Good morning, everyone. I'm Lisa Walter, Senior Biotech Analyst here at RBC Capital Markets. Thanks for joining us at RBC's inaugural Ophthalmology Conference. This morning, we have EyePoint Pharmaceuticals' Jay Duker, who's President and CEO, and Ramiro Ribeiro, who is the CMO. Jay, Ramiro, thank you so much for joining us today.
Thanks for having us, Lisa. It's great to be here.
Excellent. Jay, maybe we can just start off. Can you give us a brief overview of the company, the Durasert technology, and what stage of development the wet AMD and diabetic eye disease programs are in?
Of course. EyePoint is a phase III clinical stage biotech company. We are well positioned to be the leader in sustained-release drug delivery to the back of the eye. Our lead product is called Duravyu. Duravyu is the small molecule tyrosine kinase inhibitor, vorolanib, and our patented delivery system, which is called Durasert E. Duravyu is currently studied in two indications. The first is wet age-related macular degeneration. We are currently actively enrolling in two identical, near-simultaneous phase III pivotal trials in wet AMD. The enrollment is going incredibly well. We also completed a phase II trial in diabetic macular edema and have an active program in DME. The company is well positioned from a financial perspective with just under $400 million of cash as of December 31.
That cash runway gives us, we hope and expect, close to a year after data from the wet AMD trials. From the perspective of potential, from the perspective of safety of our product, from the perspective of the data that we've gotten from our two phase II trials, we feel that we're in a terrific position with a very large potential market in both wet AMD and DME, and a very de-risked product at this point.
Got it. Thanks for that, Jay. Just since it's on top of everyone's mind, given the recent news that the U.S. will be imposing a 10% universal tariff across foreign-made goods and reciprocal tariffs, could this be an opportunity for EyePoint given the manufacturing facility is based in the U.S.?
No, I think that at this point, so far at least, pharma has been excluded from the tariffs. Even if the tariff does start to involve pharma, we are in a very good position. Our API vorolanib is sourced in the United States. We have our own commercial manufacturing facility that we opened last fall. It is a 41,000 sq ft state-of-the-art manufacturing facility located in Northbridge, Massachusetts, which is about 45 minutes west of our headquarters in Watertown, Massachusetts. When it is fully up and running, we have the capability of making over 1 million Durasert inserts per year, which should be enough to supply, if successful, the global market for our product. We control the manufacturing ourselves. There is quite a bit of technical know-how that goes into making these inserts.
We think that we're in a very good position with respect to the global markets, given how we control our destiny with respect to manufacturing.
Got it. Jay, that's super helpful to have the clarity there. Just another event that is topical and affecting the pharma industry, what impact will the recent layoffs at the FDA have on drug development? How is EyePoint thinking about this?
To the first part of your question, I wish I had a crystal ball and I could answer the question for everybody. I think it's obviously still unfolding. We feel like we're in a very good position. First of all, we continue to interact with the FDA about various things. What I can tell you is the ophthalmology division continues to be highly responsive in giving us timelines that are unchanged from the prior timelines that we saw before this administration took over. Also, with our wet AMD program, I'd like to remind everybody that we had actually had a Type C meeting with the FDA in 2022 to discuss the pivotal program. We had come to an agreement around that pivotal because at the time, we were contemplating going directly to pivotal from our phase I.
We eventually decided to do a more traditional phase II, which, again, was very productive. It really taught us a lot about our drug and how it works. Obviously, it was a highly successful phase II. With that data, we had an end of phase II meeting in 2024 with the agency. We have, we believe, very solid written instructions and agreement over the pivotal programs so that we think that will be very helpful in the future should there be changes and new people coming into the FDA. I think it would be more likely than not that they would refer back to the written minutes and the agreements that we've already had. We think we're in a very good position from an agency perspective. Remember also, our wet AMD trials are what I refer to as tried and true.
We're doing two identical non-inferiority trials. That's the way the last five approvals in wet AMD have been done with non-inferiority trials. We think that's also very de-risking because the two identical trials, obviously the same enrollment criteria, the same patient population, the same statistical analysis. All of those from an agency and regulatory perspective, we think are de-risking.
Got it. Jay, that's very helpful. Maybe before we dive in more into Duravyu and the data and the ongoing phase IIIs, just maybe a bigger picture question on the wet AMD landscape. The anti-VEGF monoclonal antibodies, this is a $15 billion plus market today. About two-thirds of this revenue is attributed directly to wet AMD. Despite being one of the most successful therapeutic franchises today, there remains an unmet need in this disease area due to the treatment burden faced by patients. Jay, just wondering, can you remind us how is EyePoint looking to solve the treatment burden for patients who are reliant on anti-VEGF? And how could Duravyu change current standard of care?
Once again, this is at the essence of what we're trying to do, which is improve patients' lives, those who have serious retinal disease. As a retina specialist and a practicing retina specialist, I'm in a position to say that I really live this almost on a daily basis. As you pointed out, the ligand blockers have been very successful. The efficacy is very good. The safety is very good. What they lack is durability. Wet AMD is one of the few chronic diseases that's still treated in an acute staccato fashion and still treated with a single MOA. TKIs and vorolanib, they work at the receptor level. This is a different mechanism of action.
Because of our unique delivery system, we can deliver the small molecule with what's called zero-order kinetics, which means after initial burst of the drug, in about two to three weeks, we get to a steady state. We maintain that steady state for at least six months in humans. We think in humans by about nine months, the drug is completely spent from the initial inserts. This consistency of drug release, we think, can make a big difference in how patients do. One of the problems with any chronic disease, and certainly wet AMD, is that patients, because of the need of continued therapy, drop out. They can't make visits. They miss visits, and they lose vision.
With continuous sustained release for six to nine months, you can actually improve that by accounting for missed visits or late visits and the fatigue that patients can have over many years of having to come in with such frequent injections. We believe that our drug will improve the outcomes in wet AMD. We believe we've got the potential to improve patients' lives by giving them the flexibility to go longer between injections. Patients from our phase II data, two-thirds of them could go six months between injections. 50% went a year with just our drug and no further therapy. We have reasons to believe that in the phase III, we will do even better than that. Once again, for us, a supplement injection with Eylea is not a treatment failure.
If we can reduce the treatment burden for a patient, but it might require our drug plus one or two Eylea or Lucentis or biosimilar supplements during that time period, but it represents a significant reduction in their prior treatment burden, I think the patients and the physicians would be very happy with that. The idea of flexibility to reduce the number of visits and reduce the treatment burden is what we're really going to offer. Now, I have to add, we have the potential to do even better than just be a longer-acting medication. Because of the new MOA, it's conceivable that some patients may do even better with a receptor blocker than a ligand blocker. We've seen some evidence of that, and certainly in our DME trial, which we can talk about. We also should have an antifibrotic effect.
We block PDGF, which theoretically should block fibrosis. When you ask retina physicians, why do patients in the long term lose vision in wet AMD? The number one answer is the patients stop coming in for the injections. The number two answer is they get geographic atrophy, dry AMD. The number three answer is fibrosis. We are in a position to take care of two of those three long-term reasons why wet AMD patients lose vision. If in fact we are antifibrotic, that's something that the ligand blockers can't offer. In addition, we've done preclinical studies, animal studies that suggested that vorolanib may be neuroprotective, meaning in patients with retinal detachment, fluid under the retina, animals that got vorolanib showed that there was less loss of the photoreceptors.
If we can show that also in patients, I think that would be another reason why doctors would really be motivated to use our drug because in the long term, we may be protective to the outer retina. I think, again, we're in a position to offer patients and practitioners flexibility to go longer between visits and injections. Beyond that, the second MOA, the antifibrosis, the potential for neuroprotection is something that really may push us into a position where doctors have to find a hard reason not to use us.
Jay, thanks for that. I just maybe want to dive in. You mentioned this antifibrotic effect as something that could be differentiating from a tyrosine kinase inhibitor versus anti-VEGF. How could you go about measuring an antifibrotic effect? Is this something that you've explored in your clinical studies?
A good question. The answer to that question is that ancillary testing in all these wet AMD trials and DME trials are done frequently. At every visit, patients get an OCT, optical coherence tomography, which is a cross-sectional quantitative measurement of the center of the retina. Fibrosis can be detected on an OCT. It can also be detected on a fundus color photograph, which we do periodically, and also on fluorescein angiography, all of those together. Like any large clinical trial, we have what's called a reading center, which looks at these ancillary tests and rates the fibrosis at the beginning of the trial and a year into the trial. We'll do it at year two as well.
What we hope to show is that for eyes that have progressive fibrosis, our drug shows a difference between the fibrotic effect versus the Eylea control. There will be quantitative ability to show that. We hope that we can show that as a differentiation between our drug and the ligand blockers.
Jay, for fibrosis, and since you're looking at patients quite frequently, trying to assess the effect here of the TKI, should we be anticipating versus the Eylea arm a slower rate of decline in terms of fibrosis? Should we be looking at perhaps stability with the TKI versus decline with Eylea? Is there potential to even reverse fibrosis in TKI-treated patients? How should we think about that?
I think it's really, again, a slowing down of the fibrotic process so that the fibrosis can be measured quantitatively in an area. Eyes that don't have fibrosis at the beginning can develop fibrosis. Eyes that have fibrosis can get more. We will be looking quantitatively at the area of the fibrosis as it enlarges to see if there's a difference between the treatment and the control groups. Reversing of fibrosis, I don't know that our mechanism of action is going to allow for that. It's conceivable that blocking PDGF may allow for that. There were some early trials done on choroidal neovascularization that was a type II where there did show some reversal of that. That type of choroidal neovascularization is rated on an OCT. Type II CNV used to be much more common.
Nowadays, since wet AMD is being diagnosed earlier, most of the choroidal neovascularizations we see are type I, which are a little less associated with fibrosis. While that may be possible even in this population to show reversal of fibrosis, that's not our expectation. I do think in the end, it's all about visual acuity. Fibrosis is a long-term problem. I believe my colleagues will accept that if we show significant decrease in fibrosis at one year, that will eventually show up as improved visual acuity in the long term.
Jay, just digging in here a bit more, are you potentially thinking you could explore having an antifibrotic effect on the label should Duravyu get approved? Is that something that could end up in the clinical section of the label as a differentiating feature? How are you thinking about that?
I think that's certainly possible depending on what the results are. Yes. It is an endpoint that we'll be looking at. If it's achieved, then I think we will be able to put that on the label.
Got it. That's helpful. You already touched a little bit on the phase II data in terms of efficacy. Just wondering if you can remind us about what the safety profile has looked like with Duravyu across the 190-plus patients that EyePoint has treated to date.
Sure. Let me start out with the preclinical safety. We have not found a maximally tolerated dose of vorolanib in animals. We have done a scaled dose in rabbits of 10 times higher than what we put into humans or could put into humans with no toxicity seen. We have also not found a maximally tolerated number of inserts. We have had up to six inserts in the rabbit eye simultaneously with no toxicity. From a preclinical perspective, we are very comfortable with both vorolanib and our delivery system. Now, remember also, the delivery system has been used in tens of thousands of patients prior. It was a little different. It was not erodible. The non-erodible for previously treated FDA-approved products had a polyamide shell around the core of the drug. That polyamide shell is inert, but it never goes away. That made the previous inserts non-erodible.
We took away the polyamide shell for Duravyu to make it completely bioerodible. That also gives us comfort that the inserts and the matrix that's used in the insert, which has been in tens of thousands of patients, is safe. Finally, as you mentioned, we've put Duravyu in over 190 patients with at least a year of follow-up. We've had no ocular or systemic SAEs reported due to our product. The AEs have been basically what we would expect in a wet AMD population. For the most part, they're grade I or grade II from the phase II trial. They're things like subconjunctival hemorrhage, which is a broken blood vessel on the white of the eye from the injection, which is common with any injection. Of course, we had patients who in the phase II had AEs reported as progression of wet AMD.
Some of them did progress and required supplement injections in that regard. As you look at the AE tables, again, we just had the DME trial reported out. The number of AEs in the DME trial was exceedingly small. From a safety perspective, we're very comfortable with Duravyu. We're very comfortable with vorolanib. As I said, so far, so good. We believe that the safety so far has been terrific.
Got it. Thanks, Jay. Maybe let's talk about the Lugano Lucia trials. You mentioned these are two ongoing phase III non-inferiority studies. I'm getting a question here from the audience. Can you remind us what the rescue treatment criteria is?
Sure. Just to give, if you like, if you don't mind, I'll give you a little background. These.
Sure, of course.
Simultaneous non-inferiority trials enrolling approximately 400 patients into two arms. The first arm is the treatment arm, which is 2.7 milligram of our insert. This is, again, inserts that are 94% drug. In the phase II, we used lower payload inserts that had about five times more matrix in them. The patients are about 75% will be treatment naive. About 25% will be previously treated. All patients get randomized on day one. On day one, they all receive 2 milligrams of Eylea. They receive another 2 milligrams of Eylea on week four. On week eight, they receive 2 milligrams of Eylea. Thirty minutes later, they either receive Duravyu or they receive a sham injection for masking. The patients are then watched monthly. Every other month, the Eylea arm gets another Eylea. The Duravyu arm gets a sham.
At month eight, six months after the first Duravyu, the patients will get a second Duravyu. The primary endpoint is non-inferiority change in visual acuity combined weeks 52 and weeks 56. Both arms can be rescued. This is a little bit of a unique aspect of our trial design. The physician who determines if an eye meets rescue or supplement criteria is masked to which arm that eye is in. The supplement criteria, and Ramiro Ribeiro, our CMO, who's on the call as well, was instrumental at really studying the phase II to determine which rescue criteria really mattered. We have really simplified rescue down to a drop in five letters from best on study due to wet AMD, along with 75 microns of new subretinal or intraretinal fluid due to wet AMD. The eye has to have both of those simultaneously to meet rescue criteria.
If they do, we want them to be rescued. We do not want patients to lose vision. We want them to have that protection of a supplement injection in either arm if they need it. I go back to either arm. Remember, the Eylea arm is going to get treated every other month. In the real world, about 20% of patients still need monthly treatment. Clearly, some of the patients in the control arm will be relatively undertreated. Those eyes will also have the ability to be rescued. In the end, when we compare the rescue numbers, it is going to be a comparison between our arm, the treatment arm, and the control arm. In addition, we have one of the rescue criteria, which is new hemorrhage due to wet AMD. That is going to be adjudicated along with the help of a rescue monitor.
The reason we added the rescue monitor to the hemorrhage is that when we looked at the hemorrhages in phase II, and there were nine hemorrhages across the three arms, it turned out that six out of nine, they either weren't a hemorrhage or they weren't due to wet AMD. We wanted to be sure that the eyes that had active disease get rescued, but the ones who did not have active disease do not. Hence, the rescue monitor with respect to hemorrhage. We no longer allow physician discretion to do a rescue. We did in the phase II. It turned out about 20% of the rescues didn't meet any criteria. We wanted to eliminate that in the phase III. That's the supplement criteria. We're quite comfortable that this will accomplish the goals that we like.
Jay, just a couple of questions on the rescue criteria. Is there no option to retreat just if there's presence of fluid? You have to have both BCVA reduction and presence of fluid. Is that correct?
That's correct. That's correct. One of the things that I think people should be aware of, and this is a little subtle, but we retina specialists, we use OCT in the presence of fluid as a biomarker for activity. When in reality, what a patient cares about and what a doctor cares about is visual acuity. As it turns out, eyes that have a little bit of subretinal fluid in wet AMD, there are multiple trials that show that the end result for visual acuity is actually better in an eye with a little bit of subretinal fluid, as long as it's stable, than eyes that have no subretinal fluid. That implies, and I think it's true, that fluid in and of itself is not necessarily a bad thing in wet AMD.
Toleration of stable small amounts of fluid is now something that is, I think, becoming acceptable. Because, of course, there are certain eyes that you can't get rid of all the fluid. Fluid alone, especially subretinal fluid, does not necessarily mean a drop in the vision. Therefore, going back to that question, fluid alone is not a rescue criteria for us because ultimately, our primary endpoint is visual acuity. It is in fluid. We care about fluid. We especially care about fluctuations in fluid, which, again, since the topic was brought up, I'd like to go back and remind people of our results of the fluid stability in the phase II. While the control group, every other month, Eylea had a typical sawtooth pattern that you see with every other month, Eylea, meaning the two months after the last injection, the eyes were gaining fluid.
The Duravyu eyes did not have a sawtooth pattern. They were rock stable.
Thanks, Jay. That's really helpful. I do have a couple of other questions here from being emailed into me. Are there any limits to the number of rescues patients in the treatment arm can have? Once they get one rescue, are they still eligible for more? Would this be a triggering or a safety issue to the FDA if a patient in the treatment arm is getting multiple rescue injections?
Yes. There is no limitation. Anytime they meet a rescue criteria, they should be, and we hope will be, rescued. There is no limitation per se. The rescues are handled with sensitivity analysis. It is a statistical way that they are handled. It would make sense that an eye that has multiple rescues would be handled differently than an eye that only had one or that an eye that had none. That is a statistic sensitivity analysis that will be done after the totality of the data is there.
Jay, just on the non-inferiority BCVA primary endpoint, do you have a written agreement with the FDA that the margin is negative 4.5 letters?
Yes.
Yes? Okay.
We do. Yes. We had that written agreement at the Type C meeting in 2022. It was reiterated at the end of phase II meeting in 2024, minus 4.5 letters.
Got it. Got it. That's super helpful. Maybe just let's talk about the enrollment and how that's going. I believe the last update you gave, you were getting closer to over halfway enrolled. Is that right?
Actually, a little more than that. We were halfway enrolled. I think we updated that in January in the first trial. I think we updated again about a month later that we were close to 60% enrollment. That was in early February. Here we are now in April. What I can say is that the pattern of enrollment has not slowed down. While we have not yet changed our guidance to full enrollment in both trials in the second half of the year, what I can say about the first trial, Lugano, is that there has been no slowdown in enrollment. We are literally setting records with enrollment. The second trial is going with the curves of enrollment looking almost identical. The second trial is also enrolling very, very rapidly. I think this is a testament to a couple of things.
First of all, we did a phase II trial. The doctors know the data from the phase II. They're impressed with the efficacy. They're impressed with the safety. It makes it a lot easier to talk to the patients when they can say, "Look, almost 200 patients have had this treatment already. It looks like it works. It looks like it's safe." The second thing is everybody gets treated. We don't withhold treatment. If you are randomized to the control arm, you're getting state-of-the-art 2 milligram Eylea. Obviously, if you get the treatment arm and you need supplement, you're going to get it. It's an easy trial to understand. It's an easy trial to explain to patients. It's a real-world trial. It's a two-year trial.
I think that's another advantage that we have from out the start is that the physicians know that this trial from the beginning was a two-year trial. I think that that gives them comfort about planning on keeping the patients in. Enrollment has been absolutely fantastic. I need to call out my colleague, Ramiro, our Chief Medical Officer. He and his team have just done a fabulous job with enrollment.
Got it. Thanks, Jay. I just want to get a sense of your expectations. The primary endpoint, the 4.5 letter delta, that's pretty well accepted. You have a written agreement there. That is not up for debate. What do you need to see in terms of reduction in injections or percentage of patients that are supplemental injection-free at the six-month interval mark to get excited about the commercial prospects for Duravyu? We saw 63% in DAVIO 2 from the phase II. Is that the right bar?
Let me start with the primary endpoint again, as you say, non-inferior visual acuity. At this point in the pivotal trial, as long as we are statistically non-inferior, I don't believe the actual numerical difference matters if we are less than Eylea. What's the evidence of that? Look at high-dose Eylea. It was minus 1.4 letters worse than 2 milligram Eylea. It was statistically non-inferior. I've never heard one of my colleagues say, "I'm not going to use high-dose Eylea because it was 1.4 letters worse." That small amount is not meaningful to doctors or patients. The actual numerical difference, if we are less than Eylea, is not relevant as long as we are statistically non-inferior. Obviously, safety, our safety track record has been great. We talked about that already. We hope and expect to see similar safety from the phase III.
The reduction in treatment burden, there's no number that the agency has attached to that. I don't think this is a regulatory number that needs to be hit. Clearly, the better the reduction in treatment burden, the more effective your drug, and the more likely you're going to be commercially successful. We were about 80% reduction in treatment burden, even at one year in the phase II. I would expect that we will be similar or even perhaps slightly better in the pivotal trial. I think we don't need to be that good to be commercially successful. When we queried KOLs before the phase II data and we asked them that question, which is, "What type of reduction in treatment burden would you want to see for you to use this?" Most of them were around 50% was good enough.
There is evidence of that too. If you look at the real-world use of Vabysmo, Vabysmo is doing great. It is a $4 billion drug right now. It only offers about a week or two longer longevity over 2 milligram Eylea. Yet retina specialists are using it, even that small amount of longevity, a relatively small amount. We think the majority of eyes being able to go six months or longer will open up a very large market for us.
Got it. Jay, we're just about at time here. I do want to just touch on DME. You shared the positive 24-week results from the phase II Verona study earlier this year. What are the next steps for the DME program?
Yeah. We are really excited about the potential of DME. When you really look at the data, and especially you look at the rapidity with which our drug worked and how it was significantly better than a single shot of Eylea as early as week four with a tremendous drying effect. You look at the eyes that were supplement-free, and they had a drying effect of almost 125 microns and letter improvement of 10 letters, which is better than what we saw in the phase III trials for 2 milligram Eylea and DME. We are really excited about the potential. The DME, we continue to work internally on the program. We have plans to meet with the FDA at the end of this quarter to talk about the DME program.
The first patient in the initial start of the DME trial, if you want to call it first patient, is going to be a 2026 event.
Got it. Thanks so much, Jay. We're over time. We'll end it there. Could ask you 1,000 more questions. We'll keep on schedule. Jay, Ramiro, thank you so much for joining us today. It was a pleasure to have EyePoint participate in our inaugural ophthalmology conference.
Thanks a lot, Lisa.
Bye. Take care.