Okay. I think we are live again. Good afternoon, everyone. Welcome to Guggenheim's 3rd Annual Healthcare Innovation Conference. My name is Yatin Suneja, one of the Biotech Analysts here at the firm. It is my pleasure to introduce our next presenting company, EyePoint. From the company, we have the Chief Executive Officer, Dr. Jay Duker. Jay, thank you so much for spending time with us. Why don't you make some opening comments, tell us some of the learnings that you have now from LUGANO and LUCIA study, how we are applying that into the ongoing programs, and then I have some Q&A that I have prepared for you.
Sure. Yatin, first of all, thanks very much for the invitation. I think most people are aware that we were running two near-simultaneous phase III trials in wet age-related macular degeneration for our lead asset, DURAVYU. The first trial, LUGANO, read out in July. Second trial, LUCIA, read out in October. Unfortunately, and quite unexpectedly, both trials missed the primary endpoint, which was non-inferiority change in visual acuity at week 52, week 56, averaged compared to an on-label two milligram EYLEA control. The positive part of the study, of course, were the secondary endpoints, and we did very well with the secondary endpoints, which again made the primary result even that much more surprising. First of all, from a safety perspective, we treated about 450 patients with DURAVYU between these two studies, and we re-injected them.
The safety at week 56 included a re-injection in all patients. We showed that the drug continues to have a very, very nice safety profile, with really no concerns, and we believe that the read-through to diabetic macular edema, or DME, from a safety perspective, de-risks the DME results. Some of the mild asymmetries we saw in the safety really had to do with the fact that there were more active patients with wet AMD in the wet AMD trial in the DURAVYU arm than in the control arm, which was, I would say, intuitively obvious when you saw that there were more rescues in the DURAVYU arm than in the control arm. Obviously, we don't expect to see something like that in DME, nor would we expect to see something like geographic atrophy, which is an AMD-related effect. The second thing that's encouraging is the control of the fluid.
The difference in the pooled data on OCT from the two studies at week 56 was only 10 microns, which is about the same difference, frankly, we saw in the phase II. 10 microns from a clinical perspective is not meaningful. Normal foveal thickness, or CST, on the OCT is about 325 microns, so you are talking about a standard deviation worth of change. That, again, quite encouraging that we were able to control the exudation quite well. Finally, both trials showed a near-identical reduction in the treatment burden after the load of, on average, two fewer injections in the DURAVYU arm. While maintaining vision is a prerequisite for approval, and improved vision, which we did show, by the way, both trials did show that DURAVYU could improve the vision, you want to see the added benefit of reduction in treatment burden.
That type of result also, we believe, is going to be a positive read-through to diabetic macular edema.
Got it. I think going into LUGANO and LUCIA, I think one additional focus for investor was on the safety that comes with the second dose, which it seems like you did not see anything. So that also is sort of reassuring from a safety perspective.
Correct. Again, to be fair, there was about two and a half times more floaters-
Yeah
in the DURAVYU arm, but it was under 10% in the pooled data. When you look at the timing of that, remember, these are inserts. They are not a liquid being injected. It is probable that most of these safety events around floaters were the patients actually visibly seeing the inserts as they were injected or shortly thereafter. We have used inserts in retina for decades now, and patients do occasionally note that they can visualize them, but virtually never is it a concern.
Got it. Maybe one more question on wet AMD, then we go to DME. In the phase III, you enrolled naive and experienced patient as well. How consistent was the effect across these two subsets?
Yeah, that is a good question. Just to recall, in the phase II, we enrolled only previously treated patients and had a quite positive result. The decision to enroll naive patients was several-fold. First of all, we believed it would de-risk the trial, and secondly, a broader label.
But in the end, when we looked at the results and broke it down by previously treated or naive, there really was not a big difference in the results. The previously treated patients did a little bit better, but not, again, statistically non-inferior given the size of that arm.
Got it. Okay. Let's go to DME. You have conducted VERONA study. I think they are. Maybe recap the data, why it gives you confidence, because I think the onset and the data actually at that time looked very different than AMD data in itself, more robust.
Yes. I'd like to add before we talk about the studies, if I could go into a little bit of the pathophysiology.
Absolutely.
DME and wet AMD are both exudative diseases, and VEGF plays a role, but it appears that VEGF is the primary role in wet AMD.
While important in DME, there's other factors that go into the pathogenesis of the disease. We've known that for a long time. Corticosteroids, intravitreal corticosteroids work quite well in DME. Actually, if you look at eyes that have already had cataract surgery, pseudophakic eyes, and you compare anti-VEGF to corticosteroids, they give the same result. Corticosteroids have very little positive effect in wet AMD. Moreover, we just saw another company that has a Wnt agonist-
Yep
report positive data in DME. Wnt agonism does not directly affect VEGF. I think both of those pieces of evidence suggest that DME is a different disease. We have very good evidence that our active ingredient, vorolanib, blocks the JAK1 receptor, and in blocking the JAK1, we should block the downstream effects of IL-6. IL-6 is the inflammatory component that has really been implicated in DME.
Okay.
It is known to be at much higher levels. All of that together leads to us having more confidence in the DME result. Back to the VERONA trial. The VERONA trial was the first trial that we did that enrolled only active patients, meaning they had decreased vision and they had fluid. They were randomized into three arms, 2.7 milligrams of DURAVYU, which is our phase III dose, 1.3 milligrams, obviously half the dose, or EYLEA control. On day one, all of the patients received an EYLEA injection, and then 30 minutes later, they either got our drug or they got a sham, depending on what group they were in.
When you look at the first endpoint, which was four weeks, what was remarkable was at four weeks, the DURAVYU eyes already saw about four letters better than the EYLEA eyes and were about 40-50 microns drier. That improved drying effect continued through the whole study. At the end of the trial, in all of the patients, the final visual acuity was about seven letters positive in both control and DURAVYU, so there wasn't a big difference. On the other hand, if you looked at, for example, all the eyes that were rescue-free-
Yeah
which was over 70% of the DURAVYU eyes, those eyes gained over 10 letters and had 120 microns reduction in fluid. So they did exceptionally well on our drug alone, and we've shown some cases of eyes that had been previously treated with other anti-VEGFs and were still active that became dry and had improved vision with our 2.7 milligram arm and no rescue. The other important takeaway messages, though, was we looked at other things in the trial. For example, we looked at leakage of the blood vessels.
Leakage is a sign of vascular instability, and that can be measured on fluorescein angiography. In a dose-dependent fashion, the DURAVYU eyes had significantly less leakage at the end of the study than did the EYLEA eyes. Again, we can't directly attribute that to the IL-6 effect, but it's possible that that's what gave that result. Also, at the end of the trial, if you asked how many patients no longer had diabetic macular edema, about half of the DURAVYU eyes no longer had DME, whereas all of the EYLEA eyes still had some degree of DME at the end. All of those results together give us confidence in the DME result, including the fact that there's still quite an unmet need-
Yeah
in DME.
What was their prior VEGF status for these patients in VERONA? Did they have prior, or they were all naive?
Oh, they had all been previously treated.
Previously treated, right.
However, there was a washout period.
They could not have been treated for eight weeks prior to the study. That is why they all entered the study with some degree of fluid
Yep
and decreased vision.
Got it. Now for this study, for COMO and CAPRI, what is the patient mix that you are targeting? It is still 75/25? Would you expect some of a differential effect or a consistent effect across both patient types?
Yes, it is 75% treatment-naive, 25% previously treated, and as you may know, we are fully enrolled in both studies, a total of about 550 patients in total. Based on the results that we have seen in the phase III of some of the recent approved anti-VEGFs that also enrolled the combination of naive and previously treated, you expect that the two arms will actually give similar results.
Yeah. Got it. This is also a non-inferiority design. Are the margins similar to the wet AMD studies?
Yes. The FDA has given us a non-inferiority margin of -4.5 letters.
- 4.5 letters. Okay. What is the endpoint? Is it a blend of 52-week and basically replicating
Yeah, it is the same endpoint of average of 52, 56 weeks. The reason the agency asked us in both the wet AMD and the DME trials to go out that long is because of the load, because in wet AMD, we loaded the DURAVYU eyes as well. In the DME patients, we did not fully load them. That is one of the really two major differences, I would say, between the wet AMD trial and the DME trials in how they were structured. The first is we are delivering the DURAVYU on day one. The reason is we have an important secondary endpoint, which is change in vision and change in fluid status at week four.
I see.
We would think about it this way. If we can show that we are non-inferior to on-label two milligram EYLEA and we are approved, but we get the same improvement, but we get it at four weeks
Four weeks
and they get it at five months.
Yeah
I think from a commercial perspective, that speaks very, very well for how successful we would be, because who wouldn't want to see better faster with fewer needles in the eye?
Yeah. The COMO and CAPRI were already recruited, almost recruited when LUGANO and LUCIA read out, right?
That's correct.
Were there any learnings that were incorporated into it? What about the handling of the 15-letter loss, patient who lose 15 letter from a statistical standpoint?
I would say that there's some minor protocol changes that we're in the process of doing
Okay
with respect to COMO and CAPRI. Nothing significant. But the 15-letter losers, again, that was a mismatch that really was most marked in the LUGANO trial. And given that most of that was related to geographic atrophy which is not something we see in the DME population.
Yes
we are not looking at necessarily 15-letter losers in that population. Again, we would not expect to see that type of mismatch in the DME population.
What about the interim analysis or the DSMC review, right, in your case? How are they planned? How many have been conducted?
The DSMC meets every six months.
Six months.
They see both masked safety that we share as a company with them, and then, on their own, they are able to view the unmasked safety.
Yeah
We do not see. They have met every six months since the start of the wet AMD trial. The last time they met, they did look at the DME trial also from a safety perspective, but at that point, I think they had just maybe a dozen patients enrolled, so really was nothing to report. They will meet again in December, and we would expect to have an update about their findings.
Okay. What is the regulatory requirement in DME? You just need two more studies?
Yes. We had asked the FDA multiple times about single trial, including as early as six months ago, and they had been adamant that they wanted to see two trials in both wet AMD and DME.
Got it. Then maybe talk a little bit about the commercial opportunity in DME. How big you think of the retina market is DME. How is the competition there between the high dose and VABYSMO?
Sure. Globally, it is probably about a $5 billion market. In the U.S., it is about a $3 billion market right now. It is, again, a little more fractured, I would say.
Yeah
Because I already mentioned that corticosteroids work, and so there are several approved corticosteroids that can be used and off-label corticosteroids. They do not tend to be used often, though, because of the side effects. They do create cataracts, and they can raise intraocular pressure, and so they do not tend to be first or sometimes even second line. The tried and true before we had medications was, of course, laser treatment, and laser treatment does give some benefit, but it is pretty rare that retina surgeons use laser at this point for diabetic macular edema. I do think that the second-generation anti-VEGFs are being used more, but as we see the real-world data from those agents, they are not providing the type of extension between injections that many of us, I believe, had hoped.
The need in DME is probably, I mentioned, is probably even greater than wet AMD. First of all, remember, this is generally a working-age population. They also have multiple doctors that they see. Unlike wet AMD, where if you give an anti-VEGF agent, typically within a week or two, patients know they are better. Because presumably, since this is not just a VEGF-mediated disease, it can take many injections on DME before patients realize that they are actually getting better, which can result in patients dropping out. In the United States, according to the studies, in the first year, diabetics should probably receive 11 injections, and on average, they receive three. By one year, about 40% of diabetics are no longer under treatment. So there is still a huge opportunity for a sustained-release agent to come in and provide faster improvement, and even if not faster, fewer injections.
I think that that will be much more attractive in this population.
Got it. What is your view on the combination approaches, right? I mean, obviously, we are seeing now VEGF being combined with Ang-2, with VABYSMO, right? Some additional drying. We are going to see what happens with Wnt plus VEGF. Do you think there is more room? Is there an opportunity for you also to have some sort of a combination approach at some point?
Oh, absolutely. I think that, again, as you look at our wet AMD data and the way we have structured the DME, one could argue that the eyes that get rescued, in fact, that is combination therapy. There are two different mechanisms of action.
I see.
You know, biologic ligand blocker working extracellularly versus a TKI working intracellularly. There's reason to believe that there'd be some synergy.
But there's no reason at all that a doctor would not choose to necessarily use them together, even if they see that a patient is under good control, in order to gain the confidence that the patient would remain under control.
This has been the promise, frankly. I can still recall almost 20 years ago when anti-VEGFs first came, we would listen to our colleagues talk about how this was going to be like treating cancer, and we would have all these different MOAs, and we would pick and choose. Here we are, 15, 20 years later, and we started to scratch the surface, as you point out, with Ang-2 and perhaps Wnt and perhaps Tie2, but the mainstay remains anti-VEGF.
Anti-VEGF, for sure. What is the official guidance for data readout? Are we going to get both the readouts together for COMO and CAPRI in Q4 of next year?
That is the intent right now. They finished recruiting within weeks of each other.
I see.
At present time, given how successful we were in getting the data out quickly in wet AMD, we are confident that at this point, we can guide to very early Q4.
I see.
with data for both.
Okay. Maybe one question for George. George, how is the financial, or what does the capital look like? How the burn rate look like?
Yeah, so we ended September with about $118 million of cash, which includes the ongoing funding of the DME trials. We did announce a restructuring.
Yeah
on the heels of the wet AMD data. That program, the clinical program is being wound down, and we reduced the organization size by about 53%. We're working through scenarios to make our cash last at least through data.
I see.
There's more to follow on that. I think there's a lot of activity on the wind-down of the trial, on the timing of the exits, and we're laser-focused on making sure our cash gets us there from here.
Got it. Well, very good, gentlemen. Thank you so much.
Thank you.
Thank you.
Appreciate the time.
Thanks for your interest.
Thank you.
Good luck for the rest of the day.