Good morning. Welcome to the H.C. Wainwright Fifth Annual Ophthalmology Virtual Conference. For this session, we'll have a fireside chat with Dr. Jay Duker, the Chief Executive Officer of EyePoint Pharmaceuticals. Welcome.
Thank you, Yi. It's a pleasure to be here this morning.
Dr. Duker, we know that EyePoint recently reported that both pivotal phase III trials of DURAVYU™, which are the Lugano and Lucia trials, have completed enrollment. Could you tell us whether both trials have enrolled treatment-naive as well as treatment-experienced patients, and will that potentially have an impact on the future data readout?
Yes, they did, Yi. In fact, both trials are essentially identical, which we believe gives us an advantage with respect to the FDA evaluating the results. We do expect that the inclusion of treatment-naive wet age-related macular degeneration patients will be an advantage for several reasons. First of all, I'd like to remind the listeners that we did a very robust phase II trial of our drug, DURAVYU™, in wet age-related macular degeneration in previously treated patients. This was a tough-to-treat population in the phase II. On average, those patients had 10 injections normalized in the year leading into the trial. In the United States, on average, patients get about six injections. We got very few patients in that trial that had been treatment extended successfully out beyond two- three months. We did really well.
Again, to remind the audience of the results, both treatment arms of DURAVYU™, 2 mg and 3 mg, were essentially identical visually to the Eylea on-label control. The inclusion of naive patients, we believe, will give us even better results than we got in the phase II. The reason is there's probably 20%- 25% of the wet AMD population that is fairly easy to treat. They can be treatment extended out to about three-month intervals with virtually any drug. We think our drug will do very well in that population. We think automatically, by including those patients in the pivotal trials, that our results and our number of supplements should go down. From a safety perspective in the phase II, there were really no safety signals at all from either our drug or our insert.
Of course, we've had no ocular or systemic SAEs secondary to our drug in any of the trials that we've run in over 190 patients. From a safety perspective, we wouldn't expect the naive patients to act any differently, certainly. To remind everybody, everybody in the pivotal trials gets a monthly load of Eylea. By the time DURAVYU™ gets inserted at week eight, those patients aren't technically treatment-naive anymore. They've already had a load of Eylea. We also think this will potentially lead to a broader label. We would anticipate, if approved, our label should look something like DURAVYU™ is indicated in either naive or previously treated wet age-related macular degeneration after three injections of an anti-VEGF on a q6mo basis. Again, we think the inclusion of treatment-naive patients is an advantage and will de-risk the program.
Just to let you know, both trials have about a 75%/ 25% ratio, naive to previously treated.
Got it. This is an ideal ratio, right? 75% versus 25%?
We think so. When you say ideal, we believe that that is a good mix that allows the FDA to see how we also do in the naive population. We would expect that the previously treated patients would probably be similar to what we saw in the phase II, relatively tough to treat. You know that makes sense because if you're a wet AMD patient and you're already treatment extended out to three months and doing well, chances are you're not going to enroll in a trial that requires monthly visits. Another good thing about doing a phase II is we know our statistics. We know our standard deviation. We believe we found the optimal dosing of the drug, the optimal dose of the drug. Therefore, we believe that 75%/25% ratio gives us the best chance for success.
Got it. Thank you. Can you talk about the rescue criteria for supplemental injections in the trials? Are the current rescue rates in line with expectations?
First of all, with respect to rescue or supplementation, this is a concept that has been present really since the start of sustained-release therapy. If you're looking at various clinical trials of sustained-release therapies, you'll note that there's no set way to have your rescues delivered. Each sponsor and even various trials, it can differ. That's an important concept. The FDA doesn't appear to mandate a fixed idea of how to supplement. Our supplement criteria came out of work that we did on the phase II. Once again, a big advantage to doing a phase II. What we discovered in the phase II, that there were certain supplement criteria, for example, new fluid without a change in vision, that we really didn't need to use in the phase III. It makes sense. If your eye has stable vision but has new fluid, there's no reason to supplement.
That eye isn't going to see any better from a supplement. Ultimately, that's the primary endpoint, visual acuity. Our supplement criteria became simple, which is a loss of five letters of vision from best on study associated with a 75 increase in fluid, CST, as measured in OCT from best on study. They have to be together. We believe that will not only protect patients from visual loss, which is critical, obviously, for the patient, but also for the result of our non-inferiority trial. It's simple. It's easy. It's easy for the physicians to remember. In addition, we had supplement criteria in the phase III that has to do with hemorrhage. We want doctors to supplement if there's a site-threatening new hemorrhage due to wet AMD.
When we evaluated the patients in the phase II trial in all three arms that were supplemented due to hemorrhage, there were nine of them in total. What we discovered was six out of the nine either didn't have a hemorrhage, or the hemorrhage wasn't from wet AMD, or it wasn't considered site-threatening. What we've done is added a criteria for the sites to take a picture of the hemorrhage and adjudicate it with a rescue monitor to see if the rescue monitor agrees that this is a site-threatening hemorrhage. It's simple. Those are the only two criteria that we have. Again, in the phase II, we allowed physicians to rescue at their discretion. 20% of the rescues in the phase II met no criteria at all.
That is another reason why we're optimistic that the supplemental rate in the pivotal trials will be less than what we saw in the phase II. As for monitoring the supplemental rate, we believe that at this point, making public statements that include potential results, even masked results, may put us at risk with the agency. We really don't want to do that at this point because we feel like we are, to use a golf analogy, we're hitting it straight down the fairway right now and hitting it far. We're in line to break par here. There really doesn't seem to be an advantage for us to take a risky shot right now.
Thank you for that. I understand DURAVYU™ utilized the bioerodible Durasert E™ technology. Can you tell us how it is different from the Durasert technology used in currently commercialized products? Could the difference have an impact on DURAVYU™'s efficacy or safety profile?
Oh, sure. Again, going back historically, the Durasert technology has been around for several decades and is in four FDA-approved products. When you have a drug that is very soluble, even if you mix that drug with a matrix to solidify it and sustain release it, if it's soluble, it's going to go away fast. The first medications, APIs that were put into this system were highly soluble drugs, corticosteroid and ganciclovir. As a result, to slow down the release, it was necessary to put a polyamide, essentially plastic inert shell, around the matrix, leaving pores to allow the drug to diffuse out through the pores. Vorolanib is not that soluble. For wet AMD, we didn't need the polyamide shell, and we didn't want the polyamide shell. It wasn't necessary. Polyamide, although inert, hasn't caused problems, it doesn't go away.
If you really think about how long wet AMD patients live after their diagnosis, we didn't see any advantage to have these polyamide shells built up in the eye. The bioerodible form, quite simply, is drug with matrix, but no polyamide shell. The entire insert should be fully bioerodible. I do want to add Durasert was designed so that the matrix holds the drug together and controls the release until the drug is essentially gone. Animal studies suggest that in humans, it should be completely gone from the inserts in about nine months. The matrix is fully bioerodible and should go away, based on animal studies, in several more months. That was by design because what you don't want is free drug particles floating inside the eye. At that point, you wouldn't control the drug release anymore.
You run the risk of those free drug particles actually blocking the vision, being visible to the patient and being visible to doctors. We don't have that. We shouldn't have that. We've never had that. In over 190 patients that we have complete follow-up on from the phase I and three- phase II trials that we've run, we've had no patients report loss of vision due to the inserts. Overall, if you think about the proven track record of Durasert with the polyamide shell, we've actually taken away excipients. From a safety perspective, we think there really is no reason to believe that there would be a problem. We haven't seen a problem. In animal trials, there hasn't been any safety issues, even with multiple frequent reinjections. Overall, the next generation Durasert E™, the next generation refers to the higher payload, we think it will perform very, very well.
The evidence we've seen so far from a mass safety perspective would indicate that. I will add one more thing about our inserts. They are now 94% drug, only 6% matrix. Given each insert is only about one 5,000th for the vitreous cavity, when you do the math again, that little nubbin of residual matrix that might be left after the drug is gone in nine months or sooner really shouldn't be any kind of problem as it fully bio-erodes. It doesn't break into pieces. It doesn't emulsify. There's no PEG in it. There's no PLGA in it. From a safety perspective, we're very comfortable with next generation Durasert E™.
The drug itself should go away in about nine months. The matrix could take a little bit longer to completely disappear.
It should, yes.
There shouldn't be any safety concern associated with Durasert E™ for re-dosing at six months, right?
No. As I said, in animals, we've re-dosed multiple times, even at a shorter interval than six months, and found no safety concerns.
I see. OK.
From the phase I and phase II studies we ran, we've had up to three inserts in about 80 eyes with no problems, no issues related to the number of inserts or inserts causing visual loss or be a problem. The fact that they're 94% drug and there's two inserts with each injection, when you kind of do the math, you end up at a steady state every six months with a volume and a mass less than three inserts. Not a concern.
Got it. That's very helpful. Has the Data and Safety Monitoring Committee reviewed the mass data from both trials?
Yes, it has. We did report that the Data Safety Monitoring Committee advised no changes in the protocol from the first meeting of both trials. That's important. Our phase III was informed by our previous trials, especially the large phase II that we ran. We've had no significant changes in the protocol, nor do we expect any now that we're fully enrolled. We don't expect any. That's, again, a de-risking issue. Changing one's protocol in the midst of a pivotal trial does nothing but add risk to the program.
Yeah. Got it. I understand Lugano is now expected to report top line data in mid-2026 and Lucia in the second half of 2026. Could you remind us the primary endpoints of the trials and your expectations for the data readout based on existing clinical evidence of DURAVYU™?
Sure. Yes. I can't emphasize enough what a great accomplishment it was for not just EyePoint and our clinical team, but the sites, the doctors, and the patients to get these two trials enrolled so rapidly. About seven months, over 400 patients in each trial. It was very, very rapid enrollment, which I think speaks to the enthusiasm that the doctors and patients have for our drug. The primary endpoint is a blended visual acuity endpoint at week 52 and week 56. If you do the simple math, allowing for some weeks to get the data together and confirm that it's right, we should have top line from the first trial sometime in the middle of next summer, less than a year from now.
Because the second trial is identical, we would expect that if the results are positive from the first trial, they should be positive from the second as well. From an expectation perspective, I think it's simple. We hope and expect fully that we will be non-inferior to on-label Eylea statistically and numerically. I wouldn't rule out that we possibly could be numerically and perhaps even statistically superior. What's the basis of that? If you look at DAVIO 2, the patients who were not rescued in DAVIO 2 ended up with numerically better vision than the unrescued eyes in the control group. We may be able to replicate that in the phase III. I also would point to the visual acuity results in our diabetic macular edema phase II, a 10-letter improvement in the unrescued eyes, which is superior to what you'd see from a treatment-naive population treated with Eylea alone.
There is some evidence that we might actually have numerical superiority to the control. Obviously, we don't need it. Statistical non-inferiority gives us our primary endpoint. We would expect safety to match what we've seen in the past. We have no evidence that there would be any difference in the safety perspective. As I've said already, I think from the perspective of supplements, we would expect the supplementation rate to be down. That also leads to one of our important primary endpoints, our secondary endpoint, which is reduction in treatment burden against the control group. We believe we will be able to achieve that. That's the expectations. We're obviously very excited to be where we are today. It's been an incredible journey of incredible execution and dedication by our team here. We're really excited for next summer.
Yeah. That's very helpful. Has vorolanib been approved in any country in the world? What are the available approaches to facilitate the regulatory pathway in the U.S. for DURAVYU™?
Interestingly, the whole history of vorolanib goes back to the same protein chemist who developed sunitinib. The thought was that sunitinib, which was at the time being used or tested orally for kidney cancer, would accomplish the same thing, but with fewer off-target effects. In the laboratory, that was true. The company that was developing it decided, instead of being the second one in for a relatively small indication, why not be the first one in for a big indication? They tested vorolanib orally for wet age-related macular degeneration. It went through phase I and phase II, had very good efficacy as an oral drug. Of course, systemic TKIs and the doses used can have side effects. It had hepatobiliary side effects, which limited its use. It didn't get out of phase II as an oral drug.
We have a partner in China, Betta Pharmaceuticals, which has the rights to vorolanib outside of the eye. Just recently, in the past year, Betta got vorolanib orally approved in China for kidney cancer. That is the only approval worldwide of vorolanib. It's a new drug entity in the United States, which gives us some advantages in, obviously, potential advantages if we're approved with respect to patent protection and things like that, which we think is also of value. Vorolanib, again, well-tested, known safety in the eye. We believe it has some real advantages as a sustained-release API.
Got it. How do you expect DURAVYU™ to be used in real-world practice among existing wet AMD therapies, including Lucentis and Eylea, both of which have biosimilar drugs on the market, and also Vabysmo, as well as off-label Avastin? On that front, Avastin could become an on-label drug later this month.
All of the drugs that you just mentioned all have the same methods of action. They are relatively large molecules that block the ligand extracellularly. Obviously, there's differences, and there's longevity differences. I think everybody's well aware of how well Vabysmo has done with the promise of one or two more weeks of extension for patients between injections. We think that speaks very well for a drug that we think, based on the phase II, should, in the majority of wet AMD eyes, be able to go six months or longer between injections. Now, the way it's going to get used, again, I think we can speculate. I'm positioned to know the retina community pretty well. I think that if the phase II data holds, you're going to see probably the same general three ways that retina specialists approach wet AMD. The primary is treat and extend.
I think you could see a treat and extend protocol with patients who are already being treated with a ligand blocker, adding DURAVYU™, and then extending out the intervals to see how long the patient goes. Remember, in that situation, if I've got a patient who I have to treat every four weeks with Eylea, and I add a DURAVYU™, and I don't see fluid again for four months, even though it's not six months, I can then give the patient another Eylea, and then at six months, give them another DURAVYU™. All of a sudden, you're talking about two to three shots a year instead of 12 shots a year. That's a win. That's a win for everybody. Plus, the doctor is going to be able to take advantage of two MOAs.
We're used to chronic disease all over the body, including the eye, approaching chronic disease with more than one MOA. We don't do that right now for wet AMD or diabetic macular edema. We think our drug gives the opportunity to add a second MOA, also with what I like to call an insurance policy. You know, if you've got an elderly patient who you've tried to treat and extend out three to four months, that's a long time to go between visits. If they get sick, or they go on vacation, or they miss a visit, it's hard for doctors to get them back in. I think doctors will like the peace of mind of having a sustained-release insert in the eye, knowing that they're still getting drug, even if they miss a visit.
The other advantages that we have, which probably will lead to even more uptake, is we potentially will be antifibrotic. As you may know, we've had some preclinical data to suggest that we're neuroprotective. If we can show either or both of those in the pivotal trial, I think that would make it a situation where doctors would use us without hesitation if we're approved. I think that the integration of a second MOA that's sustained-release is something that doctors are really looking forward to now. I believe that, given positive data, our uptake will be rapid.
Can you talk about your expectation on how receptive the payers will be for a six-month TKI treatment for wet AMD?
Given that we've done a lot of work already on that, we've had an early product development group working for two years to work with retina specialists, not just the KOLs, but the retina community in general, working with payers and working with administrators of various retina groups, both private equity and nonprivate equity, large and small, to really find out what it is they want and how can we best position DURAVYU™ to give them what they want. The payers have been very receptive. They just have. The idea of a new MOA with sustained release and the ability to take at least some patients out longer between injections, because remember, the burden isn't just the cost of the drug. The burden is the visit. The burden is the OCT. The burden is the cost of injection.
There's other peripheral charges around visits that payers would like to see more efficiency, if possible. We hope to provide that.
Got it. What is your current manufacturing capacity for DURAVYU™?
Currently, at the moment, we manufacture and are capable of manufacturing thousands of inserts here in Watertown, in our main office. As we've announced and made people aware, we built a manufacturing facility that is about a 45-minute drive west of here in Northbridge, Massachusetts. This is a 41,000 sq ft facility built to our specifications, controlled by us, that is at the present time only going to be manufacturing DURAVYU™ for wet AMD and DME. That facility is up and running. We're currently doing registration batches there. At the current potential capacity with the eight clean rooms, we would estimate that we can make hundreds of thousands of inserts there a year, which should be adequate not only for the United States, but should we choose to launch out of the United States, there as well.
We also have capacity in that site to expand, not just within the current footprint and add to it. In the future, we have the potential to make about a million inserts a year there. Obviously, that's not where we made the inserts that we're currently using in study. We don't believe we're going to have to do any kind of human bridging study between it. We are actively preparing for NDA pre-approval inspection and eventual commercial success.
Got it. Thank you. Switching to the indication of diabetic macular edema, can you talk about your plan for this indication and whether you expect DURAVYU™ to show comparable performance in these patients?
From the plan's perspective, we had an end of phase II meeting with the FDA in the middle of the summer. We've had some back-and-forth exchanges with them and expect to see the final written minutes shortly. Once we've fully evaluated that, we're going to talk publicly about what our plans are. The meeting went very well. We've really reached alignment on virtually everything that we wanted to with respect to the plans. As we've said already, the first patient in DME is a 2026 event. While we're doing some of the early work now to get ready for manufacturing and hiring some new clinical positions, et cetera, the first patient in will be next year. With respect to how we're going to do, I am really excited about our phase II Verona study.
The first thing to look at, if you look at the results here, is our higher dose arm, 2.7 mg, which is what we're using in the wet AMD trials and what we expect to go to market with, did incredibly well. It did it fast. If you look at the four-week visual acuity results against Eylea in this population where everybody was active with DME, everybody was wet, within four weeks, we were already much better than Eylea, both anatomically and visually. In the eyes that were not rescued, it was over 10 letters improvement with about 120 µ improvement in fluid, much better than what Eylea showed in this trial. We think the odds of us being non-inferior are very high.
We also think that we may be able to achieve this type of visual acuity improvement and anatomic improvement faster than Eylea, which would be a huge advantage in the marketplace.
Got it. Does the company currently have enough cash to complete the pivotal trials in wet AMD, obtain regulatory approval, and commercially launch it?
The first part, yes. We have a cash runway that is into 2027, about approximately a year beyond data. So cash runway for that is good. We talked about all the current NDA prep that we're doing, the manufacturing prep that we're doing, getting prepared for the DME trial. That's all within that cash. The DME trial is not. Obviously, commercialization is not in that either. I'm going to state the obvious. We're optimistic that if we achieve the type of results we fully expect to achieve from the phase III trial, the value creation that will come to our investors and the position that we will be in, I don't think we'll have any problem through multiple avenues to raising enough cash to be able to successfully launch the drug in the United States ourselves.
Got it. Dr. Duker, we are getting to the end of the chat. Do you have any closing remarks to the audience?
I again want to thank you, Yi, for having me on and just say how excited we are here at EyePoint to be in the position that we're in. The first patient was dosed with our drug only four and a half years ago. Here we are after a robust phase II wet AMD trial, having fully enrolled very rapidly to phase III trials and expecting the results in less than a year. We're in a really good position.
Thank you very much. Best wishes.