Okay, welcome everyone. Thanks for being here. I'm Jennifer Kim, one of the biotech analysts at Cantor. I'm looking forward to hosting this fireside chat with EyePoint Pharmaceuticals. We have Jay Duker, President and CEO, and George Elston, the CFO. Guys, thanks for being here.
Thanks.
Thanks for inviting us.
I'm especially appreciative because I know you're flying in between conferences in Europe, to be here. Maybe to kick things off, can you give a quick snapshot of EyePoint?
Sure. EyePoint is a company that is dedicated to improve the lives of patients who have serious retinal disease. At our heart, we are a drug delivery company. We are able to sustain release small molecules and perhaps peptides to the back of the eye, anywhere from weeks to years, in order to, we hope, have better visual outcomes in serious retinal diseases like wet age-related macular degeneration and diabetic macular edema. We are a clinical stage company about to embark in two pivotal trials in a very large market, wet AMD. Those trials should be commencing within weeks and are very excited, based on our program, based on our terrific phase II results, about the potential outcomes.
Okay, and then advancement towards phase III were really driven by the strong DAVIO 2 data.
Yes.
Could you just recap what we saw and put that in the context of?
Sure. DAVIO 2 was the name of the phase II trial. It was a wet AMD trial, all previously treated patients. We enrolled 160 patients, and they were randomized to approximately 3 mg of our drug, which we're now calling Duravyu. The active ingredient is vorolanib. The lower dose was approximately 2 mg of vorolanib, and it was versus an on-label Eylea control. One of the unique parts of the trial is everybody got a loading dose of Eylea at the beginning of the trial, and this is important to understand, that we're advancing our drug as maintenance therapy in wet AMD, and that will also be the way the pivotal trials are designed. Everybody will get the three-month loading dose, at week eight. Our drug is then given 30 minutes after the last Eylea load. The Eylea arm will be receive a sham at that time, and then the Eylea, just like we did in the phase II, goes into every other month dosing. In the phase II DAVIO 2 trial, we didn't redose our drug, but we plan on six-month redosing in the pivotal trials to get a label for every six months.
Okay, and you sort of touched on the high-level design aspects of the phase III program. Can you just walk through the decisions there and what you signed off at the FDA?
Sure. Well, I think a lot of the decisions were really based on the excellent top-line data we had in the phase II. The primary endpoint for non-inferiority trial is non-inferiority change in visual acuity against the control group, and in DAVIO 2, we essentially tied Eylea. There was no statistically significant difference in visual acuity outcomes. We just reported the 12-month data from DAVIO 2. Without a re-injection, we tied Eylea at month 12, so that gives us a lot of confidence that we should be able to hit the non-inferiority margin in the pivotal trials, where we will be doing re-injection at the 8-month and beyond, so the safety looks great. We've treated a total of 191 patients with our drug and have yet to have a reported ocular or systemic SAE.
And so that really checks in another important box for not just the FDA, but obviously for the treating physicians. Anatomy followed the visual acuity, and we had a supplement-free rate of about two-thirds of the patients up to month eight. So based on that, the structure of the phase III trial is really similar in a lot of ways. The main differences are, we need to have a one-year endpoint, not the eight-month endpoint that we had in the phase II. And that's due to the load that we're doing.
So, to be a little more specific, in a wet AMD trial, the FDA will allow you a nine-month efficacy endpoint, but our nine months doesn't start until after the load is done, and that's why our endpoint will be a blended endpoint of week fifty-two, week fifty-six, or approximately in a year into the study. So that's change number one. Change number two, I talked about we're gonna re-inject every six months, re-inject our drug, because we think that's obviously the inserts we believe in humans are deplete of drug by about eight to nine months. Some eyes may be a little faster. And that will give doctors flexibility to re-inject at six months, should they choose to.
The patient population, we're gonna be enrolling both naive and previously treated patients, and we actually think that change is gonna result in better outcomes. If you look at the DAVIO 2 data, we enrolled a tough-to-treat population in that study. On average, the patients had 10 injections in the year leading into the trial, and in the United States, on average, patients get six injections, and most doctors will still tell you they're probably undertreated with six. We had very few patients who were easy to treat, and one of the ways to get easier to treat patients is get a naive population involved, which is, when you think about it, it depends who you talk to. Anywhere from 20%, 25%, up to 30% doctors will tell you, in a naive population, they don't need much treatment at all.
I think our drug's gonna do really well with that patient group that we really didn't get to see in the phase II. In addition, you know, again, from the regulatory perspective, the global acceptance, the label, having previously treated and naive, I think is an advantage. Other differences, we're using just one dose of our drug, not two. That decision was made based on when we really drilled into the evaluation of the data. There really didn't seem to be much of dose response in phase II, except when we looked at anatomy. Over and over, when we looked at the OCT results, the higher dose did a little bit better, and that was consistent. The other thing it allows us to do with only one treatment arm is, obviously, we can power the study more.
That gives us, again, a little more confidence in getting the result that we need to get. So we're going with a single dose. It's approximately 2.7 mg. And the way we're doing that is to re-educate or recall, we've tested inserts with various payload. In the phase I, we had 440 µg, we had an insert with 1 mg, and now in our VERONA trial, which is our DME trial, we have an insert that is up to 1.3 mg payload. And that is the insert we're gonna be using in the pivotal trials in commercial. That insert, by the way, is 94% drug. The previous inserts were about 75% drug.
So we've been able to do process improvement without changing the core matrix to reduce the actual matrix of the drug, and therefore, we're able to deliver the high dose with two inserts as opposed to three inserts, which we think, from a COGS perspective, is acceptable.
Okay, I want to touch on what you said about the differences in, in functional and anatomical outcomes of the doses.
Mm-hmm.
Can you just talk about why your therapy... or how that therapy works in the context of how anatomical outcomes versus functional outcomes should be looked at, and then, how is that sort of fed into the design of your phase III trial and the rescue criteria in that trial?
Yeah, so I think that historically, retina specialists have come to accept that anatomy on OCT is a good biomarker for disease activity, and I think that's true to a degree, and we're learning more about that, but the FDA cares about vision. They don't really care about anatomy. They've never really accepted OCT in an AMD or a DME study as an endpoint, and so that while it's important and we need to report it, in order to get FDA approval, you have to show non-inferior visual acuity, and that's what we aim to do. For the doctors, though, they want to see that you are able to control the disease anatomically, and that control can come in different forms.
One of the things that we noticed ever since with Eylea's approval many years ago with the VIEW 1, VIEW 2 study, is if you give a group of patients every other month Eylea, you get a sawtooth pattern in OCT. Every other month, the fluid starts to come back, and you'd look at that and you'd say: "Well, you know, that drug for not everybody is lasting two months." We know that, and that's why there's still a lot of patients who need to be treated every four to six weeks. But we at Retina Specialists accepted that because the visual acuities weren't any different.
So one of the things that we've learned is changes in anatomy don't necessarily correlate to changes in visual acuity, and that while we look at new fluid as a biomarker, having a little bit of fluid, there's plenty of studies that show persistent fluid that's not changing is not bad for the eye. The other things we've learned is if you were giving an acute therapy like a ligand blocker that's out of the eye in several weeks, if you have new fluid after two months, you better treat that patient because there's no drug in the eye. If you have a sustained release, and whether it's us or a gene therapy or the port delivery, after two months, three months, four months, we're still delivering drug, and so you can see fluctuations in fluid that are not going to affect the vision, may in fact, go away.
This is a little bit of a paradigm shift for docs, but I think we're starting to realize that if you have a sustained-release device, insert, whatever on board, and you see a little bit of new fluid, that isn't a panic that you need to retreat the patient. You can watch, and maybe in a month or two, it'll go away. And we've seen cases of that, and again, port delivery has shown it. And interestingly, you may know there's now home OCT, and home OCT is showing it, too, that there are patients who will periodically get a little fluid one day, and it'll be gone the next. Fluid that comes in and builds up, that usually means you need to treat them again.
Okay, and then in terms of the rescue criteria for the pivotal program, what have you disclosed?
The rescue criteria is a little different in the pivotal program. The main rescue criteria, the one that we consider to be the core rescue criteria, is not changing. Five-letter loss from best on study with 75 microns of new fluid. When we went back and analyzed the rescues from the DAVIO 2 trial, we did pretty well, but 20% of the rescues in DAVIO 2 did not meet criteria. We're not allowing rescues in the pivotals that don't meet criteria. What we're asking the sites to do is if it does meet that criteria of the five letters, 75 microns, you must rescue. We want to protect the patients, and we want to protect the visual acuities.
On the other hand, we had some anatomic and some hemorrhage rescue in the DAVIO 2 trial, and it turned out the eyes that got rescued for anatomy alone, under 100 microns of new fluid, the rescue didn't change the vision at all. And it goes back to what I was saying, is that this whole paradigm about fluid is bad and you need to treat it, maybe not all the time. So we're not using that one.
Based on that rescue criteria and the design of the pivotal-
Mm-hmm.
... how do you think the supplement rate in the pivotal would compare to the phase II and why?
We expect it to go down and for several reasons. First, again, we're enrolling a naive population, too, as well. And so embedded into that naive population will be patients who don't need a lot of treatment, and I think our drug will do very well there. We have some evidence of that. We had a handful of patients in the DAVIO 2 trial that we called pseudo-naive. Pseudo-naive, the way we defined it, is they just had the diagnosis before the trial, and less than three months, they got two injections. Those pseudo-naive patients had a supplement-free rate of 80%, better than the group as a whole.
Now, we're reinjecting, and so the reinjection, if, again, we're not all the way at the height of the dose response, even if we still have a little bit of drug left at six months in the previous, we're reinjecting, and so that we should do better after the reinjection. Because at six months, seven months, eight months, some of those inserts have run out of drug. So we expect for those reasons that we should see a supplementation rate less. We're sticking to the criteria. We're not allowing supplements that don't meet criteria, reinjection, and a more broader patient population to include less needy patients.
Okay, and Retina Society just wrapped up. What has the feedback from physicians been on the DAVIO 2 data, but also on the pivotal program?
Yeah, so the DAVIO 2 data continues to look really strong. Again, you can recall, prior to December 2023, when we released the data, we talked to a lot of KOLs, a lot of the analyst investors talked to KOLs, and they'd ask the question: "Now, how much vision would you be willing to sacrifice to get sustained release?" And the KOLs would generally say, "Oh, two to three letters. Patients don't even notice that." Well, we were exactly the same as Eylea. We're not hopefully gonna ask them to sacrifice any. And I will add, high-dose 8 mg Eylea was 1.4 letters worse than 2 mg Eylea in their pivotal trial. Nobody really talks about that because the doctors and the patients don't really care about that 1.4 letters, as long as it meets the non-inferiority margin.
So the 12-month data showed the same, that despite no reinjection, we were essentially equivalent to Eylea. And one other thing we reported at Retina Society is we took a look at one of the other unique aspects of the trial is because the doctor that determined whether the patient met rescue criteria was masked to which group the patient was in, we have an apples-to-apples comparison. We can take a look at how many eyes in the Eylea group who were getting every month Eylea met criteria, versus how many in the Duravyu group met criteria, who only got one shot of Duravyu over that same time. And the answer is, it wasn't statistically different. It was about 32% versus about 48%. So numerically different, but when it ran stats, we basically tied Eylea in the need for supplements in a masked fashion.
We thought that was really important data that we reported at Retina Society. I think the doctors understand our phase III trial. They've done it before. This is the last five approvals in wet AMD have been with a non-inferiority study, and in fact, some ways our study is more straightforward because both Vabysmo and high-dose Eylea had an alteration in their treatment interval in the phase III, depending on disease activity. We're not altering our treatment interval. We are an every six-month drug going against maintenance every two months. That's pretty straightforward. They like the two-year study. They like the fact that everybody is getting treated, and I think that that speaks well for our ability to recruit for the studies.
As real-world evidence emerges from some of these newer therapies, Vabysmo, Eylea HD, I guess what is the key, what are the key learnings in terms of the added benefit of these new therapies and the unmet need for something new?
So, this is obvious, but Regeneron and Genentech are very smart companies, and they ran trials that were designed to show longevity, and they did show that in the trial. What we're learning in the real world is that same longevity that was shown in the trials, getting patients out four months, for example, is not necessarily what's correlating in the real world, and I mentioned the reason already. Whether you're using high-dose Eylea, you're using Vabysmo, whatever you're using, after a month or so, that drug's out of the eye. So if you see new fluid at month two, you're gonna treat again, and that's what people are doing in the real world. So the real-world data that's coming out is Vabysmo is a longer-lasting drug than high-dose Eylea. We...
A pretty good trial that was done out of the RCA group that was talked about a few months ago, eight days was compared to 2 mg Eylea. Now, for us, we think that's great because Vabysmo is a billion-dollar drug, and it's giving approximately one more week to the treat and extend. We're gonna be able to do, hopefully, if the data holds, at least two-thirds of the patients out six months or longer. And so that we think that there's real value there, and there's real gonna be real appreciation in the market for the ability to do that. Safety, again, we know about the biologic safety. They're generally safe. There was a report at Retina Society of a Vabysmo patient getting severe posterior segment inflammation. You know, that happens with these drugs, but they're generally safe. I don't think that there's an issue.
I also think, you know, again, Regeneron is running a monthly trial right now because they don't have a label for monthly, and that came out at Retina Society, that some of the doctors, because you can't use it monthly, and they need to use it monthly, it's been a problem for the label.
Okay, that's useful. So what's left between now and getting enrollment started in your pivotal?
So, I like to call it basic blocking and tackling. You know, there's a lot of prep work that needs to be done to internally and externally with the CRO to make sure you're ready to go. In some of the, you know, again, when the clock starts ticking, if you really look at the clock, we had an end-of-phase II meeting with the FDA in the spring, where we asked some questions about the pivotal trial, and they answered them, and they actually, you know, answered them in a very favorable fashion. But until we knew, for example, they were okay with one arm of our drug, we can't really package the drug until we know that. And so once we knew those things, then things like the drug packaging, the drug loading into the injectors, the drug sterilization, and then, of course, it gets sent out to someone else for, you know, randomization.
You know, to make sure it's randomized, we buy the Eylea for the sites to have them preloaded with the Eylea to make it easier for them. That all takes time. And of course, sites have to agree. We have over one hundred and thirty sites that agreed to be in the trial. We have to site visit them, get a contract. That's all, that's all being done, but we are optimistic that in the coming weeks, we will have first patient in, and we are optimistic at the time we have the first patient in, and for us, first patient in means dosed and randomized, that we will have, we hope, thirty to forty sites up and running at that time, and hopefully, another sixty or more within six weeks of that first patient in. We're still on target for the second trial to start several months after the first.
Okay. First of all, congrats on getting 130 sites signed up.
Yeah.
That, that's great, and are those sites reserved for the first pivotal trial?
Both.
Okay. How does that work?
We're trying to. So the most important thing isn't first patient in, it's last patient in your second trial. Because that's when you're, for the one-year data, we're allowed to submit the NDA after the one-year data. That's when your clock really starts. So if your two trials are too disconnected, both in start time and enrollment, then there will be a gap between the final data. We want to close that. And so I think we're trying to be predictive by having some of the known high enrolling sites in the, let's call it the second trial. And the other thing we plan on doing is, a center can't enroll both trials simultaneously. They're gonna be in one or the other.
Once they hit the cap, though, meaning, you know, we don't want a center to certainly enroll more than 10% of the patients, and the industry is usually about 5% in a pivotal trial. We're gonna be able to enroll, roll them over into the other one, and so some of the really high enrolling sites we would expect they may cap pretty quickly based on history, and we want to be able to enroll, roll them more, so it's a little bit of a matrix to try to end both studies as quickly as possible.
With the inclusion of both treatment-naive and previously treated patients, how should we think about the enrollment between those two groups, and how are you balancing that out?
Yeah, well, the way we think about it is it's another advantage because there's a whole pool of previously treated patients out there, and right now, these 130 sites are identifying them. So we would expect, hope, that out of the gate, we do get a bolus of enrollment of these patients who are waiting for the trial to open. And we're gonna need to balance that because we, you know, do have some plans in mind about the ratio between naive and previously treated. But we would expect at the beginning, you know, we're taking the history, we're gonna know how many. We don't know how they're randomized. It's that we're gonna get a bolus of previously treated patients at the beginning.
Okay, and ahead of some of the milestones in wet AMD, we're gonna see phase II DME data in the first quarter of next year. Can you just walk through the design of that trial, and is there a way to level set expectations?
The design of the trial, it's previously treated DME patients, but they have to be active. They had to have fluid, and that is to ensure that we weren't enrolling DME patients who had the disease for a long time and were at the point where they didn't need much treatment. There are three arms: 2.7 mg, the high dose, 1.3 mg, the low dose, against Eylea control. Everybody gets a single shot of Eylea, and thirty minutes later, they either get our drug or they get sham, and then they get observed. It's a PRN study in a sense, and what they're getting observed for is the supplemental criteria.
What we hope to see is a better visual acuity in the treated patients, because ultimately, that's going to be the primary endpoint of a pivotal trial, which is non-inferiority change in visual acuity. That's really... Obviously, we're looking for safety, too, but I can tell you, it's just so far, the safety's been impeccable. But we wanna see not only a visual improvement and a difference, but an anatomic improvement that would back up the visual improvement.
How do you put the phase II NPDR data earlier this year in context with your programs in wet AMD and then DME?
Yeah, so NPDR, of course, is a very different disease than wet AMD. There is no symptoms, there's no fluid, it's not active, and that the primary endpoint when we designed the NPDR trial was improvement in the degree of retinopathy, which we weren't able to show. What we did show is that we slowed down worsening and we did it in a dose-dependent fashion compared to the control group. That is an approvable endpoint now, two-step slowing of worsening. But the difference, again, to us, wasn't great enough to warrant going forward with the pivotal trials. You could show that in a superiority trial. You just need a big N, and then are you gonna have, you know, what's gonna be your commercial success if you're, you know, the number of patients who actually you help is relatively low?
So we've decided that we are tabling the NPDR for now. We're focusing on wet AMD, and hopefully, in the first quarter of next year, we'll add DME to the focusing list. Why it showed that? You know, seven trials over the last ten years of TKIs of various delivery systems in wet AMD have all been positive. I don't think there's any question that TKIs work in wet AMD. There's now two trials of TKIs in NPDR, and one could argue that neither of them were positive, and I would. So I think this is a disease-specific entity, and our explanation is not that we're not blocking VEGF. We're clearly blocking the VEGF receptors at the doses we're using. But there's probably off-target receptors that early in NPDR you don't want to block, that the TKIs, both vorolanib and axitinib , are probably blocking.
And we're doing a little work to try to determine what those might be, but we don't think that those are active at later when there's exudation, for example, in DME later, and the VEGF levels are higher, and we don't think that's clearly gonna be true of wet AMD, so as the phase II data was so strong in wet AMD.
Then thinking about DME, I know the priority is wet AMD and putting that program forward, but what kind of signals are you looking for to determine next steps in DME?
So again, I think because the primary endpoint in a non-inferiority trial is change in visual acuity, we'd like to see, not just stability, but some improvement in the visual acuity using our drug. That would be great. You know, again, because we're not going against an Eylea control group on label, which would be every other month, that would be hard to extrapolate the control group to see how we would do. But in a previously treated DME group, after the load, you expect stability, maybe a little bit of improvement. So if we can show that, then I think that would speak well for our ability to be non-inferior in a pivotal trial.
Okay, so we'll see that DME data, early next year. But a lot of focus is on execution. You've had a history of good execution, but-
We have.
There have been some questions about... There are going to be a few programs enrolling in wet AMD around the same time as you guys. How do you think about that in terms of, your enrollment estimates?
Sure. So first of all, we learned a lot from doing our phase II program. And there, as I've said before, you know, we had a Type C meeting with the FDA in 2022 'cause we were contemplating going straight to pivotal. Well, I'm glad we didn't for a lot of reasons, and one of them is we learned a lot about how to enroll these trials. If you look at the enrollment, we didn't really talk about this much, but two-thirds of the trial in wet AMD was enrolled in the last three months 'cause we learned lessons, and we're gonna apply those. There is competition. There's always competition for wet AMD, but again, our trial, I believe, is very easy for the doctors to understand. It's easy for the patients to understand. Everybody's getting treated. It's a two-year study.
The doctors like two-year studies. And we are positioning ourselves with... I already mentioned, you said, "Why, why can't you start the trial right away?" Buying the Eylea and getting the Eylea to them packaged and ready to go, they like that. They don't have to buy it themselves and bill us. So that, that's one of the lessons we learned, that's we believe is gonna have the doctors really be enthusiastic about putting patients into our trial.
Okay, great. Maybe, in the last twenty seconds, any last remarks and what should people keep an eye on?
No, we're really excited about where we are. We have great phase II data. Our phase III program is aligned with the FDA, and as you say, it's an execution story now. From a financial perspective, we've got cash out to top line from the pivotal trials, and so we think we're in a terrific position right now.