Our CEO, and George Elston, the Chief Financial Officer. Thank you guys so much for joining us. Maybe just to start off with, can you give us an overview of the company, some of your recent updates and progress?
Sure, I'd be happy to. Thank you very much for inviting us. So, EyePoint Pharmaceuticals is a drug delivery company to the back of the eye. Our lead product is called DURAVYU. DURAVYU is currently in phase III trials in wet age-related macular degeneration and in a phase II trial for diabetic macular edema. DURAVYU is the small molecule, tyrosine kinase inhibitor, vorolanib that is put into our sustained release platform, which allows drug release for between six to nine months of the human eye. We had excellent wet AMD data last December, and then we followed this up with some top line data from a DME trial just several weeks ago. And so, yeah, we had a very busy week. We were just talking about how it doesn't really get much better than that.
Within six days, we had the first patient in our first wet AMD trial and an announcement that we will start the second wet AMD trial before the end of the year, followed by a really exciting investigator meeting, and then we had this new data from DME, followed the next day by a capital raise of $161 million, and then the day after that, we had a ribbon cutting on our new commercial manufacturing facility, so it was a busy end of October for us.
Mm-hmm. Well, congratulations.
Thank you.
Yeah, let's start with DME. Can you tell us a little bit about the design of the VERONA trial?
Happy to. Yes, the phase II trial was called the VERONA trial. We enrolled 27 patients and they were randomized to either a high dose of our drug of 2.7 mg or low dose of 1.34 mg or to an Eylea control, and the randomization was 2:2:1. The patients all had active diabetic macular edema. So what that meant is they all had to have fluid over 325 microns at least. They all had to have decreased vision and all had been previously treated. This was the first trial that we did where all the participants in the trial had active disease with wet maculas. The trial was designed really as what I'd refer to as a PRN trial.
On day one, everybody got a shot of Eylea, and then 30 minutes later, they either got a dose of DURAVYU, their assigned dose, or they got a sham. Then they came in monthly, and there were no other assigned treatments unless they needed and met criteria for supplement. The supplement criteria was very similar to what we used in wet AMD, in the, in the DAVIO 2 trial, with one exception. We added a fifth supplement criteria for the VERONA trial, which was if a patient hadn't had an improvement of 10% or more in their OCT from day one by week 12, then they got supplemented.
The reason we added that is we knew these patients had severe disease going through the trial, and we really thought it was wouldn't be fair to the patient to keep them with a wet macula and decreased vision for all six months. This was always an open label trial that the patients were masked, but we were not, or nor were the investigators. We made a decision to take a look at the data early. What we found was really so positive in, I won't say surprising. We had every confidence we were gonna do well in DME, but we frankly did better than expected. And again, to summarize, at week four, both of our doses had substantially better vision improvement than did the Eylea arm and substantially drier maculas.
So what that showed us was something that we believed all along is that our drug is immediately bioavailable, and that improvement at week four could only be explained by our drug. Interestingly, that improvement continued in the high dose through the data that we released week 16. And at week 16, those eyes at the 2.7 mg dose had improved nine letters, and they had dropped their thickness on OCT by 70 microns, substantially better than the Eylea control. Couldn't be explained by supplements because 82% of the high dose were still unsupplemented at that visit, whereas 60% were unsupplemented in the control arm. So this really was an exciting result for several reasons. First of all, as I said, this was the first time we took a wet population, we dried them, and we dried them immediately, and we dried them better than Eylea did.
So this gives us a lot of confidence that entering a pivotal trial in DME that we could do quite well. Once again, there was, because of our NPDR data, which again was directionally positive and safe, but a little disappointing, there was some, you know, talk out there that our drug wasn't that strong, well, that our results in DME show it's quite strong and worked right away. There was talk that we wouldn't work in diabetic eye disease. Clearly, we do. There was also discussion that we needed to do a load in everybody to work. We never believed that because we knew our drug was immediately bioavailable, and again, these eyes were not fully loaded yet. We had a great result.
So it also brings up the possibility that if we're nine letters better, that we may think about in a pivotal trial doing a superiority study, and so we're gonna wait until the full six-month data's available, and then we're gonna analyze it and internally make some decisions about what our program's gonna look like, and then, of course, we wanna align with the FDA, but we are very excited to be entering DME as another potential billion-dollar space, and right now we're the only company, TKI company, in DME, and so I'd like to think with all these accomplishments that, I believe we are the leader in sustained release right now of all the TKI companies and the gene therapy companies. We've got the best phase II data.
We've got a delivery system that's been FDA approved and four other products, and we believe we're gonna be first to market. So overall, I think we are in terrific shape.
Great. Maybe sort of what contributed to the decision to take, I guess, the earlier interim look on the study?
Some of it was just frankly, the data was so positive in that it was very clear it was our drug alone and very clear through month four that that data was really, you know, held up by DURAVYU and nothing else. Secondly, there was this persistent, I would say, negativity due to our NPDR data, and we felt this was a great opportunity to show just how good our drug did in active wet DME patients.
Mm-hmm. Great. And as we look to the six-month data, you mentioned that you're gonna be analyzing that in terms of thinking about a potential superiority study.
Correct.
What should we be looking for in this data?
Again, I think the case has been made.
Mm-hmm.
The data is, we think, is really, really strong. We announced when we did announce the PR on this that we about two-thirds of the patients at that time had completed the trial, and directionally things were holding vis-a-vis visual acuity, OCT safety, and rescue-free rates. So I don't think externally that the case has been made of how powerful DURAVYU is in DME. I think for us internally, we're anxious to see what is the difference and how much improvement did we get statistically. While this study certainly wasn't powered to show statistics, we're gonna run various models to make that decision about what is the best way for us to go forward in pivotal trials.
Mm-hmm. Makes sense. And how should we think about the timelines for, you know, when you might speak to the FDA, say more about next steps?
Yeah. So, so the timelines are still, I would say, a bit nebulous. First of all, with the recent raise, we are now able to start some of the things that we need to do to gear up for DME pivotals. There's a lot of work that goes into pivotal trial, including making the drug, getting the right people in the clinical trial area to make sure that, you know, we'll do it successfully. And we're gonna. We've started that process already. On the other hand, deciding what the pivotal program's gonna look like and asking the agency some really important questions. In particular, can we do one trial? Do we have to run two? I mean, that's, that's very big for us, obviously.
I would say the top line, all the data that's been checked for the top line is first quarter of next year, and then 60 days to get a Type C meeting with the FDA. I think, you know, we're probably talking about sometime mid-next year before we're gonna be able to publicly talk about what we're doing and when we're doing it.
Mm-hmm. Understood. Hence all the investigator meetings, I assume.
For DME?
Mm-hmm.
Oh yeah, that typically, what we're doing for wet AMD, I mentioned that already. We had our first investigator meeting for the wet AMD trials, third week of October, and we're having actually, great timing at our second meetings in San Diego in two days. And we have about 160 people coming to that investigator meeting. I've been to a lot of investigator meetings. I've never been to ones that are this large. A lot of enthusiasm. But yeah, that's part of the process. And I think we'll be able for DME to improve on some of the process because, you know, we have a CRO that we like.
Mm-hmm.
We may use them again. That shortens the process. The clinical team knows what to do. The sites in the IRBs know about our product. So that streamlines some of what we're gonna need to do. But yeah, we, you know, there's a proper process that needs to run itself out to make sure you're doing this the right way.
Mm-hmm. Absolutely, and I wanna talk through, you know, wet AMD and, you know, the trial designs. But before we get there, just especially in light of the, you know, recent DME data, just taking a step back, I mean, these are both very competitive spaces, both in terms of the number of drugs on the market and in development. Could you frame for us maybe just how you see, you know, yourself fitting in the DME space as well as in the wet AMD space?
Sure. Well, I think the way to think about it is all the ligand blockers are short-acting. We're a long-acting option in that that's something that we can offer patients and practitioners and payers, frankly, that they really can't. That if our wet AMD data holds, about two-thirds of the patients should be able to go six months or longer with our drug alone. But even the one-third of patients that had a supplement in the phase II trial, when you go back and look at the reduction in treatment burden, even with the supplement, it was still substantially better than what they were getting leading into the trial. So remember, a patient doesn't really care what they get as an injection. And doctors all want the same thing. It's a great result, but the ability to safely go longer if they can.
So that paradigm of, you know, more ligand blockers available, and it really shouldn't affect our market at all because we can do something that none of them can do, which is go six months or longer in what looks like the majority of patients. Now, it may turn out that we have additional benefit. We gain nine letters in four months in DME. So that type of benefit where it's not just longevity, but it's potentially visual acuity benefit, and there's several reasons why that may be true, one of which may just be using two methods of action. That's true in a lot of diseases. When you combine two MOAs, you get an additive effect. It could be that we block VEGF- C and D, which may or may not be advantageous.
If we can show visual acuity improvements in wet AMD and/or DME, then our market gets even bigger.
Mm-hmm.
Of course, we have some preclinical data that suggests we're neuroprotective if we can show that in the pivotal trials or we show that we're anti-fibrotic due to the anti-PDGF effect. Those are all reasons that doctors will want to use us in perhaps the majority, if not all of their patients because they, they don't wanna have the, the leave visual acuity on the table, so to speak.
Mm-hmm.
If there's a safe, effective, tolerable solution that allows their patients to gain more vision, they'll choose it.
Mm-hmm.
And lastly, I like to talk about what I call the insurance policy. Now, these are elderly patients, and in DME, these are patients who miss visits and don't wanna come back because they're younger and they're working and they have a lot of doctor's appointments to go through. They don't wanna come back and get a shot in the eye every month for years. So the ability to have sustained release over six months or longer is really advantageous. And it's what I call the insurance policy. If I have an elderly patient whose treatment I've extended out to three or four months, and I'm running a really busy clinic with 80 patients a day, and that patient misses a visit, they're gonna be running three, four, five months with no drug in their eye. And we really don't like them to recur in wet AMD.
Having the confidence of a sustained release option that's bioerodible, and every six months, I think will be very attractive to doctors to be able to be more confident to run patients longer interval.
Mm-hmm. Absolutely. Talking more about some of the, you know, wet AMD data, can you give us kind of an overview of the phase III program?
Sure. So, first of all, we, in 2022, were contemplating going directly to pivotal from our phase one. And so we had a Type C meeting with the FDA back in 2022, and we reached alignment on the pivotal trial structure. We obviously decided not to do that, and we did a more traditional phase II, the DAVIO 2 trial, but we based the DAVIO 2 trial on what the FDA had really, the alignment we had reached with the FDA on how a pivotal trial should look. So there aren't a lot of differences between the phase II DAVIO 2 trial and the phase III. Some of them are obvious. We had an eight-month endpoint for efficacy in DAVIO 2, and it's a one-year endpoint in the pivotal trials, and that is FDA mandate. We're perfectly fine with us.
They are two-year trials, but the second year is safety only. Another difference is we are re-injecting DURAVYU every six months in that we plan and hope to get a label for every six months, and we will do that through the second year of the trial also. One other difference is that we are now gonna be enrolling both, treatment naive and treatment experienced patients. In DAVIO 2, it was only previously treated patients that we enrolled, and I have to add, we did quite well with them, but as we analyzed the data, what we came to realize is we had enrolled a very tough-to-treat population. On average, in the phase II, the patients required 10 injections per year in the year leading into the trial. In the United States, on average, doctors give about six injections a year, so it was a tough-to-treat population.
We did really well with them, but we also reached the conclusion if we had some of those easier-to-treat patients, the patients who could be treatment extended to 10 weeks or 12 weeks, we would do really well with them. And the only way to really do that would be to enroll some naive patients because the naive patients have automatically within that naive population, there's depends who you talk to, 20%, 25%, maybe up to 30% of patients who are able to be out of the gate treatment extended out that long. And we think our drug will do very well with them. It also mimics the real population in wet AMD. It's not taking a subgroup of tough-to-treat populations.
We think it will not only help recruitment to the phase III to have both treatment experienced and treatment naive, but we also think it will help us with a label, and help us from a regulatory perspective.
Mm-hmm.
I think that's about it. I mean, there are minor little tweaks that are probably, you know, again, not outcome related, but those are the big differences, and I will add, I will keep saying we did very well in DAVIO 2, and several months ago, we showed the 12-month data from DAVIO 2. And in the high dose, which is the dose we're going forward with in the pivotal trial, we had the exact same visual acuity at month 12 that the Eylea control arm had. Oh, I should say there is one more difference, and it is we've been able to change the payload of the inserts. We've tested 440 microgram inserts. We tested 1 mg inserts. In DAVIO 2, they were 1 mg inserts. The high dose was three inserts, 3 mg. Low dose was two inserts, 2 mg.
We can now put 1.34 mg of Vorolanib in the insert. So the inserts are now 94% drug, only 6% matrix. And that's actually the inserts we used in the VERONA trial . That was the first time we used them in humans and performed admirably as expected. But that's the high dose that we're using in the pivotal trials will be 2.7 mg, two inserts, and we're only using one arm. We're not dosing with two arms in the pivotal trial.
Mm-hmm. Interesting. Does that composition, do you think, affect the efficacy?
No, not at all. If you look at the way the 2 mg and 3 mg arms performed in DAVIO 2, they were almost identical in every way except there was a consistent dry better drying effect with a higher dose.
Mm-hmm.
through really throughout the study. And also, I will note that there does appear to be a dose response in the vorolanib trial also with the 2.7 mg doing better. The 2.7 mg and 3 mg from the perspective of how much drug is released on a daily basis, they're almost identical. And so there's really not a big difference. But the advantage, again, is first of all, two inserts versus three.
Mm-hmm.
Lower COGS. Secondly, the fact that you're left with a 6% matrix, the drug completely elutes in nine months in humans. And so at nine months, there's just a little nubbin of matrix that's left that should go away over several more months. But the previous iterations of the inserts were about 75% drug, 25% matrix. So at nine months, there was clearly more matrix left. Now, I have to add, from a safety perspective, we haven't really talked about safety. Nice segue, if you don't mind. From a safety perspective, we've never had a safety issue. We've had three inserts in the eyes of almost 100 patients. We've dosed DURAVYU in over 190 patients, and there really has been a very, very clean safety record. That was also true in vorolanib. No ocular or systemic SAEs.
At the time of, when we had the data cut October 1st, there were only three TEAEs in the study eye. Three.
Mm-hmm.
Subconjunctival hemorrhage, elevated IOP, and floaters. That was it. So and by the way, the elevated IOP was in the control arm. So this is a, you know, shaking out right now is a very, very safe, safe alternative. And so from the perspective of, you know, going forward with two inserts, we're very, very comfortable in that.
Great. In terms of the powering for the phase III program, can you walk us through the details of that and kind of the minimum thresholds that you need to see for non-inferiority, any testing for?
First of all, the non-inferiority margin that the FDA has granted us is - 4.5 letters, which is standard.
Mm-hmm.
We haven't really talked publicly about powering. We have approximately 400 patients in each study. The LUGANO and LUCIA study are gonna be near simultaneous studies. There'll be approximately 200 in the control arm and 200 in the treatment arm. We learned how our drug did very nicely in a tough-to-treat population in DAVIO 2. Despite the fact that it was not powered necessarily to show a result, we were statistically non-inferior to the Eylea control to a 97.5% probability. The lower limit of the non-inferiority margin in DAVIO 2 was - 2.6 letters.
Mm-hmm.
The margin we have is - 4.5 letters. We have a long way that's as I like to say a mile away in statistics. So we're comfortable very much so with the statistics as they've been laid out. And one of the decisions we made not to go with the 1.3 mg dose as well as the 2.7 mg dose was we were able to power the study more in the higher dose. And of course, as we look at the vorolanib data, I think we made the right choice.
Mm-hmm. And I guess, what was sort of the rationale for including the sham injections in the design of the pivotal?
Sham injections, what everybody does.
Mm-hmm.
From a rationale perspective, wouldn't make sense not to use sham. It may not be perfect masking, but it does provide some masking. And that every trial since LUCENTIS was approved used sham.
Mm-hmm.
and we are as well. And by the way, you know, I mentioned we had a Type C meeting with the FDA in 2022 where they said sham was acceptable. They reiterated that at our end of phase II meeting where they.
Mm-hmm.
Told us that our masking was acceptable. So yeah, sham is, I know there's some noise out there about it, but, we are not the only company going forward in pivotal trials using sham. And of course, VABYSMO used it.
Mm-hmm.
You know, there are other companies that use it when the dosing interval is not exactly the same. So yeah, we're certainly comfortable using sham.
Mm-hmm. Yeah. Makes sense. And I guess just how are you thinking about enrollment timelines here and, you know, when we could see data?
So, we dosed our first patient approximately three weeks ago. And, we have, at this point, about 40 sites up and running with, looks like in the next six weeks, we'll probably at least double that. So we plan on having at the end up to 150 sites in each trial. And we are so far exceeding expectations with enrollment. We have guided that we believe we will have the last patient enrolled sometime in the middle of 2025 with top-line data about a year later sometime in the middle of 2026.
Mm-hmm. Great. And just going back to the powering for a second, we talked about non-inferiority. Will there also be a test for superiority?
There will. Yeah. So, in a non-inferiority trial, if you meet your non-inferiority margin, you can then test for superiority without penalty.
Mm-hmm.
We will be doing that. So we think there's a chance we could be superior. Certainly the DME data gives us, you know, a lot of encouragement that if after the load is given in a wet AMD population, there's still eyes that have fluid, we may do better than control in those eyes.
Mm-hmm.
If you look at the phase II data, we looked at a subgroup which was the eyes that received no supplement. There had been some pushback at the beginning that, well, maybe your great result in DAVIO 2 was because of the supplements. The supplements is what gave you the better vision. In the end, it was the opposite. The unsupplemented eyes numerically had better vision than the Eylea unsupplemented eyes.
Mm-hmm.
I think again, perhaps in a population that is more indicative of the broad wet AMD population, it's possible we may do even better.
Mm-hmm. Interesting. And if you can, any color on when you get to that secondary test with superiority, the powering assumptions?
You know, I don't have that off the top of my head. I know that from DAVIO 2 that had we been about 1.4 letters, 1.5 letters better than Eylea, that would have met the criteria as superiority. But some of that also depends on the standard deviation. Obviously, the broader the standard deviation, the broader the potential there. So, let me say this, it's not unachievable.
Mm-hmm. Great. Exciting. Maybe just one last one on the design. Just can you walk us through the rescue criteria in the phase III studies?
Sure.
You know, relative to the phase II?
Yeah. So, that is a difference also. I'm glad you pointed it out. Ramiro Ribeiro, who's our Chief Medical Officer, went back and did a very nice analysis of reasons for rescue in DAVIO 2 and did the rescues matter. So first of all, 20% of the rescues in the DURAVYU arms in DAVIO 2 did not meet any criteria. And so one of the things we're doing in the phase III is we're not allowing physician discretion. The number one rescue criteria that mattered was, drop in five letters from best on study accompanied by 75 microns of new fluid. And with that one we kept in the pivotals because we wanna protect the patient's vision and we wanna protect, frankly, the minus 4.5 margin.
but the other ones that we had used, including rescue criteria around drop in vision that didn't include fluid or fluid that didn't include drop of vision, it turned out those didn't matter because when a rescue was given, it didn't affect, didn't change the vision in any of those patients, so we eliminated those. The second criterion we have is sight-threatening hemorrhage. In DAVIO 2, in all three groups, there were nine rescues given due to hemorrhage. And we went back and looked and we had our KOLs look, and six out of those nine either didn't have a hemorrhage on fundus photographs or the hemorrhage wasn't due to wet AMD, due to something else.
Mm-hmm.
So what we've also instituted in the pivotal trials is if the doctor wants to rescue for a hemorrhage, we have monitors who are peers, they're going to be contacting the peer to go over the case with them to discuss whether or not to rescue or not. But for that first criteria that I talked about, we want them to rescue with that criteria. They don't have to, you know, go through any hoop to rescue. So that's the criteria. We simplified it for the doctors and the patients.
Great. Well, taking a step back, you have a lot of exciting programs and studies going on. Where do you stand currently from a cash runway perspective?
Yeah. Thank you for that question. So as Jay mentioned, we raised $161 million in a follow-on offering, just a few weeks ago now, which puts our cash runway into 2027, which is about a year, nine months to a year on the other side of the wet AMD phase III readout. It also allows us to continue to fund some of the early work to prepare for phase III in DME.
Mm-hmm.
So we're in a great place on our cash position. We also did a ribbon cutting on our facility in Northbridge, Massachusetts, which will be our commercial manufacturing facility. And while that's always been baked into our cash runway, what that does is it gives us the ability to ultimately produce millions of inserts for commercial launch and complete the registration studies over the next year or so, to be ready for our filing.
What's your perspective on potential partnerships or collaborations and, you know, what might be the value, inflection points to consider those?
Yeah. So we've talked publicly about certainly interest in XUS. We're a small company and for our ability to commercialize outside of the U.S. is probably one step too far, at least where we sit today. We are certainly interested in OUS partnership, although the nice thing about our cash position and our runway is we're not in a hurry to do it. You know, we'll ultimately do the right deal, should that appear. If someone wants the U.S., that's a very different conversation. I think where we sit today, we don't need to enter into those discussions. I think we're all in execution mode, but certainly open to partnerships, as potential, to expand the program and get it to patients beyond the U.S., nearer- term.
Mm-hmm. Great. And then in terms of, you know, the pipeline and broader portfolio, can you tell us a little bit about 2301 and how you're thinking about, you know, the potential opportunity for an extended release Tie-2 agonist?
Sure. So, by agonizing Tie-2, you downregulate Angiopoietin-2 and upregulate Angiopoietin-1. As you may be aware and others may be aware of, VABYSMO is one of the reasons that they've been successful is that they are bispecific, that not only blocks VEGF but blocks Angiopoietin-2. By doing it at the Tie-2 receptor level, however, you really should have a more beneficial effect because you also have the stabilizing effect of upregulating Angiopoietin-1. So we were able to gain the assets of a company that had studied this drug, AKB-9778, in diabetic retinopathy and diabetic macular edema some years ago as a subcutaneous injection. And so the molecule, which is called razuprotafib, actually performed really well from an anatomic perspective, better than an anti-VEGF alone.
When they combined it with anti-VEGF, they had some benefit, but it really wasn't enough statistically to go forward as a superiority trial. We believe some of that was just the fact that it was being delivered systemically and not locally, and so that we've been able to reformulate razuprotafib into a drug that will now work in sustained release, and we believe we can get levels of six months or longer with a single injection, so we're still preclinical there.
Mm-hmm.
And we're still honing the formulation. But we really hope to start IND-enabling trials this year and then perhaps as soon as next year, maybe late, get it into humans.
Mm-hmm. Interesting. Maybe just to recap and, you know, take a step back. Maybe just what are the key catalysts that we can expect over the next 12-18 months?
So, first patient in our second trial by the end of the year, the LUCIA trial, and again, I'd like to remind everybody, first patient in's a great step, but what really matters is last patient in the second trial.
Mm-hmm.
Because that's the rate-limiting step to get your one-year data and submit the NDA. So we think we're gonna be well on our way, hopefully by the end of the year with that second trial. First quarter, we will have the full results of DME, and I've already, you know, talked about that directionally. We would expect it to be in the same direction, but our case has been proven already by the four-month data. Next year, we will have last patient in both trials at some point. We're confident of that, and then we'll have an announcement about the DME program sometime around mid-next year and hopefully start it either the end of next year or beginning of the year after.
Mm-hmm. Mm-hmm. Great. Well, thank you both so much for joining us.
Thank you very much.
Appreciate all the color.
Great. Thanks so much.
Very much.
Appreciate your time.
Thank you.