety profile and shown very solid data that I'm comfortable and confident in.
Does the idea of induction therapy and maintenance therapy, that's essentially what we're trying to do here.
Mm.
Is that, Yasha, is that something that makes sense to you?
Absolutely.
Yeah.
You know, but it's important to realize, you know, for somebody who treats uveitis, when you're talking about maintenance therapy for inflammatory disease, you're talking about a years-long process, and the analogy actually holds true to that of AMD as well. This is a years-long or decades-long disease process. Once they convert to exudative disease, we sort of think of it as a forever treatment. And so the idea of basically giving them induction therapy with sort of a hard-hitting aflibercept injections, faricimab injections, whatever it is, and then maintaining them to get sort of a more durable anatomy, makes a lot of sense. So I sort of see this in clinical practice as sort of a combination approach.
Mm-hmm.
That this certainly won't get rid of anti-VEGF injections as we know it, but I think will be a really excellent supplement for the overwhelming majority of our patients.
That leads really into my next question about supplements. Does the idea of supplementing maybe a third of the eyes that are being treated with DURAVYU, does that bother you?
No, no, not at all.
Yeah.
Um-
In fact, I don't understand why you-
It's still the same thing. You're coming to the office, you're looking at disease control, and the goal is to keep those vision gains that you got when you first did the induction phase. And to do another injection or two for the patient, it's all, it's all one, same thing. Gonna get prepped in the same way, they're gonna get an injection. And to get less injections is highly desirable to maintain the same disease control.
... And Yasha, you showed patient 53 from the 2 milligram arm, which was the patient that arguably did the worst with three supplements, the only one that got three. Yet, if you look at the treatment burden, it was still reduced. And so if that, in the real world, that patient who went from, you know, 10 injections in the prior year, they would have 6 + 2, 8 injections. If that data holds with DURAVYU, they're happy, doctor's happy, everybody's happy.
Yeah, I want to add one more thing. You know, we sometimes dwell a lot on this supplemental free to be injection free, but obviously, you're still going to get an injection at 6 months or 8 months, and in practice, with a product like this, there's some patients that are going to get it every 8, 12 months or less-
Mm.
-which is great. Patients will love that. But basically, I've been asked, what's more important, injection-free or reduction in treatment burden? And I say, "Yes, they're both important." Like you said, patient 53 would love the idea of getting 50% less injections, instead of every visit, every other visit or something like that.
Yeah.
It's still of value to that patient.
Can I ask you, Carl, what, what do you think the role of home OCT is going to be in the future? And then ask you both, is that going to impact some of these longer-acting therapies?
I think it's going to be a useful technology. I don't think it's going to be necessarily widely adopted. I think it can be a little cumbersome, but I like it, and I like it, especially for a sustained delivery platform, whatever that may be. A TKI here, gene therapy there, anything where it may be a little less predictable when a patient's going to recur.
Mm-hmm.
You could. What it will help to do is minimize the burden of coming to the office, potentially. But I've heard a lot of colleagues, and I, too, am a little reluctant. It's a lot more work, and these dashboards I've seen are very cumbersome and such, and it's sort of like taking the blood pressure of your hypertensive patient every day. It's like a lot of data that may be overkill.
Yeah.
But I do think it's going to play a role. I don't think it's going to get widespread adoption, and it's not necessary to adopt this product or a product like this in the field to have home OCT. We can do without it for sure.
Yasha, any differing opinions?
I have a slightly different opinion on this. I-
Really?
You know, so one full disclosure, I did get to play around with the home OCT device, which I think was surprisingly cool. I think it's a new technology where clinicians don't know how to use the data right now.
Yeah.
And I think you're absolutely right. It's sort of like, think about the original iPhone. It was amazing, but compared to an iPhone 15, they're two totally separate levels of technological products. And so I think it... Yes, it will take a lot of time to slowly adopt it. Yes, we will have to learn how to use it. You know, the clinical science is there, the regulatory pathway is there. It's FDA approved now. They still need an economic model to make it worthwhile. But if they succeed in that venture, I think that when you start thinking about these really long-acting drugs, I think it plays a really important role, exactly to what you said-
Yeah
... when you're thinking about going out six months without seeing them. 'Cause ultimately, the panacea is not only just going out six months without an injection, but maybe going out six months and never seeing your retina doctor, right? So I think, and how do you do that if you have these patients who are recurring? I think we need some sort of imaging technology to help us get there.
Great. Carl, you've obviously done a lot of clinical trials and pivotal trials. You just saw our trial design for phase III non-inferiority. What's your impression?
It's the exact type of study we'd want to see and do in practice and in a clinical trial as a clinical investigator. It's pretty standard. It's the way we've done all our phase III programs is non-inferiority, comparing to standard of care. All patients get good treatment that's gonna have a good outcome. So, I think there's really no other way to do it.
Any comment again on the ability to rescue in the Eylea arm? It's a bit of a unique aspect, and, one of the things, again, when we, you know, eventually submit the data, the, the supplemental rate that DURAVYU shows is not just going to be looked in isolation, it'll be looked against the Eylea arm. And so that, given the patient population that we talked about, over a year, think we'll get 22% supplemented in the Eylea arm in that patient population again?
Yeah.
Jascha?
Yeah, I think so. What I love about the study design is it's safe. It's maximally safe for all patients in the study.
Mm.
As clinicians, it's really easy for us to enroll these patients-
Yeah
... because there's so many outlets to maintain their safety and maintain excellent vision. Through the non-inferiority study, you're de facto showing some level of value through a longer duration and less supplements, supplemental injections.
Yasha, in a naive patient, if you give them... First of all, do you load everybody three times? Is that your standard?
I actually don't. I come from the camp of Phil Rosenfeld from the PRONTO study, and that was a... You know, I'm a descendant of the Bascom Palmer sort of mentality-
Mm-hmm
... where it's probably not required. But the reality is, essentially, I treat them until there's the absence of fluid. So for patients with really active disease, they effectively get loaded, and maybe it's 6 loading injections or 8 loading injections, and for those with less disease activity, maybe they get 1 or 2 injections before they extend to longer intervals.
Carl, what do you do?
... Yeah, the same. I, I treat to dry monthly with whatever agent it is. That's the way, pretty standard. The CATT study also just had one dose, and didn't have a set three minimum loading. The three minimum loading is just because the curves look like this. After three months, it's on average dry. And the fact is three injections will get well over 75% of the patients dry or effectively dry or under control. And that's where it comes from. It doesn't mean every individual patient needs three. One patient may need only one, as you indicated, and some may need four. It's pretty rare, though, to need more than four or five monthly injections to get the macular dry in wet AMD. You see that in DME, where you may need more-
Yeah
... monthly, intensive, longer induction.
And the one thing I'd like to point out is even in the rare patient who may still have a little bit of fluid after 3, DURAVYU doesn't have to do better than Eylea, we just have to tie them. And so if 3 shots of Eylea didn't get rid of the fluid, and the Eylea arm goes into every other month, and they'll have persistent fluid in the Eylea arm, too. And the case that you showed, Yasha-
Yeah
... where there was even previously treated after a load, there was still a little bit of fluid. That's a case that illustrates, we actually in some ways did better because there were visits where there was no fluid in that eye.
Yeah.
So, let's go to the future and say we've got an FDA-approved product with a label for every six months, and let's just say we replicate the data we did in DAVIO 2. Yasha, how are you gonna use it in practice?
Yeah, I think so. For patients who want a longer duration of treatment, who are essentially getting the standard of care of, let's say, faricimab or 8 milligram aflibercept, and then are stuck, I think this is a really excellent supplemental medication. I sort of see this initially as a supplemental medication to try and get them longer durations of intervals, and that's also where I think, you know, we're, as a retina practice and as a society, will have to learn, how do we follow these patients?
Mm-hmm.
Do we continue to see them and maybe just avoid their treat-and-extend? Do we use home technologies to help us? I love where this is going. It kind of keeps us really creative, and we have to be constantly evolving to think about how to maximize, you know, outcomes as well as decrease the number, you know, treatment visits for patients.
Carl, how would you do it?
Exactly as the phase III proposed study design. Start the patient on monthly injections, and then after the macula's dry, if that's two, three, four treatments, tell them about this as an option. Either continue to do an anti-VEGF biologic or transition to a longer, more durable approach. And I could introduce... I don't have to introduce it at month three, as in the study. I can introduce it as soon as the macula's dry and at any point thereafter. So it could be a year or two into therapy, and we have this huge patient population out there. 98% of my wet AMD patients, of course, are previously treated.
Right.
Any of those patients, this is potentially on the table as an option for them.
So-
Even if, like you said, they may not always have to be a frequent flyer-
Right
... to consider this. It could take a 3-monther and extend them to a 6-, 9-month.
Well, and again, the example, Yasha, you gave of how we're doing with Vabysmo. For eight days, it's, you know, been a tremendously accepted new product to get us basically probably a week longer.
Yeah.
So, but yeah. So let's go to treatment-naïve. Would you use it in only patients who are 8-weekers or less or 9-weekers? Or, you know, if you had somebody who's every 3 months, would you offer it?
I think the natural tendency is to, when we first have it in our hands, to first offer it to the more frequent flyers.
Mm-hmm.
They're gonna be most motivated to make a change or to want to adopt something new and different. But that doesn't mean the 10-weeker, 12-weeker, they should hear about it as an option, too. And I think ultimately, when you get comfortable with the product, and it's been on the market and such, you'll expand the patient population you'll treat. So I think really, any of these patients potentially could benefit from that transition of trying the product.
Yasha, let's just suppose we are anti-fibrotic and neuroprotective.
Mm-hmm.
Maybe we're not even that, but let's suppose our supplementation, non-supplemented eyes, look like what you just went over, maybe a half a letter, maybe even a letter better than Eylea.
Yeah.
So maybe not statistically superior, but numerically superior. Do you think that would resonate?
I absolutely do. When we think about who loses vision in exudative AMD, patients who are consistently getting treatment, those are patients who develop subretinal fibrosis and those patients who develop geographic atrophy. So those are the patients who fall off the curves in the setting of showing up regularly and getting the best of care. So this is not a disease where we can stabilize their vision in the current era. There are always gonna be people who will lose vision. So if you can demonstrate a decrease, sort of incidence of fibrosis, that's gonna be huge.
Terrific. Thank you very much, both of you.
Pleasure.
Thanks.
Excellent. Thanks.
Thanks, Yasha.... Oh, yeah, we are gonna. I'm sorry. We're gonna keep you up for the question and answer.
Oh.
It's not, it's not just gonna be me. I'm gonna open it up to you guys as well. So sorry to make you walk up and down.
I can see it closer.
Hmm?
I can see it.
Okay.
Let's see, let's see.
We'll start on the right side here.
Thanks. Sure, yeah. This is Eddie Hickman from Guggenheim. Thanks for all the color on the phase 3 design. Do you have a goal for the percentage of naive versus previously treated patients you're looking to enroll, or the number of previous treatments? Like you said, it was 10 in DAVIO 2. Do you have sort of a goal for what you'd want to see as baseline for these patients?
Not at present. It's something we will be monitoring, and one or the other may get capped at some point, but we'll see how enrollment goes. I don't think that there's gonna be any numbers of... for previously treated. Again, looking at the data, the eyes that came into the study previously treated but were already treatment extended out, those are the eyes that we really would like to try to enroll, but we're not gonna be able to do that a priori. That's not gonna be something that we're gonna, you know, outside of the study, be able to determine.
Got it, and then after that initial loading dose, is there any sort of control for excluding patients that don't have any response to those?
No.
three loading doses?
No. There's... Again, I touched on that. There's no reason to. So if we have a non-responder to Eylea, the DURAVYU arm doesn't have to show a better response. It just has to maintain them. And in a smaller trial, where you might get one or two bad patients into one of your treatment arms, and that can skew the result, in a larger trial with two arms and 200 patients in each arm, we believe that randomization would take care of that. And plus, I can ask my panelists here, you know, how many real non-responders are out there? In other words, naive patient, give them three shots, give them four shots, give them five shots, and they still have a lot of fluid. What's the percentage in your, Carl?
It's actually super rare. I'm not even sure you can say there's a, quote, "non-responder." There's a small segment, I'm gonna say 5%, that are suboptimal responders, where you see some improvement, but there's some persistent fluid that you think is excessive that you would like to see get better. But even then, a lot of these poor non-responder scenarios, I think, are often patients that we have advanced disease at the time of diagnosis-
Mm-hmm.
have some fibrosis, and often there's persistent fluid or thickening or cystic change over that fibrosis that you may not get dry. And, but nonetheless, they all seem to derive at least some benefit, because even if they don't improve, they don't worsen-
Yeah.
In the vast majority of cases. Occasionally, you get some breakthrough hemorrhage that sets the patient back, but that's really rare. And like you said, with randomization, it's gonna occur occasionally, and with the big numbers, it shouldn't impact the data.
And once again, the point is we don't have to do better.
Right.
We just need to tie them. Yasha, any other thoughts there about non-response? Completely agree. Yeah. Yeah. Great.
Yeah, keep in mind, a lot of frequent flyers are these patients. I said 25% are on aflibercept every four, five, six weeks. Many of them are actually good responders, just need drug frequently and can't extend them or else significant fluid comes back. So it's good disease control, but it doesn't last very long. And the durability of any product, any anti-VEGF in the eye is partly related to maybe disease activity and VEGF levels, but also on how fast the patient clears the drug. We know, for example, in an eye that's had a vitrectomy, the vitreous gel acts like a depot. When we do a vitrectomy, all these drugs, all the biologics that we inject, last a lot less. The durability goes way down.
So, a more liquefied vitreous in one patient could account for why the drugs don't last as long. And the nice thing about zero-order kinetics and sustained release technology is that-
It doesn't matter.
It doesn't matter anymore.
Right.
Great. Yeah, Tyler Van Buren, TD Cowen. Thanks very much for the presentation. I thought the 12-month data was, was indeed pretty exciting. Regarding the phase III LUGANO and LUCIA trial designs, the inclusion of naive patients is interesting. It makes a lot of sense from a commercial standpoint. On one of the slides, I think, you guys mentioned that DURAVYU performed numerically better on vision than aflibercept in supplement-free or in the pseudo-naive patients, in DAVIO 2. So is there a hypothesis as to why that occurred as we think about the phase III? And if you had to estimate, also, again, some client questions on just how the BCVA and CST baseline criteria might differ given the inclusion of those patients.
First of all, if you look at wet AMD as a continuum, there's easy to treat and hard to treat. In DAVIO 2, we were way over here in the hard to treats. What became clear as we went through the data is that the supplement-free eyes did best, and the prediction about supplement-free, it wasn't how long they had the disease at all. It was the eyes that seemed to be less VEGF needy were more likely to be supplement-free. And in fact, those pseudo-naive eyes, we did enroll some patients who only had the disease for three months and only got two shots. And from a supplement perspective, in the high dose, 87% were supplement-free.
That's the kind of result, especially if we wanna see if we're actually numerically superior to Eylea, that's the type of result we'd be looking for. Now, back to how the naive patients are gonna do. We already heard. You load them. First of all, they're not naive anymore after 3, and once you load them, most of them are dry, and even the ones who may have persistent fluid, we can do pretty well with them. There was a patient, in fact, you can go back through the old decks from the phase I trial, that had been previously treated, had got an Eylea, and still had about 80 microns of subretinal fluid. Never went away, never got supplemented, and DURAVYU was able to keep them stable at 80 microns through 8 months.
So that's the kind of eye where you might say: "Well, you didn't dry him out." But my response is: "Well, neither did Eylea." And we don't have to dry out everybody because all we need to do is keep their vision stable.
Okay. And just a follow-up. As we think about probability of success for the Phase 3, is the rescue criteria the same as DAVIO 2?
The rescue criteria, the number one rescue criteria that's important, was a 5-letter loss of BCVA in the study with 75 microns of fluid, and that one it will be the same. The other rescue criteria, and Ramiro's done a pretty deep analysis on them. Some of the rescues, frankly, didn't meet any criteria, and we're gonna try to really rein that in if we can. We want to... You know, eyes that need to be rescued are gonna get rescued. That's gonna be a mandate. But the eyes that don't meet criteria, we're gonna really see if we can have medical monitors discuss it with the sites. And some of the rescue criteria that we used actually didn't result in any improvement in the vision, and that's the purpose of rescue.
Ramiro, I don't know if you wanna go into any more-
Yeah. I think when we evaluated data in detail, we saw that, there were actually some supplemental criteria that some supplemental injections that didn't meet the criteria and didn't bring any outcomes to that patient. So we discussed with some of the investigators and tried to understand the reasons behind it. Then on the phase III study, what we wanna make sure is that supplemental injections are given for patients that meet the criteria so that we don't have unnecessary supplemental injections.
Thanks. This is, Colleen Kusy with Baird. Thanks for taking our questions for, for the presentation today. Can you talk about the decision to go with just one dose in the phase III and what you think some of the benefits of that are? And then, with the inclusion of the naive patients in the phase III, would you expect the label to include naive patients, or to your point on those naive patients will be previously treated when they get the drug? Would you not expect naive patients?
Oh, they will be enrolled as naive, and we would anticipate that it would be mainly, you know, naive patients or previously treated as maintenance. The one-dose route actually in some ways was easy. You know, we talked earlier about using two doses. The masking that we are proposing will work with one dose, and so it's not a masking issue. And by looking at the results, while there was no clear dose response, I think Carl referred to the OCT data, and as you look deeper into it, it does appear anatomically, consistently, the higher dose worked better. And some other statistical analysis that Ramiro's group does, again, points to the higher dose performing a little bit better.
Doesn't mean the lower dose wouldn't be non-inferior, but now we can actually get the end of the study, the power of the study even higher by just having one treatment arm. And that's really the goal, is that the four, approximately 400 patients, we're increasing the power by not having 75 or 100 in the lower dose, 'cause we don't need to.
Hi, thanks for taking my questions. Oh!
Sorry.
This is, Jennifer from Cantor Fitzgerald. I mean, I was especially encouraged by the 12-month BCVA curves, especially taking into account the number of rescues, in the Eylea arm. I'm getting a couple of questions, just thinking about the differences in some of the design aspects of the pivotal trials. Can you talk about maybe what the screening conditions would be for treatment-naive patients after the three loading doses? And how do you expect that to impact the non-inferiority margin, and expected standard deviation? Maybe I'll start there.
Yeah. So the screening occurs prior to the load. Patients get randomized at day one, and so there's no exclusion after the load. Everybody's in, provided there's not a problem, and they have to be removed. So there's the... There'll be screening, you know, kind of the standard screening stuff that we used in DAVIO 2, to screen out large lesions or hemorrhagic lesions or fibrotic lesions. But after day one, they're randomized day one, and they're in.
Can I ask then, in this treatment-naive patients, the inclusion criteria to get them into the trial, are there any differences in terms of OCT or baselines, that might affect standard deviation compared to some of the other treatment-naive trials we've seen?
There may be, I would answer. I mean, I'm not quite sure that the standard deviation would likely, with inclusion of naive patients, be a little bit higher. We would anticipate that. Is that the question?
Yes. I guess it would be the average between previously treated and treatment-naive patients, but also within the treatment-naive patients, is there a way to screen for them before... There isn't a screening period, but is there a way to selectively-
The answer is... I see what you mean. The answer is yes. So there are studies that have looked at what are the parameters of a CNV that suggests they're gonna need a lot of therapy. And we'll be using some of that data to, at the beginning, screen out those patients.
Okay, um-
But that's, again, that's no different than what we did in DAVIO 2 to a degree, and what every other study's done. You know, there's visual acuity range. It's not every visual acuity. Fibrosis gets excluded, large hemorrhages get excluded.
Okay, and my last question is, someone's asking, in terms of, the regulatory back and forth, I just wanna clarify, what's been signed off on, and are there any aspects that you're still waiting on or, anything there?
No, we're good. We're waiting for nothing. We're full speed ahead. The protocol that you just saw is getting submitted to the IRBs, and this is our protocol. So, we're aligned with the FDA, and we're not waiting for anything.
Great. Thanks. Congrats, guys.
Hi, this is Caroline Palomeque on for Tess Romero at JP Morgan. Thanks for taking our questions. So were there any common characteristics across the 50% of patients who were anti-VEGF supplement-free at 12 months? And then I just have a follow-up.
Yeah. So that, you know, this data is really fresh. That analysis is not complete yet. Ramira, you may want to comment on that. But, we will be presenting the data at various, places, you know, over the next several months, and we should be able to have that data, by the fall, when we are presenting at Retina Society, and Carl's presenting at the AAO.
Okay, great. And then, can you just outline your powering assumptions for the phase IIIs?
We're really not making that public. Our discussions with the FDA, based on what other companies are saying, you know, we've been very clear, and they've been very clear with their responses, and so we're comfortable with the powering assumptions, using the 400 patients and knowing that we're using a mix of naive and previously treated. But we're actually not, you know, for proprietary reasons, talking about exactly what they are.
Okay, great. Thank you so much.
Great. Hey, I'm Graig Suvannavejh at Mizuho. Thanks for doing this event, and, thanks for taking my questions. I was curious, now that you've shared with us the plans for the pivotal, phase II trial designs, will you be in a position to comment on when you expect to kick off, LUGANO, you know, in terms of more specific timing, just more, granular timelines around, like, enrollment times and, and maybe, projecting on-
Yeah, we'll have that in the future. I think, when we get first patient into the study, I think that will all kind of lay out pretty nicely. We're still guiding to, second half of this year, and we'll be honing in on that soon. But as of today, second half of this year, we're on target.
Great, thanks. I just wanted to follow up on some comments around use of sham, and in the context of FDA draft guidance and whether there was a consideration of other potential mechanisms and also, did you consider perhaps an SPA, as perhaps a competitor has? Thanks.
Use of sham is interesting. You know, Ramiro outlined all the interactions we've had with the FDA, and at no point did they ever say to us, "We don't like the use of sham the way you have it designed." The draft guidelines, which I remind everybody, are draft guidelines for public commentary. They're not things that have to be adhered to at this point, although our study adheres to every single one when you read them. There's nothing in there about masking. This well-designed trial, two of them, that's what you mean.
So you're not thinking about an SPA at all?
No. There's no reason to think about an SPA because we're not a special protocol. We are a vanilla, non-inferiority trial that's been run five times successfully. In fact, in some ways, we're more vanilla than faricimab in high-dose Eylea because they were varying their treatment intervals. We're not doing that. We're in every six – we're gonna be an every six-month drug. There's no reason to get an SPA. If at some point an advantage pops up, we might consider it, but as of now, we're not getting an SPA. We don't need an SPA. I think we have time for one more because I promised I'd get you out of here on time.
Yale Jen Laidlaw & Company. Thanks for the great presentations. Just two questions here. The first one is, in terms of the naive versus treatment-experienced patients, what if the trial doesn't balance the two groups in into two arms? What might be the possible sort of shortcoming or shortfall, or was there any impact at all?
Yes. So if they're not balanced in the two arms, we wouldn't anticipate that these two are gonna act any differently. Again, we would expect the naive population to actually do better than the population that we enrolled in DAVIO 2, for the reasons that we've already given. It's a broader expanse of the population. More of those eyes are not gonna be needy. They're not gonna be eyes that need 10 shots a year. So we wouldn't expect that there would be a big difference based on what we're seeing in DAVIO 2 with the way our drug performed in the phase II.
If they are moved more into the control arm, that would that be a little bit issues there?
It shouldn't be. They're randomized.
Okay, and just a follow-up here that, just for the doctors here. In terms of if the drug get approved over time, would you consider patients still visiting you every year, you know, routinely, but their visit will be, it will feel that or experience whether they need another injection or it could be without for that particular visit? Would that be a scenario you envision over time if this drug gets approved?
Yeah, I think it's gonna benefit patients in two ways. Definitely decrease treatment burden, and could also decrease ultimately as we get comfortable, especially with a given patient, of the durability of the product and the performance for a given patient, even decrease their office visit burden, too. With or without, as we talked about, the OCT, home OCT technology. Part of the reason why we see patients somewhat frequently in general, that we don't extend much in practice beyond three months, even with second-generation drugs, is because we're also monitoring the fellow eye and such, and so some of that will still be at play here.
Thanks.
Great. I just want to say one thing about the... For any of you who've ever been to a, you know, get a standard eye exam, essentially, it's you get your vision checked, you oftentimes will get your pressure checked, they'll dilate your eyes. You'll then wait a little bit of time, you'll get your imaging, you'll then go see somebody who'll clinically examine you, and that's about sort of the whole process is somewhere around 2-3 hours from when you're in the door to out the door, which maybe you're less.
Hopefully not like that.
Yeah, NYU is a little slower. But I think what, you know, we're gonna have to do is sort of recalibrate how we do these visits, 'cause I think to your point, are you just going to be-- are you still gonna have to see them the same number of times, right? Because that's relevant to patients. And I think the answer is we're gonna have to be creative. And I think there's one paper by Phil Rosenfeld, who essentially he sees like 100 people, all AMD, at every clinic day that he's at Bascom Palmer. And so he essentially does vision and OCT, then he got rid of vision and just uses OCT and injection.
So he's creating a streamlined process to get people out the door in 30 minutes, and I can very easily conceive of a strategy where we at NYU would maybe just have them come in for OCT visits, walk in and out on their way to work, no dilation, and then we can make sort of real-time decisions on whether or not they need treatment. So we will have to get creative on this.
How about an OCT kiosk on every corner?
Drive-up window. Just drive-up window.
Basically, yeah, we just sort of build the OCT visit, and they, I think, you know, when you start talking about longer-acting drugs, the whole goal is to not only decrease the number of injections, but decrease the, the time that they spend with us.
Right. So on this slide, you have a listing of upcoming presentations of the DAVIO 2 data and further discussion about the phase III program, and we've got two publications. Links are right there, and you've got one of the copies on your table. So again, to close, we believe we have the best sustained release program out there. We've got excellent safety through both the oral and the intravitreal routes. We've got a clear non-inferiority pathway that's aligned with the FDA. Robust data set from the phase II that now out to 12 months really continues to look excellent, with essentially no change in vision against the Eylea control, despite 22% of the Eylea control getting extra shots. We've got a phase III trial design that includes redosing.
We're the only ones gonna be looking at redosing, which is really important for patients and practitioners. It does align with the FDA and also aligns with clinical use. And finally, our molecule is patented, and we have a best-in-class delivery system. Thank you very much, and thanks to our panelists and our KOLs for coming. Really appreciate your attention.