All right. Good afternoon, everyone. My name is Tara Bancroft. I'm one of the senior biotech analysts at TD Cowen. I wanna thank you all for coming to TD Cowen's 46th Annual Healthcare Conference. For our next session, we have a fireside chat with EyePoint, and it is my pleasure to introduce Dr. Jay Duker, the CEO and President of EyePoint, George Elston, the Executive Vice President and CFO, and Dr. Ramiro Ribeiro, the CMO. It's a privilege to have all three of you here. Thank you so much for joining me. Before we get started, I wanna say to anyone in the audience, please do raise your hand if you have any questions, and I will make sure that they get answered. I guess, Jay, to start, maybe you can give us a high-level overview, recent highlights, thoughts, feelings.
Sure, Tara. Thank you very much for having us. It really is a pleasure to be back here. Well, some of you may be aware that yesterday we announced that we had dosed patients in both of our phase III diabetic macular edema trials, the COMO and CAPRI trial. We had guided to first patient in first quarter, and that's what we accomplished. We're really excited about the DME opportunity. Diabetic macular edema is soon to be a $3 billion business a year in the United States, so it's quite a market opportunity. Based on our phase II VERONA data, we're really excited about the potential for DURAVYU and DME. As you're may be aware, we're the only sustained release TKI doing DME, so we're now in the two largest markets in VEGF markets, wet AMD and DME.
Our DME trials are identical, international trials, about 240 patients to be enrolled in each. The reason we're able to keep the N relatively low is that the agency has allowed us to use the safety database from our wet AMD trials for the DME trials. That's why you may notice that the trials are relatively small but well-powered. We are again using 1 dose of DURAVYU, 2.7 milligrams dosed every six months. I think the probably the biggest difference between the wet AMD trials and the DME trials is we're dosing DURAVYU on day one. You may be aware in wet AMD, everybody got loaded with three injections, and we dosed DURAVYU on week eight. Why did we change that? Well, the answer is simple.
If you go back and look at our VERONA data and you look at the four-week result, our drug was better than EYLEA. On day one, patients either got our drug with an EYLEA or they got an EYLEA alone. At week four, we were already four to five letters better than EYLEA, and we about 50 microns drier. If we can show that same benefit in our phase III trials, we believe that we will become the treatment of choice in DME. 'Cause who wouldn't want, as a patient, to see better faster and to see better with fewer injections? Even if we end up tied with EYLEA in the end and non-inferior, if we can show that earlier benefit, we really believe we will be commercially successful.
With respect to DME, our, you know, Ramiro's teams that did an outstanding job recruiting in our two wet AMD trials. We recruited each trial in about 7 months. That, to our mind, was the fastest ever in phase III, wet AMD trials. We believe we should be able to fully enroll both trials, by 3Q this year, which puts us top-line data in 4Q of 2027 for DME. We're able to leverage a lot of the infrastructure that we had for wet AMD, which is keeping the cost of the trial down and should also help the speed of the trial. One, you may feel it's a small point, but I really think it's important to know, is we're using about 90 sites from the wet AMD trial, same sites in DME.
All of those sites that we invited to be sites for DME, 100% of them said yes. Not one site turned it down. Indirectly, what that tells us is they were, although it's masked, they were excited about what they saw in the wet AMD trial, and they were comfortable with the safety of DURAVYU. That's DME update. Wet AMD is going great. We have two fully enrolled trials. The first trial, the LUGANO trial enrolled about 432 patients. The LUCIA trial enrolled about 475. The trial conduct is terrific. Retention of patients is very good. We're 5% or less dropout rate at this point in each of the trials, which is better than expected. We've made public comments about the masked safety.
We're Ramiro's group is looking regularly at the masked safety. We've had two DSMC meetings which we've reported on. The masked safety so far looks essentially the same as what we've seen in the 191 patients that we've already reported in our first four trials. Again, anything can happen, but most of these trials, the safety issues come up at the time of injection. At this point, 100% of the LUGANO patients have received their second injection, and about 60% of the LUCIA patients have received their second injection. We're feeling pretty good about the safety in a masked fashion that we've seen. We expect the top line from the LUGANO trial to read out sometime in August. We like to say August-ish.
Again, there's always, you know, you've gotta make sure that you've got the top-line results and you're confident in them. We should have top-line data somewhere around August from the first trial. The second trial is approximately eight weeks behind.
I'm happy to just let you go the whole 30 minutes.
Oh, okay.
No, I'm kidding.
All right. What about?
Okay.
Okay. I will keep going. You can ask me a question. It's fine.
All right. Okay. While we're on the topic of new revelations, though, and new updates, along with the DME dosing, you recently updated a new mechanistic finding, the IL-6 blockade. Maybe you could tell us a little bit more about how you came to know this and what it adds to the profile?
Sure. That's I think a little bit of an interesting story that I'd like to tell. Our drug, Vorolanib, was originally developed by a company called Tyrogenex and was studied orally in wet AMD. They turned the drug over to a Chinese company called Betta, and we've licensed the drug from Betta Pharmaceuticals. Betta Pharmaceuticals is a primarily a cancer company, and they were interested in Vorolanib for kidney cancer. In fact, they've got it approved in China as an oral agent for kidney cancer. It's not approved in the United States at this point. They did some Kinome analyses, but they only looked at specific receptors that were interesting for them for cancer.
They only did very low dilutions because systemically, the amount of Vorolanib that you can give a patient is less than what we can deliver from a safety perspective inside the eye. The original Kinome analysis only included JAK2 and didn't really show much activity. We looked at the VERONA data. I've already described the 4-week data, but I looked at that 4-week data, and I said, "You know, we have a pretty good anti-VEGF agent here, but I don't believe we're this much better than EYLEA. There must be another mechanism of action going on." I asked the R&D folks to go back and look at other potential receptors that we would be blocking beneficially. And as we did that, we discovered we're a potent blocker of JAK1.
Our IC50 is about 80 nM, which we are well above, in patients with the doses that we're using. We went on to replicate that multiple times. I said, "Look, it's not enough to know we block JAK1." Of course, IL-6 downstream works through JAK1. Let's take a look at how we do in a cell-based assay in IL-6. We used a cell-based assay and looked at the downstream activity of IL-6, and we blocked the downstream activity at doses that we're using approximately in humans by about 55%. We happened to look at the other TKIs that have been studied in ophthalmology, and they followed their IC50s, which means Sunitinib had a higher IC50. It was about a 15% blockage in IL-6 activity, and Axitinib didn't have any. We believe the IL-6 block is important. Why?
Well, there's been evidence in ophthalmology for decades that IL-6 plays a role in a disease called uveitis. Uveitis is inflammation in the eye. Systemic IL-6 blockers have been used for uveitis, and now there's some local IL-6 blockers that you may be aware of. Kodiak Sciences has a combined IL-6 anti-VEGF that they're looking at on either a monthly or bimonthly basis for both wet AMD and for inflammatory macular edema. Genentech has shown phase II data of the combined blockage of IL-6 in an anti-VEGF on a monthly basis that appeared to give better results for DME, similar to the results that we saw.
We believe that based on some other data, IL-6 is important in both DME and wet AMD, and we believe that's gonna be a differentiator for us, especially in DME, because we're the only ones developing an anti-VEGF, anti-IL-6, anti-PGF that is sustained release and repeatable. That is a bit of a long story, but that's how we've came up with that. We're gonna have more data at ARVO this year, and we're doing additional studies again to try to delineate how effective our drug is at IL-6 blockage.
Okay, great. Thank you for that. I guess maybe I wanna get into phase III expectations, of course. Maybe you could start by giving us some context from the various learnings, maybe your top three learnings from phase II that give you confidence in phase III.
Well, it again, for retina drugs, wet AMD drugs, the important things are, of course, efficacy and safety. Let's talk about efficacy. Our drug head-to-head against on-label EYLEA was statistically identical to EYLEA. At the eight-month time point, one of the arms was 0.3 letters worse, the other arm was 0.4 letters worse. You've all been at an eye chart. You've all read the eye chart. A line is 5 letters, and, you know, if you can't read half a letter, that doesn't count. Of course, half letters is no different. From a non-inferiority margin, we have a non-inferiority margin of our phase III of -4.5 letters. From a non-inferiority margin, our lower limit of non-inferiority in the phase II was 2.6 letters.
We were way away from 4.5. Even accounting for perhaps some differences in the phase III, that gives us confidence that we will be non-inferior. Let's talk about safety. Again, we've treated 191 patients, reported on them in 4 trials. In those patients, there have been no ocular or systemic SAEs associated with our drug, and there is no safety signals associated with our drug. Our safety, we are, you know, quite comfortable with. Again, I've already talked about the mass safety in the, in the phase III trials. That also gives us confidence. There were multiple learnings from a phase II. I think doing a phase II is typical drug development, and we learned a lot about how to recruit trials, what the patients want, what the doctors want, and what's working and what isn't working.
I'm actually gonna ask Romero perhaps to comment on the rescue criteria and what we learned in the phase II and how it informed the phase III.
For the phase II study, we enrolled previously treated patients that are very tough to treat. They had an average of 10 injections before the study, coming into the study. One of the key aspect for this type of study is the supplemental criteria. We had for our phase II studies five different criteria for supplementation. One was combination of vision loss and fluid, just vision loss, just fluid, hemorrhage, or investigator discretion. What we learned from the phase II study is that the criteria that really matters in the end of the day, the one that provides good vision outcome for patients, are the criteria that combine vision loss and fluid and hemorrhage. Those are the ones that protect your primary endpoint while maintaining a good treatment burden.
Those were the two criteria that we selected for the phase II study. That's one of the difference with our phase III program. I think just to recap on Jay one more thing, when we look at our supplemental free patients in the phase II study, it was really good to see that those patients gain about two letters in the study.
Yeah. Overall, the patients gained about a letter in the phase II trial, the supplement free patients did even better, 2.1, that was actually numerically better than on-label Eylea that gained about 1.7 letters. Again, glad you mentioned that, Romero. Now on to phase III. I'd like to say that in some ways I think our data should be very easy to interpret because there's basically three things we need to hit. We need to be non-inferior against the control arm. That's obvious. That's the primary endpoint. If we're non-inferior, the second issue is safety. Now, we've already talked a lot about safety, and anything can happen, and the phase III's not over, but we're in a comfortable position with safety. The third bar we need to cross is superiority in the treatment burden.
Now, a little more detail on that. Everybody in the phase III trial in wet AMD gets a full load of EYLEA, which is three injections. The treatment burden starts after the load. In the DURAVYU arm, everybody is mandated to get two DURAVYUs before the end of the first year. In the EYLEA arm, everyone's mandated to get five EYLEAs. If we have no supplements, it will be a 60% reduction in treatment burden. There's gonna be supplements. We expect fewer supplements in the phase III than we saw in the phase II. If we have about the same supplementation in the phase III that we had in the phase II, we'll have a 40% reduction in treatment burden.
The nice part about the statistics, though, is because it's such the studies are so well powered that we could have somewhere around a 7% or 8% reduction in treatment burden, and it would still be statistically superior. That should be... If we hit the first bar of non-inferiority, I think it's hard to miss the third bar. Again, I think our results will be very easy for you to interpret. If we hit all three, I think we're highly likely from a clinical perspective to be approved. Then of course, there's the CMC aspect, which you haven't asked about yet, but I'm happy to talk about it.
I will.
Okay, go ahead.
Just go into that a little bit more. Yes, I'm happy to ask on that. Why the difference in the requirement for supplements between phase II and phase III? Can you go into a little bit more difference on the patient baseline characteristics or anything that underpins that?
Why we expect fewer supplementation. The first reason is what Romero just discussed. 20% of the supplements that were given in the phase II were given because of investigator discretion and met no criteria. If you look at the visual acuities, what happened after the supplement? Nothing. They didn't need a supplement. Just like if you supplement for fluid alone, if your vision is stable, but you have an increase in fluid, you have a supplement, what happens to the vision? Nothing. The vision hadn't changed. I'll flip it around. If you have a patient who's lost vision but has no fluid, they didn't lose vision due to wet AMD. They lost vision through a cataract or geographic atrophy. What happens when you give them a supplement? They don't improve. Those are all what I would kinda call wasted supplements.
You don't wanna give those. That's the number 1 reason, better supplement criteria. Number two reason why I expect fewer supplements is we're reinjecting. We didn't reinject in the first trial. I have to believe that some of the supplements that occurred later in the trial were probably due 'cause the inserts were devoid of drug. We should be able to get past that by two. The third reason is we did enroll, I should say, 75% treatment-naive patients. Romero already mentioned in the phase II, we had a really tough-to-treat population. They needed a lot of injections, and we did pretty well. There's about 20%-25% of the wet AMD population out there that will do really well with any drug. Doesn't matter. They can go three months, four months with any drug.
We didn't get many of those in the phase II. Our hypothesis, which makes sense, is if you have a patient who can go three months with Avastin, they should do really well with our drug. That's the way, again, hope to capture them is by allowing those easier to treat that are made up of 20%-25% of the naive population.
All right. Great. I think expectations are pretty clear. How about then after LUGANO, after LUCIA, how soon can you submit an NDA and get to market?
Okay, Romero. Pressure's on.
I think, you know, the beauty of our clinical program is that the studies are identical. We're gonna get the results from Lugano end of the summer. With that, we're gonna be able to start writing the clinical study reports and the modules. We're gonna have Lucia about two months after that.
Because these studies are identical, we should assume that their study results are gonna be very similar, and we're gonna be able to leverage all the write-up for the LUGANO, essentially just change the name now to LUCIA, and then be expediting our submission. If you look at standard timelines for biotech NDA submission is about six months. I believe we can do much better than that.
Does the recent editorial change your perspective on single trial attempt at all?
Down the road, perhaps. We already have two trials underway in wet AMD and 2 simultaneous identical trials underway in DME. We asked the agency in July, not that long ago, when we had an end of phase II DME meeting, we asked if we could do a single trial as an NDA in DME, and they said, "No, you need to do two trials." We believe that as of recently, the agency in ophthalmology is not quite at that a single trial cliff, let's say. Of course, when you do a single trial, you need a large N because the P value is gonna be lower, and you need other data that's supportive, you know, from the drug used in other indications perhaps, or other models or other studies. You need that supportive data as well.
You also, again, I don't think there's any indication that the FDA is gonna get away from their 300 evaluable patients at the go-to-market dose, at the go-to-market interval for safety on. We should have that. You know, with our two trials, we enrolled approximately 450 patients with DURAVYU. Back to DME. You know, we asked for single trial, but in a way, while they didn't grant single trial, the fact that they're allowing us to leverage the safety data enabled us to do two smaller simultaneous trials. Had we done single trial, it might have been in a 1,000-patient study. It would have taken longer to enroll and probably be more expensive. There's also, this is in the U.S. You wanna be in Europe and elsewhere in the world. I think they're still looking for two trials.
We're comfortable with that, but it will be, I think, good for the space if eventually the ophthalmology division under those circumstances agrees to single trial. We'll see.
Okay, great. Let's move on now to the market opportunity. We had a really good discussion on our ophthalmology panel, which really we should be calling retina panel.
Thank you.
You know you used to frequent it.
I used to for many years, yes.
Really, how in practice this drug or just TKIs will be used in general, is it more of a treat and extend, treat and maintain? How do you, how do you envision it? New patients, even…
I, you know, I think it's evolving because, at least, you know, obviously we don't have them yet, and we don't have the phase III data yet. We don't have the label yet. All that's critically important. Doctors are starting to accept that this is a different paradigm. For over 15 years, we've had one MOA. It was ligand blocker with a biologic, and every new biologic said, "Don't use the old one. Use us. We last longer." Couldn't show better vision, just last longer. TKIs are a different MOA, and this is one of the few chronic diseases, big chronic diseases that are currently just treated with one MOA. The mantra is not us or them. Remember, we're loading everybody in our trial. We're using our drug with ligand blockers, and there will be supplements.
I think doctors are now understanding that a use of a supplement in a trial may not be may affect the primary endpoint, let's say, if it's a lot, but use of a supplement in the real world is fine. You know, the example I always give, if I have a patient that I'm injecting every other month with EYLEA 6 x a year, and DURAVYU's now approved, and I put in 2 DURAVYUs, and I still need to do two EYLEAs, everybody's happy. I went from six injections to four injections. I had the advantage of 2 MOAs, maybe anti-fibrosis, maybe the IL-6 blockage is important. What's becoming abundantly clear now with other data is that long-term suppression of VEGF gives better results. This isn't a let's cut down on the number of injections.
The number of injections cutting down the treatment burden issue is a secondary benefit. What we believe is the primary benefit is gonna be better visual acuity in the long term because you're having forced compliance by having sustained-release inserts in the eye. Again, you can think psychologically, if you're an older patient who gets AMD, and you know you've got a problem, and the doctor says, "I'm gonna start injections." You say, "How many am I gonna need?" "You're gonna need them for the rest of your life, maybe monthly." That's a huge burden. If you can say to that patient, "We might be able to get you to every six months," I think that's gonna be a lot easier to accept. 40% of wet AMD patients stop treatment after one year.
There's a huge opportunity here to make patients' lives better in the long term, and that's what our aim is.
Not to mention the retinal health doing to the bolus and removal.
Yeah.
Can lead to retinal hemorrhaging.
Well, again, I don't think retinal hemorrhaging is so much the issue. Most retinal hemorrhages actually occur within a few weeks of an injection.
Mm-hmm.
It's not lack of injections on the hemorrhage side. Now there's plenty of evidence that the large fluctuations in the fluid lead to atrophy and fibrosis, and that even though we all, each retina specialist, you'll say, you know, "How you do a good job treating our patients." "I do a great job." "But why does the vision gets worse in the long term?" "Well, that's the other guy or the other girl." It's also what's clear is patients develop fibrosis from that in the long term, and we also hope to show that by being anti-PDGF, that we help the fibrosis, which should help the vision in the long term.
Got it. Okay. Also once on the market, how should we think about step the requirements? Can you be used in a naive patient, or you're gonna have to go through Eylea and do the loading?
Yeah. Well, our label, which, you know, again, which I don't know what the label is gonna be.
Mm-hmm.
One can speculate, and one could speculate based on our phase III trial design that the label might look something like for wet AMD patients every 6 months, naive or previously treated after 3 injections of an anti-VEGF. One could speculate that if the doctor has given 3 injections of an anti-VEGF sometime during that point in the patient's cycle, that they can give our drug. I will say we're gonna try to make the case that due to IL-6 blockage and due to the fact that we're a receptor blocker and we have anti-PDGF, that we are not just another anti-VEGF, and we shouldn't be bucketed with them. We're a new MOA. You know, we I can't tell you that strategy will be effective, we are trying to have that strategy.
we're not worried about step therapy because three injections of an anti-VEGF are probably gonna be on the label anyway. That automatically takes you into our drug.
Okay. Got it. I do wanna give you some more time to go into a little bit more detail on DME. Maybe, could you talk about any differences between VERONA and COMO and CAPRI, that could affect our interpretation of the data when we eventually see it?
Romero, do you wanna talk about that?
I think the purpose of the VERONA study was really to assess the effect of DURAVYU in active patient population and assess the need for the supplement injection after that. It was a small study looking at time to the first anti-VEGF. We saw, as Jay mentioned, the improvement in BCVA and CST early on, which was very encouraging. COMO and CAPRI are designed just like our wet AMD study. Are designed to show that DURAVYU is non-inferior to aflibercept on label with a reduction in treatment burden and hopefully on the long-term better visual outcomes. In terms of patient population, it's relatively similar than our phase II study. We are also including patients with active disease, both previously treated as well as naive patients.
Okay, great. Maybe, your prediction for the rate of enrollment in COMO and CAPRI, because I think in LUGANO and LUCIA, it was a little bit faster than anticipated, maybe could the same thing happen here?
Yeah. I think now we have an even bigger team at EyePoint. We have all the efficiencies from the wet AMD study. We have a very strong MSL team. We have a very strong collaboration with our CRO, with our clinical sites, and it's a relatively smaller study, 240 per study. Our assumption is that we can do better than what we did for wet AMD.
Great.
Of course, one more part that Jay...
Yeah.
George mentioned is that there is no phase III study in DME ongoing right now. We are the only one.
Correct. Okay. We have about two minutes left. I believe in you, Jay. I love asking this question, especially as it evolves over time, what do you believe right now is the most underappreciated aspect of EyePoint?
The market opportunity in both wet AMD and DME. This is a huge opportunity. It's, you know, combined $15 billion worldwide. When DME, by the time we launch, will be $13 billion. If we are non-inferior and we have no other advantages, our research right now suggests we're gonna get about a third of the wet AMD market. If we can show anti-fibrosis, if we can show better vision, I think we're gonna do even better than that. I think the entire and perhaps investment community is not appreciating how big this could be for all the sustained release companies. We are really excited for the data coming out later this year and hopefully the recognition that will come with it.
Absolutely. I agree. So are we. I guess that is all the time we have. I just wanna thank all three of you for being here and at Cowen and all of you for listening. Thanks so much.