Good morning, everyone. I'm Lisa Walter, biotech analyst here at RBC Capital Markets. Thanks for joining us at RBC's Ophthalmology Conference. This session, we have Jay Duker, Managing Director and Chief Executive Officer, and George Elston, EVP, and Chief Financial Officer from EyePoint. Jay, George, thanks so much for joining us today. How are you both doing?
I'm doing great, Lisa. Thanks for having us.
Yeah, things couldn't be better. Looking forward to the call.
Glad to hear. It's a pleasure to host you this morning. Well, team, maybe to kick things off, could you give us a big picture overview of the company and give us an idea of where things stand with the lead program, DURAVYU, for-
Sure.
retinal diseases?
Happy to do so. Lisa, big picture, things could not be going better right now. As you mentioned, our lead asset is called DURAVYU. It's a small molecule tyrosine kinase inhibitor called vorolanib, which is in our Durasert E formulation. DURAVYU is currently being tested in four ongoing phase III trials. Two in wet age-related macular degeneration and two in diabetic macular edema. The wet AMD trials are called LUGANO and LUCIA, and the DME trials are called COMO and CAPRI. We are highly confident in the results of these trials at this point for a lot of reasons, but I think most importantly, based on our robust phase II results.
Just to review for a moment, our phase II wet AMD trial, which was called DAVIO 2, enrolled about 160 patients, all previously treated wet AMD patients, and they were randomized to either on-label control, which was EYLEA, or one of two doses of DURAVYU. The results were great. There was no significant difference in the final change in visual acuity between the DURAVYU doses and EYLEA, and therefore, there was a non-inferior result that was achieved. Non-inferiority change in visual acuity is the primary endpoint for our phase III trials as well. Beyond that, we really had terrific safety.
In the phase I trial and the three phase II trials that we've completed, we've dosed over 190 patients with DURAVYU, and we have no safety signals and no ocular or systemic SAEs that are attributable to our drug. The safety really looks quite clean so far. The efficacy results beyond just non-inferiority, the eyes in the trial at primary endpoint gained about a letter, which is to be expected in a previously treated group. If you break it down and look at the eyes that were not supplemented, in other words, they made it to the primary endpoint with DURAVYU 1 dose alone or EYLEA on label. The DURAVYU doses, both numerically actually did better than on-label EYLEA.
An average of 2.1 letter improvement with DURAVYU alone versus 1.7 letters for the control arm. It actually showed that when our drug worked by itself in those eyes, those eyes did really well. There was a significant reduction in treatment burden. The way it was measured in that trial was about 80%, and about two-thirds of the eyes made it up to 6 months after DURAVYU went in without requiring any kind of supplement. The other thing that was important to note is the anatomic control. We measure anatomy in the back of the eye using the OCT machine, and normal is about 300 microns, and the standard deviation is about 10 microns.
We were about standard deviation change in OCT less than 10 microns in the higher dose and about 10 microns in the lower dose. The phase II trial was really encouraging. That there were a lot of learnings from phase II that we were able to apply to the phase III Lugano and Lucia program. Because of those learnings and because of the safety that the retina specialists saw, we were able to fully enroll both those trials in really record time. Each trial took about seven months to enroll. We enrolled about 432 patients in the first trial and about 475 in the second trial.
In that trial, they were randomized to either a single dose of DURAVYU, 2.7 mg, or EYLEA on-label control. For a non-inferiority trial, the FDA really mandates that you use an on-label control of either Lucentis or 2 mg EYLEA. The trials enrolled very rapidly and are moving along very well, with respect to the wet AMD trials. We are dosing those trials DURAVYU every six months. At this point, in both of the trials, LUGANO and LUCIA, all the patients have received their second dose of DURAVYU, and almost 50% have now received their third dose of DURAVYU. As we've talked about, we are looking at the overall safety, and we do have a data safety monitoring committee. Last time they met, they recommended no changes in the protocol.
In fact, we've made no significant changes in the protocol for the phase III trials because of the learnings of the phase II, which is of course why you really do a phase II, to de-risk your phase III. We are really, again, optimistic about the way things are going and confident in the results in wet AMD. We have the first readout for the LUGANO trial. The top line should be sometime around August of this year, so in approximately five months from now. Exciting news. We plan on reporting LUCIA approximately two months later, depending, again, how that all goes. Retention in the trials has been terrific. We're about 5% of patients dropping out in LUGANO, and about 4% in LUCIA.
Standard is about 10% in the wet AMD trial over a year, and we're doing really well with retention. When we talk about the readout, I mean, obviously the primary endpoint is non-inferiority change in visual acuity, the 2.7 milligram dose versus the control. I'd say it doesn't really matter what the actual change in vision is. I like to remind people that high-dose EYLEA, which is, you know, widely used by retina specialists, and it's a terrific drug. When they did their non-inferiority trial against 2 milligram EYLEA, it was 1.4 letters worse. That 1.4 letters, you know, that's not an amount of change in vision that is meaningful to doctors or patients.
As long as we hit the statistics, I think the actual value of change in vision probably isn't meaningful. Now I'm going to contradict myself because if we're actually like in our supplement-free arm in phase II, if we're actually a little bit better vision, I think that would be very helpful to us from a commercial perspective. We need to hit the primary endpoint, obviously. Safety again is equally important, and we have reasons to be quite encouraged about our safety, as I mentioned already. Then the final clinical aspect of things that we need to hit in the wet AMD trial is reduction in treatment burden. Now, the way that's going to be measured in these trials is everybody gets loaded with EYLEA, 3 doses in the first 8 weeks.
The treatment burden starts counting after the EYLEA load. In the first year of the trial, all the patients in the DURAVYU arm will receive mandated two DURAVYUs, and all the patients in the EYLEA arm will receive mandated five EYLEAs. If there are no supplements, that would be a 60% reduction in treatment burden. Well, I'm sure there's going to be supplements probably in both arms because we had those in phase II in both arms. If we have supplements at the same level that we had in the phase II, we have about a 40% reduction in treatment burden. We have reason to believe that we will have less supplements in the phase III than we had in the phase II.
Even if it's, you know, 25%-30%, that's going to be highly statistically superior. We're quite confident that if we hit non-inferiority, that third aspect, the reduction in treatment burden, should be really easy to hit also. Now, if we hit that, the first two, we can go back and test for superiority in change in vision against the EYLEA control without a penalty. That's again a little preview about what we would expect to see at the top line this summer. If I may, I'll go on to DME.
Please do.
Okay. We did a phase II DME trial called the VERONA trial, and that was actually the first time that we tested our higher payload inserts. The payload of the inserts that we had prior were either 400 micrograms or about 1 milligram. Our scientists were able to increase the payload to 94% drug, only 6% matrix, without any changes in the release and in the bioerodibility. We tested those in VERONA, and the inserts performed great. In fact, one of the big findings in the VERONA trial is head-to-head against EYLEA in active DME patients, meaning they had fluid, they had decreased vision. As early as week 4, we had 4-5 letters better vision in our treatment arm than EYLEA, and we were about 50 microns thinner.
Our drug worked fast, and it actually worked better than EYLEA did in the short term. Now, if you think about that and say, okay, let's suppose you're non-inferior to EYLEA, and you end up with the same vision at the primary endpoint, which is a year. If we can show that at week 4, we get better vision faster, even if we end up the same, I think we're going to have a huge portion of the DME market, because who wouldn't want to get their vision back faster and have less fluid in their retina with fewer injections? I think that would be obviously really a huge win for us. COMO and CAPRI are identical trials. They're each going to enroll about 240 patients.
They're both in the U.S. and ex-U.S. sites, and they're both up and running, recruiting patients as we speak. We expect to announce full enrollment in Q3 of this year, which would put us top-line results in Q4 of 2027 in DME.
Got it. Thanks for that overview, Jay. I think you answered a lot of questions that I had. I just wanted to ask, there was an announcement last Friday after the close. I was wondering if you wanted the opportunity to comment on that.
I'm happy to address the issue, Lisa. As I just indicated, you know, DURAVYU has really benefited from a de-risked standard, I would say, drug development program, including a phase I trial and three phase II trials, dosing over 190 patients that have been reported. As I mentioned, we use those results and learnings to inform our phase III trials that are ongoing. DURAVYU's efficacy and safety profile is well-established in those 190+ patients. Again, just to reiterate, no safety signals, no DURAVYU-related ocular or systemic SAEs. Unfortunately, the DURAVYU data, which has been publicly available for a while, has been misrepresented and falsely portrayed by a competitor. We had multiple attempts to resolve this directly with the competitor, but they were unwilling to do so.
That really left us with no choice but to pursue legal action. It's really unfortunate, but we felt it was a necessary step. We're insistent on continuing the development of DURAVYU in a fair setting, letting the full data set speak for itself. Our main priority with this action is to correct and remove the false statements and to ensure this doesn't happen again. We are completely committed to the retinal disease patients we aim to serve through our programs, and we can reassure everybody that this action is not gonna distract us from our focus on continued exceptional clinical execution of those phase III programs that I just talked about.
Given that it is an ongoing legal matter, really can't comment further, but I hope that explanation is enough to inform you and the listeners as to why we felt we had to take this action.
Got it. No, thank you, Jay, for that. That's really helpful. I just want to touch on a few things in your opening remarks here. Did you say almost 50% of patients now have had a third dose of DURAVYU? Is that across LUGANO and LUCIA?
That's in LUGANO. LUCIA, again, is, you know, started about two months later, and so some of the patients have received their third dose, but I actually don't know the actual percentage.
Got it. Okay. That's helpful. I do wanna talk about the non-inferiority endpoint. You know, in the U.S., it's pretty well established. It's in the guidelines from the FDA that they wanna see a -4.5 delta at minimum. But I'm just wondering, ex-U.S., the non-inferiority margin is a little bit tighter, correct? So-
I think it has been historically, though we asked for a 4.5 non-inferiority margin in Europe as well. I think things do evolve and things change based on evidence. Just to say the DME trial in the U.S., we were also granted the 4.5 non-inferiority margin, and that has been 4.0 for some programs in the past. Things obviously that the FDA and EMA do evolve over time.
Got it. Okay. That, that's helpful. Maybe let's just talk a little bit about LUGANO, LUCIA, and you know, the primary endpoint is very clear what you need to do there. You also mentioned you don't necessarily need to have a positive gain in BCVA. You just need to hit the margins, but it would be nice commercially if you did have a positive gain.
Well-
Is that?
I think to be clear, for us to hit the non-inferiority margin, we will need a positive gain in vision. We remember it's change in vision from day one at randomization in the two groups comparable. If you ask the question, you know, what would the change in vision in the EYLEA control group look like? Well, I think you can kind of figure it out fairly easily. Just look at the control groups in the last couple of approved products, Vabysmo and high-dose EYLEA. In those cases, in wet AMD, you had about a 5-letter improvement in the control. But remember, we're 75% naive, 25% previously treated. You can go back to our previously treated data from DAVIO 2 and notice that there was about a 1-letter gain. I mentioned that already.
You can kind of put that together and figure out approximately where one would expect the control group to do. Given that, and given the non-inferiority margin at the end of the trial and the standard deviation, we would expect that in order to be non-inferior, DURAVYU would need a positive gain in vision also. Now, when you talk about the difference, however, as I think I said already, if we were only 0.3 and 0.4 letters worse than EYLEA, which statistically was identical in DAVIO 2, that would be obviously an outstanding result. I mentioned already, clearly the market has spoken with high-dose EYLEA. 1.4 letters worse is fine. If it's non-inferior statistically, then that there's no problem with that result. That would still likely leave us with a positive outcome.
Remember, again, you know, every wet AMD drug that's been approved in the last six or so have resulted in positive visual acuity changes at the primary endpoint. We would expect a positive change for us, too, if we're, you know, hit the primary endpoint.
Got it. Positive BCVA change overall, but the delta between aflibercept and DURAVYU doesn't necessarily have to be a positive gain.
Correct. Correct.
Got it. Well, let's just touch on the secondary endpoint or one of the key secondary endpoints, the reduction in treatment burden. You already touched on this, but is reduction in treatment burden or injections calculated just by the number of supplemental injections or the total injections patients are getting?
It's a good question, Lisa. It's actually both the mandated injections, which, as I indicated in the DURAVYU arm, will be mandated 2 injections over the year of the efficacy part of the study, and 5 EYLEA is mandated. You add on the supplements in. Again, we do expect supplements in both arms. Remember in DAVIO 2, it was a tough-to-treat group, and one of the pieces of evidence for that is the control arm. Despite getting every other month EYLEA after a load, 6% still got a supplement at the primary endpoint, and at 1 year, 13% got a supplement. Even though they were getting every other month EYLEA, they met the requirement for supplements there.
In fact, if you go back and ask the question, in this tough-to-treat group, at any point, how many eyes in the EYLEA arm met supplement criteria? It was over a third, despite getting every other month EYLEA. That indicates this was a tough-to-treat group. Back to how we calculated. Again, it's the supplements plus the mandated at up to week 52. At week 56, it's gonna be both a mandated redosing of DURAVYU and a mandated redosing of EYLEA at that visit. That wouldn't count. If you've got a mandated injection, it doesn't count as a supplement. But the statistics on this is we need to show statistical superiority. When you run the numbers, you know, the end of the study is really high. There are about 450 patients approximately in each arm.
We would only have to show like a 7% or 8% reduction in treatment burden to be statistically superior. Now we fully expect to have much lower treatment burden than that, and we really need to hit our primary endpoint. My point again is if we hit the primary endpoint statistically, that secondary endpoint is pretty much gonna be hard to miss.
Got it. Maybe just to understand this a little bit more. DURAVYU is dosed at week eight in the study. You just said that the injections that are gonna be counted as part of the treatment burden are gonna be the supplemented and mandated injections.
Mm-hmm.
Up to week 52. We should be trying to look at the reduction in treatment burden from week 8 to week 52. Is that the right way to think about it?
That's correct. At the week eight, the EYLEA arm gets a mandated EYLEA, which is part of the load, so that one doesn't count. The DURAVYU gets the first DURAVYU. That one does count.
Got it. Okay.
2 total DURAVYUs, 5 total EYLEAs is how it's gonna get calculated, plus the supplements.
Okay. I think that's helpful for us to understand.
Yeah, I do wanna add, it's very much different than what we calculated in the phase II and what other companies have reported. You know, it's physically impossible to show anything better than a 60% reduction. But as I said already, a 40% reduction would be outstanding, provided we hit the primary.
Did you align with the FDA on what a meaningful reduction burden percentage would be, or it just needs to be statistically significant?
Well, no. There's no alignment there. I think that what we talked about, again, is statistical superiority in treatment burden in less treatment burden. The actual number of supplements is. There was no cutoff. That was never discussed. I would think that probably has been true in all the discussions, because this is also a totality of data, safety and efficacy. I think you can't just isolate one finding without knowing the change in visual acuity and how safe your drug is to make an assessment of what was the supplement rate acceptable or not acceptable. There's sensitivity analyses that go into that as well that obviously will be performed.
Do you think the 40% number is the bogey that the investment community wants to see? Is that what you want to see?
No, I don't think so. I think the number could be much less than that, and the KOLs would be happy with it. Because remember, supplements in the real world are not a failure. It's. That's a really important concept because this, the idea behind sustained release and our drug in particular is that we're working with the historical biologics. In fact, every patient in the study gets loaded with EYLEA and potentially will get supplemented with EYLEA. So it's not an either/or. You know, the good example here is if I'm treating a patient and I have to give them EYLEA 6 times a year to keep them under control. Let's suppose DURAVYU is now approved and available every 6 months, and I give this patient 2 DURAVYUs over the next year.
I actually also give them two EYLEAs. Well, everything's happy. Everyone's happy. The patient's gone from 6 injections to 4. The doctor is able to now spread out the injections. Remember, this is a different MOA. Wet AMD is one of the few chronic diseases that's only been treated with one MOA. I think there's evidence that treating with 2 MOAs here may actually give better results. Ultimately, this isn't about reduction in treatment burden. This is about better visual acuity in the long term. The compliance that is automatic when you give a sustained release to a patient, we believe in the long term will result in better vision.
Again, I don't think there should be necessarily a fixation on a precise number of reductions in treatment burden or number of unsupplemented patients, because in the real world, as long as we're getting the visions we wanna get and the anatomic control, and we can do it with fewer injections, supplements aren't really gonna be an issue.
Got it. That's helpful, Jay. Well, I do wanna touch on the safety profile that we've seen to date. One thing I do wanna ask is, I know in DAVIO 2, some patients did get a aqueous humor tap.
Mm-hmm.
which, you know, makes sense to measure PK, PD, that kind of thing. I was wondering if that is also gonna be a part of the phase IIIs?
No, it's not. We did aqueous humor taps at several times during phase II. Aqueous humor taps are not, you know, something that doctors necessarily do commonly in the office. If you look at the literature, while there isn't great literature on this, there is a high rate of infection, much higher with aqueous taps than there is with intravitreal injections. Unfortunately, in one patient in the DURAVYU arm, in one patient in the EYLEA arm, immediately following an anterior chamber tap, there was a case of infection endophthalmitis. Now, fortunately, both those patients did well. It was picked up rapidly, and they were well treated. After the second case, we stopped doing the aqueous humor taps, obviously for safety reasons.
Got it. That's helpful. I guess maybe just on that point, you know, we know retina docs are very sensitive when it comes to safety.
Mm-hmm.
Especially with more serious SAEs like endophthalmitis. I guess can you just remind us again overall of some of the details about DURAVYU safety profile to date?
Yeah. As I said, and I'll repeat, the 190-plus treated patients, there were no ocular or systemic SAEs due to our drug, and there were no safety signals. There were cases of endophthalmitis. We just discussed one in the DURAVYU arm of DAVIO 2 and one actually in the control arm, in the EYLEA arm from aqueous taps. But those occurred immediately after the aqueous tap, not in conjunction with it. Obviously, in the control group, there was no DURAVYU in the eye, but it was many months after the DURAVYU went in. Endophthalmitis occurs at the time of injection when bacteria, typically from the patient's flora, is introduced into the eye. So it occurs days to maybe weeks after an injection.
If you have an injection that was performed many months ago, and then temporally an EYLEA injection occurs, and a week later you get endophthalmitis, it's related to the EYLEA injection. We've had no, so far, reported cases of endophthalmitis temporally related to the injection of our drug. Now, I have to say, this is an injection-related phenomenon. You do enough injections, you will get endophthalmitis. If you look at the clinical trials, the phase III trials, and you look at what was the rate of endophthalmitis with the, with the drugs, it varies from 0.4% to up to almost 2% in the phase III trials. In the real world, which it's probably underreported, it's, you know, about 1 in 2,000, 1 in 3,000 per injection. Higher in diabetics, twice as high.
Again, you need to take all that into account. It's a per injection. If you're reducing the number of injections because you have better sustained release, you should theoretically at least reduce the risk of infection.
Jay, maybe just on that point. There were two other instances of endophthalmitis in a DURAVYU treatment arm. We already established the first one was more with the aqueous tap.
Yep.
What about the other two that occurred?
Immediately following EYLEA supplement. I think I said that.
Got it. Okay. Thank you so-
Many months after the DURAVYU went in. One was three months, the other one was five months, I believe. Immediately following a supplement of EYLEA.
Got it. Thank you so much for that. Well, we're kind of at time here, but I do wanna ask George if you can just remind us about the cash position and if you can remind us about the runway and what that runway is expected to cover.
Yeah. You know, we've been very judicious with our spend. Obviously, most of it is on our clinical trials and also our preparation for the NDA and our commercial scale-up for manufacturing, which is equally important because, you know, once we report our data this summer, everyone's going to say, "Where's your NDA? Where's your CMC package?" That is well underway. Our cash guidance is into Q4 of 2027. We ended last year with a little over $300 million of cash, and we expect to have, you know, well over a year of cash when we read our data this summer. We're in a great place. Our cash guidance is unchanged, and we're funding all four phase III trials that are ongoing, our beautiful Northbridge facility, and all of that CMC preparation.
We're in a really great place.
Got it. Great to know. Well, Jay, George, that's all the time we have. Really been a pleasure hosting you both this morning, at our Ophthalmology Conference.
Thank you, Lisa.
Well, that ends the session, everyone. Take care.