Got it. All right. Good afternoon, everyone. Thank you for those of you in the room and those on the webcast sticking through as we get towards the tail end of the day here. My name is Faisal Khurshid. I'm one of the senior biotech analysts here at Jefferies. We are live at the Jefferies Global Healthcare Conference in New York. Really pleased to have with us today the management team of EyePoint Pharmaceuticals. We have Jay Duker, CEO, George Elston, CFO, and Ramiro Ribeiro, CMO. With that, Jay, why don't I pass it off to you to just start with introducing the company a little bit?
Sure. Thanks very much for the invitation. We're really delighted to be here. Thanks for those of you in the audience who have come to stay till the end. EyePoint is a drug delivery company, and we try to improve patients' lives with serious retinal diseases. Our lead product is EYP-1901, also known as DURAVYU. DURAVYU is a small molecule tyrosine kinase inhibitor called vorolanib, which is patent protected. It is in our proprietary delivery system that we call Durasert E. DURAVYU is currently in four phase III trials, two in wet age-related macular degeneration, two in diabetic macular edema. The wet AMD trials are fully enrolled and will be reading out this year. The first trial, LUGANO, we expect to read out sometime in August, with the second trial, LUCIA, about two months later. LUGANO and LUCIA are identical.
The primary endpoint is non-inferiority change in visual acuity at week 52, week 56, averaged against an on-label two milligram Eylea control. We did a robust phase II study in wet AMD called the DAVIO 2 study. Our two doses were both highly statistically non-inferior to the control group, giving us quite a bit of confidence in the phase III results. With respect to DME, we have two, again, simultaneous trials. COMO and CAPRI are their names. They are actively enrolling. We're delighted to report today that both trials are now nearly 2/3 enrolled. First patient was enrolled in late February, so these trials are enrolling very rapidly. There's a lot of reasons for that, which we can get into if you like.
We expect that the last patient should be enrolled in Q3 of this year, giving us top-line data in diabetic macular edema in approximately one year after that.
Got it. Excellent. Definitely a very exciting time for the company with these four phase III readouts coming up on the horizon. Let's start with LUGANO and LUCIA. For the phase III wet AMD program, what does good look like?
Well, I'd rephrase it probably in a different way. I think there are three things that we should be looking at as the outcome. The first, obviously, is the primary outcome of non-inferiority change in visual acuity against the control group. Provided we are non-inferior statistically, I don't actually believe the actual number difference between us and Eylea matters much. The reason is, in the retina community, a letter or two is not really a measurable amount that is meaningful to patients. Again, we have some data on that. The high-dose Eylea arm in their phase III trial was 1.4 letters worse than the 2 mg arm. Nobody remembers it. Nobody in the retinal community ever stopped to say, "I'm not going to use that drug because of the difference." The most important thing is that we're statistically non-inferior.
Number two, and probably just below the primary endpoint, of course, is safety. Safety in retinal trials is really important, and the good news is we've had a really good safety track record. We've done four trials that we've reported, one phase I and three phase II trials, and the safety has really been quite good in those trials. There's been no safety signals reported and no ocular systemic SAEs due to our drug. With respect to safety in the phase III, we are monitoring the masked safety. We also have a data safety monitoring committee that has now met three times, most recently a few weeks ago, and their report was no change in the protocol necessary.
What we've talked about publicly is that on a masked basis, the safety that we're seeing in the wet AMD phase III is really no different than what we've seen in the prior trials. We are confident and comfortable in the safety that we've seen so far. I like to remind people, in a wet AMD trial, that the number one cause of safety events is the actual injection. In the phase III trials, the injections of our drug was done at week eight and week 32 in the first year. At the time that the last DSMC meeting occurred, all the patients in both trials had received their second injection of drug, and about a third of the patients had received their third injection of the drug. Again, so far so good with respect to safety. The study's obviously not over.
We've got the last patient visit coming in approximately a month. We're quite comfortable at this point with the safety that we're seeing on a masked basis . Now, the third thing to look for is the reduction in treatment burden. What that refers to is how many injections did the control group get versus how many injections did the study group get. The way that's calculated for the phase III trial is, for those of you who don't know, all the patients in the trial receive what's called a load, which means monthly Eylea times three. The count starts after the load, which means for the DURAVYU arm, there will be two DURAVYU injections. For the Eylea arm, that's five Eylea injections. If there were no supplemental injections given the study, that would be a 60% reduction in treatment burden.
The way we're going to report it is on a statistical superiority basis. We are going to do a statistical analysis of superiority of the DURAVYU arm against the control arm. Because the end of the trials are so large, we only need an 8% difference to be statistically superior. We believe that's a bar that's easily achievable based on the data that we've seen from the phase II. From a clinical perspective and commercial perspective, I think the answer is slightly different. I think if you talk to KOLs and they'll say, "Well, what type of treatment reduction burden would you want to see in a study like this?" The number we're hearing is about 20%. I think we've got some real-world evidence of that. If you look at the real-world usage of, for example, Vabysmo, it's approximately a 17% reduction in the treatment burden.
Even a relatively, let's call it modest reduction in treatment burden can result in a very successful and well-used drug. If you apply the percentages of rescues that occurred in the DAVIO 2 trial and apply them to the pivotal trials, we'd have about a 35% reduction in treatment burden. Going back with respect to treatment burden, the numbers are going to look different because of the way they're calculated from our trial, our previous trial, and any of the other trials that you might see. We would expect and hope for a 20% reduction or more. We only need 8% to be statistically superior.
Got it. What about in terms of injection-free rate? Is that a metric, or can you characterize the extent to which that metric matters to you? Because I think that's something that investors anchor to a little bit.
Yeah, I think that there is interest in that, and what I'll remind people is in DAVIO 2, the number of patients who were rescue-free up to month nine after the drug went in, which was month eight of the study, is about two-thirds. At one year, 50% of the eyes were rescue-free in the DURAVYU arm, and that's without a re-injection. Those patients only got one injection. Presumably by month 12, most of the inserts were devoid of drug at that point. We expect that the number of eyes that are rescue-free up to month 12 would be higher than that. It's not a metric per se that we think is really crucially important to either the agency or to the doctors. A supplemental injection in the real world is not a failure.
In fact, based on what KOLs are telling us, they may take advantage of two MOAs. Remember, DURAVYU has a new MOA. It's a receptor blocker. It's not a ligand biologic blocker. Doctors may choose to use both a ligand blocker and a receptor blocker together to take advantage of both MOAs. The other way to think about it is if you have a patient who, let's say, is getting six injections of a biologic a year, and DURAVYU is approved and it's safe, effective, and tolerable, and that doctor switches the patient to DURAVYU and they get two DURAVYUs over the next year, but they also get two biologics. Is that a failure? I would argue that's a resounding success.
That patient's gone from six injections to four injections, a 1/3 reduction in their treatment burden, and now they only have to come in four times a year, not six times a year. Again, the idea of a reduction in treatment burden and supplement-free, while I think there's value to it, doctors individualize therapy in the real world, and that means that they're going to look at the individual patient and ask the question: How is this drug doing for this patient? I also want to emphasize what we're trying to do here in the long term is preserve vision. The reduction in treatment burden, we're all interested in, and we do believe that's going to be a benefit, but that's not the primary thing we're trying to do.
We believe, and I think there's now increasing evidence, that if you can suppress VEGF constantly long term, you will get better visual acuity in these patients. Ultimately, that's what we're trying to show.
Got it. If you take us through how this works in a real-world setting, how often are these patients coming into the clinic anyways? Is there a worry? Because one pushback that I get from investors is that if the patient still has to come in every X amount of time to get checked for a potential need for a supplement injection, does that reduce the value proposition of a drug like DURAVYU? Is that fair? How should people be thinking about that?
I don't think that that's the way the real world's going to exist at all.
Yeah.
On average in the U.S., patients after the load get about six injections per year, although it diminishes to eventually about four injections, and that's partially because some of the patients just drop out. They just can't keep up with the visits. The studies obviously suggest that more injections are better than fewer injections, and pretty much every study has shown that in the real world. What's going to happen? I think that once approved or if approved, I think you're going to see the doctors use DURAVYU the same way they started to use any of the anti-VEGFs, which is basically there's three strategies that we use. The first and most commonly used right now is called treat and extend. I think you're going to see that. In other words, you'll see patients get their three monthly injections at the beginning.
Doctors will put a DURAVYU in and then maybe see them back in six weeks. If they look good, they'll give them another biologic. See them back in eight weeks. They look good, give them another biologic. See them back in 12 weeks, and if it's time to give them another DURAVYU, they'll give them another DURAVYU, and they'll continue out until they hit six months. Now remember, if at month three or month four they show fluid again, I don't think doctors will have any problem just saying, "Okay, you're going to need a biologic every other visit and a DURAVYU every other visit," and just go from there. I think as needed, which is PRN, and how some of the investors are saying that may not be an advantage. Right now, there are not a lot of doctors who do that.
The reason is if you're allowing the fluid to come back in the long term time and time again, we believe that that results in decreased vision. I think you may see it at the beginning before doctors really get used to how the drug works. Finally, the third way is put patients on a schedule. If you look at that, we individualize therapy in general, and that the number of patients, for example, when Lucentis was approved that used it monthly, which was on label, was about 5%. It happened, but it was low. If our phase II data holds, and one can extrapolate it to phase III and then to the real world, if you look at the number of eyes that after they got a DURAVYU in phase II needed either zero or one supplement, it was about 90%.
A priori, if this holds, then one could imagine that you could take about 90% of the wet AMD population and treat them every three months alternating a biologic with our drug and not have any recurrences. You might argue, Jay, aren't you over-treating some of them? We would rather over-treat than under-treat.
Yeah. Jay, just to be clear, you're saying that the real-world setting, the way that you envision it could actually work in a fundamentally different way than the trial, where instead of waiting to see a trigger for a rescue, it's actually the total opposite where they intensify treatment then de-intensify thereafter?
Correct.
To me, this strikes me as a disease area where somehow the investor bar is way higher than the clinician bar. Is that fair?
Yeah, it's an interesting observation. The Key Opinion Leader title that people get, and I always thought when I was a Key Opinion Leader, we'd tell the investors is what I think, and they'd write it down and believe it. This actually, it's an interesting observation because this actually started with our phase II. Prior to the phase II data, you asked KOLs, "Well, how much vision would you be willing to sacrifice in your patients to get durability of six months or longer?
It's like zero.
They were saying, "Oh, two or three letters. Ugh, I don't care about two or three letters." You talk to the investment community, and they were, "Oh my goodness, two or three letters." Yeah, there is a dichotomy here. Ultimately, the data is going to guide usage, and the doctors are going to figure it out. That ultimately, if the belief is sustained release is going to give me better vision in the long term, then that's what doctors are going to choose. Whether they choose to use a second MOA on top of it, I think some will.
Interesting. Okay. Obviously there's what will ultimately matter and what the bar is, per se, for the medical community. There's investor expectations. In your opinion, based on your conversations with any potential strategic partners, how do the larger companies or companies interested in this space think about what is a compelling value proposition?
Well, I think the first answer to that question is they're viewing it as a very large opportunity. Right now, it's, some would argue, over $10 billion in the United States alone. DME, we haven't talked about diabetic macular edema much. It's about a $3 billion opportunity right now in the U.S. alone. I think that strategics understand that this is an area that can really help patients because it really helps preserve sight. That there's quite a bit of interest in the results in what will ensue after that.
Got it. You spoke a bit about some of the benchmarks and observations from your phase II DAVIO 2 study. With LUGANO and LUCIA, you have a couple of differences with respect to both the characteristics of the enrolled population, and the rescue criteria as well. Can you talk about the push and pull on rescue dynamics that you'd expect from that?
Yes. We're expecting lower rates of rescue into phase III for several reasons. The first you touched on is that the population we enrolled in the phase III wet AMD is 75% naïve and 25% previously treated, approximately. We expect that the addition of the naïve patients will improve the results. The reason is, if you ask a retina specialist how many of your naïve patients are easy to treat, meaning I can give them three injections and they can go many months without another shot, or I could give them any anti-VEGF every three or four months and they'll do fine. They'll answer about 30%, approximately. Some will answer even up to 1/3. Well, we got very few of those patients in our phase II.
We expect enrolling a naïve population will get quite a few of them in the pivotals, and I think our hypothesis is that our drug should do very well in those patients. That's a dynamic we expect to be a positive. You asked about the rescue criteria, and perhaps I'll ask our Chief Medical Officer, Dr. Ramiro Ribeiro, to comment on the rescue criteria changes and why we made them.
When we look at our phase II study, which was relatively large, 160 patients, on that study, we had five different criterias. We look at the rate of rescue, but more important than that, we look at the outcomes of those injections. Did the patients actually gain vision after a supplement injection? Out of those five criterias, only two made a big difference, and they were either the presence of hemorrhage or if a patient on the same visit had decreasing vision and increasing fluid. For our phase III study, we only included those two criteria. We do not have, for example, vascular disruption in phase III study. We don't have if a patient only lost vision but no anatomy. We only have those two criteria.
Got it. Based on the observations that you've seen on a blinded basis in LUGANO and LUCIA, are the rescue rates in line with your expectations?
We are not viewing the masked rescue rates.
Got it. Okay. In terms of the inclusion of the naive patients, and you spoke about some of the reduction in treatment burden that you saw from DAVIO 2, would including the naive patients blunt the effect of that, given that you have on the control arm as well, patients that may be better controlled on just Eylea alone?
Sure. Remember, the control arm gets every other month Eylea, whether they need it or not.
You'd argue that there's some eyes in the control arm that are being over-treated. Over-treated doesn't show improved vision. In fact, if you look at the Eylea control arms in the last couple of studies that got approval, after week 12, the control arm is pretty much flat visual acuity. Also remember, about 20% of wet AMD eyes have to be treated monthly. When you shift one of those patients after the load to every other month, they're under-treated. What will that result in? Well, it may result in some rescues. We saw that in DAVIO 2 in the control arm. It also may result in just some drop in vision that doesn't quite meet rescue criteria, and that's certainly possible to see as well.
Yes, the fact that those easier-to-treat patients will be in both arms certainly doesn't hurt us and may in fact help us.
Got it. Okay. From a safety perspective, can you talk to us about what gives you confidence on the safety side? I think the history of the company is pretty important here as well.
I may be repeating myself a little bit, but in the 190 patients in the four trials that we've reported, the safety has really been quite good. Again, there have been no, in those trials, ocular systemic SAEs associated with our drug, and there are no trends toward any safety issues. We also have really good pre-clinical data. We've put doses of vorolanib into rabbits that are 10 x scaled higher than what we've ever put into a human, and we've not found the maximally tolerated dose of vorolanib. We've actually had up to six inserts simultaneously in an eye of a rabbit with no toxicity. We're comfortable again from a pre-clinical, and obviously the FDA has seen or will see that data as well. From the masked safety, again, I'll turn it over to Ramiro. He's the one monitoring this.
Any other comment on the masked safety from the phase IIIs?
Yeah. Internally, we review the masked safety data as an ongoing basis. We also have a DMC every six months that review the data on a masked fashion. What we're seeing so far in terms of the type of adverse events, the frequency of the adverse event, is very similar to what we saw in our phase II study. As Jay mentioned before, our DMC met last month. They saw the data both for our wet AMD study as well as for our DME study, and they recommended no changes to the protocol or no safety concerns.
Great. As you think about the competitive landscape, there's a lot of development happening in wet AMD. Would love to hear your thoughts on how DURAVYU is positioned relative to the plethora of things in development, including novel mechanisms, other TKIs, and gene therapy.
Maybe I'll ask our CFO, George Elston, to answer that question.
Yeah. I think as we look at the competitive landscape, and I think what's important as you think about DURAVYU versus other programs is we are not another anti-VEGF biologic. We're bringing a new MOA. We block all VEGF isoforms intracellularly. We block PDGF. We've published data recently that suggests that we meaningfully block JAK1, which gives us this inflammatory benefit as well. We've never viewed the biologics as our competition because historically, the message was each biologic is the same MOA, and the message was, "We last longer. Use us. Don't use the other guys." Our message is very different. It's really use both. Because we are bringing this second MOA, we can last six months or longer, which a biologic can't do. Gene therapy we see as a different category. They're producing the same biologics.
Even the biosimilar space, they're competing with the anti-VEGFs, which we don't see as direct competition.
One other advantage we have, which may prove to be very beneficial commercially, is we're shipped and stored at room temperature. All the biologics and the other competitors either have to be refrigerated or frozen. Given the number of anti-VEGFs that are approved out there, you can imagine retina specialists have huge refrigerators already. I think it will be nice for them to just put us into the closet and not have to put us into a refrigerator or a freezer. That, again, I think it will prove to be a commercial advantage if we're approved.
Got it. Then just shifting over to DME, can you talk to us about expectations for that study and the evidence base that's supporting it?
Well, I think if you talk to retina specialists, they're likely to tell you that the need for sustained release is even more important in DME than it is in wet AMD for several reasons. I think one of the reasons is it's generally a younger patient population who are generally working. They have multiple doctor's appointments. You don't get what I call the wow factor with an anti-VEGF in DME typically, meaning if you treat a wet AMD patient with an anti-VEGF, usually in a week or two, they know they're better, even if their visual acuity hasn't improved. Most of them will come in four weeks and say, "Please give me another one.
That worked really well. DME takes longer to work, probably because it's more of a multifactorial disease, and sometimes it can take four, five, six injections before the patient realizes that they're improving, which means after one or two or three, if they're not feeling like it's worth it's very easy for them to drop out of treatment. The real-world data suggests that on average in the first year, DME patients are getting three injections. They should be getting 11. There's a need for sustained release. Looking at our data, one of the things that really struck us when we looked at our VERONA phase II data is the four-week result. The only difference between our drug and the control group was our drug at week four. There were no supplements obviously given that early.
Yet we were already in the high dose, four to five letters better, and we were 40 to 50 microns drier at week four. We've designed the phase III trials to try to show that as well. We do have a secondary endpoint about week four vision and fluid. Even if in the end we're non-inferior and we're equivalent to Eylea, we can show that we get there better and faster, I think we will get quite a bit of the market. Once again, the idea of being able to give somebody sustained release if they miss visits, I think is going to be very attractive to patients and retina specialists should we be approved.
Great. Talk to us about the overall market size and growth outlook for vascular retinal diseases.
Again, I think in the U.S., which is over 50% of the worldwide market, it's approximately $13 billion next year. Year-over-year growth rate is high single digits, aging population. Remember also that about 40% of wet AMD patients stop treatment after a year or so. That's another portion of the population that we may be able to capture with sustained release. That if they're not feeling the benefit of monthly or bimonthly injections, if the doctor says, "Well, I can switch you to twice a year," they may stay under treatment under those circumstances. We think that this isn't a zero sum. This isn't taking from one and adding to the other. I think that all the sustained release, if approved, are likely to grow the market.
Great. In terms of how the market has performed, there was the patient foundation disruption last year. Just for our investors' benefit, can you recap what happened there and if that's all set now?
Well, again, there were several funds that are funded typically by the companies that have approved products. That's to help with patients who have a large copay. Wet AMD is almost all Medicare, obviously. I believe about two years ago, the companies chose not to continue the funding, which left some patients unable to afford their branded drugs. We believe that hopefully will be solved. As a company, again, we're really dedicated to patients, and should this need arise, that we will be doing what we can to make sure that patients can get our drug. We think, though, the value will be there. Again, I can look at the success of the Vabysmo launch during that time also. Quite successful because they offered a benefit to patients.
If you poll retina specialists in the ASRS PAT Survey it's called, done every year, the number one unmet need still in wet AMD and DME is for sustained release, longer duration. We believe that if we can provide that, then the payers will compensate.
Excellent. Assuming these two phase III's later this year read out positively, could be in a situation where second half of 2027, you're transitioning towards a commercial stage company. How are you preparing for that transition? Are you engaging in any partnership discussions as well?
George, why don't you take it there too?
We do drug development at EyePoint. We prepare in advance. We recently announced the appointment of a new chief commercial officer who has brought in several key hires, including someone focused on hub services and someone focused on market access. You need to have that in place and ready well before. We have a rollout plan, obviously, on the other side of data to be prepared for commercial. I think another important part of this is CMC. We have our own manufacturing facility in Northbridge, Massachusetts. We are well aware that most CRLs happen on CMC, and we've been planning for this for years. We've got a great team there. We have registration batches on stability, and we're focused on being prepared for a pre-approval inspection.
As we get into next year, assuming good positive data, we'll file the NDA and scale up the commercial side in parallel, both on the manufacturing front and the commercial team as well.
Got it. Is the goal of the company to be a fully integrated company?
Yeah. Our plan is to launch DURAVYU in the United States ourselves. I think the beauty of retina is you can do that with a fairly limited commercial footprint. We've got long-established relationships in that community. Remember, we've had 200-plus sites in the wet AMD trial and slightly fewer in the DME trial. We've already got established relationships. It's a market where you can address as a small company in the United States. I think from a strategic perspective, there's certainly been a lot of strategic interest, but we are well-positioned and prepared to launch in the U.S. ourselves. Ex-U.S., I think we'll see.
Our trial should support a regulatory filing in the EU, and we'll see what happens with most favored nation pricing, because what we don't want to do is affect the U.S. market with a small deal in Europe that may impact our operations here.
Excellent. Makes sense. Well, thank you so much. I think that's all we have time for, but really appreciate you, Jay, George, and Ramiro, for joining us.
Thank you for inviting us.