Greg Nothstein:

We've heard rumblings about the potential of the Wnt pathway to address DME. Could remigromig be the agent to affect change?

Scott Krzywonos:

I'm Scott Krzywonos here with Greg Nothstein, and you are listening to New Retina Radio from Retina Today and Bryn Mawr Communications.

Dr. Don D’Amico joins the show to review the Phase 2B/3 BRUNELLO study data, which assessed the safety and efficacy of remigromig for DME.

Greg Nothstein:

And Dr. Carl Regillo sits down to examine the results of LUGANO, a Phase 3 study assessing the safety and efficacy of EYP-1901 for treatment of wet AMD. The study didn’t reach its primary endpoint, but what learnings from the dataset can inform our understanding of TKI’s potential to address exudative disease? Stick with us to find out.

Scott Krzywonos:

We’ve heard rumblings about the Wnt pathway’s ability to mediate exudative disease activity, and at AAO subspecialty day this year, we heard data from the BRUNELLO study, which was by far the largest data set exploring this potential. The drug in question, remigromig and the disease, DME.

Greg Nothstein:

Dr. Don D’Amico presented the Phase 2B/3 BRUNELLO data examining remigromig in DME, and he’s here today to do the same. Dr. D’Amico is the John Milton McLean Professor and Chair of Ophthalmology at Weill Cornell Medical College and the Ophthalmologist in Chief at New York Presbyterian Hospital. Dr. D’Amico, welcome to New Retina Radio.

Donald J. D’Amico, MD: Delighted to be here.

Greg Nothstein:

Now remind our listeners about the efficacy ceiling currently faced with anti-VEGF agents for DME therapy.

Donald J. D'Amico, MD:

Anti-VEGF therapy for DME has been remarkably effective and it certainly was a major, major advance. But still based on many studies, some 40% of patients either have an incomplete response, an impermanent response, and will relapse and have persistent fluid, et cetera. And so there's clearly room as an unmet need for additional therapies. Nevertheless, we're delighted to have anti-VEGF agents compared to what we had previously, which was simply grid laser treatment and perhaps some judicious use of intravitreal steroids.

Greg Nothstein:

And where does the Wnt pathway fit into all of this?

Donald J. D'Amico, MD:

Yeah, it's interesting because it is completely orthogonal to the much more widely known VEGF pathway. And by that I mean it operates through a different mechanism. So VEGF is very, very active in neovascularization, in blood vessel growth and maintenance, et cetera. The Wnt pathway is primarily active against the blood retinal barrier.

Wnt is a pathway that is very tissue specific. So Wnt receptors in one part of the body will be quite different than in another part of the body. And it has been attractive for a long time as a target, but has faced enormous technical obstacles. For example, the agents, the artificial agents such as antibodies that might activate the pathway are typically highly unstable. And then the ability to mimic Norrin, which is the natural agonist, is very difficult. You have to activate a Frizzled-4 receptor while simultaneously activating two LRP5 epitopes. And it's been a real challenge, but recently remigromig is successful in achieving this very complex activation.

As a result, one can think of it as essentially a band-aid, if you will, or a repair of the blood retinal barrier, which is quite different than inhibiting new vessel growth, et cetera, with anti-VEGF. And there's no theoretical reason why the two can't be in many ways complementary.

Scott Krzywonos:

So in the Phase 2B/3 BRUNELLO study, researchers examined remigromig for DME. Can you just tell us about the study design before we get into the details itself?

Donald J. D'Amico, MD:

Sure. It was a 984-person study, subject study, which randomized 1:1:1, two doses of remigromig, either a 0.5 milligram or a 0.8 milligram, administered monthly by intravitreal injection compared to 0.5 milligrams of ranibizumab.

The entry criteria were typical for such a study. Visual acuity was between 75 and 24 letters on an ETDRS chart and minimum central subfield thickness on OCT was 325 microns. And the study design looked to see whether the primary endpoint was measured at one year, and that was whether best corrected visual acuity with the doses of remigromig was non-inferior to the comparator monthly ranibizumab 0.5 milligrams.

The study does continue for a second year in which there will be a personalized treatment algorithm applied based on a combination of maintaining a retinal decrease in thickness and certain visual acuity parameters. But the primary endpoint is at one year, and the study met its non-inferior endpoint at one year.

Scott Krzywonos:

Let's put a pin in that for just a second. I want to better understand why ranibizumab 0.5 milligrams was used as the control arm. Can you help me there?

Donald J. D'Amico, MD:

Yeah, sure. That's an excellent and actually fairly frequent question. But when you do a non-inferiority trial, you need an active comparator that has an established non-inferiority margin. And given that this is a monthly dosing trial, the only agent which has an established monthly non-inferiority margin is ranibizumab.

There's a little interesting thing about the dose. In the United States, 0.3 milligrams of ranibizumab is used primarily, and in much of the world 0.5 milligrams ranibizumab is used monthly for diabetic macular edema. And because this agent has the potential wish to be filed worldwide, it was selected as 0.5 as the comparator. So that's the reason for the choice of ranibizumab.

Greg Nothstein:

Let's move to the results now. Now, a few moments ago you mentioned that BRUNELLO did reach its primary endpoint at the end of year one, but can we dig into the details a little bit more here?

Donald J. D'Amico, MD:

Sure, sure. So at the end of year one, the 0.5 dose achieved an improvement of on average 9.1 letters from baseline, and the 0.8 milligram dose achieved an improvement of 8.7 letters from baseline. And the ranibizumab comparator achieved an improvement of 11.8 letters from baseline. And these differences met the non-inferiority comparator, and also are within a single line of visual acuity and by many standards not considered clinically meaningful differences.

Scott Krzywonos:

So safety overall in the study was good, but there was a higher rate of PDR in the remigromig arms. And can you help us understand why, one, and then two, whether this is truly a safety issue?

Donald J. D'Amico, MD:

In the remigromig arms, in the two doses, approximately 6.5%, it was 6.7 and 6.1, but approximately 6.5% of patients experienced a PDR event compared to 0.9% in the ranibizumab comparator. These events were in general very well-controlled. 85% of patients who experienced one of these events still went on to have improved visual acuity at one year.

We're still looking at the data, and we'll learn more when the companion BAROLO trial comes out. But if you compare this with prior trials controls either true sham or say something like a macular laser grid where there was no anti-VEGF on board. So for example, RISE and RIDE, which was a sham control, experienced 16.3% of PDR events at one year. And VISTA and VIVID had 11.1% of PDR events at two years.

So it appears, and this again, I don't have full final data or full analysis, but it appears simply to be a permissive effect that it's not designed, anti-Wnt is not designed or Wnt pathway activation is not designed to be anti-neovascular and therefore it would be expected that you would see some of that occur. And I would just note that it may in fact be superior to sham control because there may be interplay between Wnt and some parts of the neovascular pathway, but that's speculative and really requires more data to be properly evaluated.

Greg Nothstein:

So Dr. D'Amico, overall, what does this mean for remigromig?

Donald J. D'Amico, MD:

Oh, I think it's incredibly exciting. I mean, a quarter of the patients in the study had prior treatment and still it met its non-inferiority margin. We don't know anything about subgroups. We don't know anything about duration. For example, what if this is used and has a prolonged duration of repairing the blood retinal barrier? Also, what about other retinal vascular diseases, retinal vein occlusion, potentially macular degeneration?

Even things such as in the same session with me, for example, Dr. Nisha Acharya presented work on the difficulty of treating uveitic macular edema. What if this drug with its blood retinal barrier can treat conditions such as uveitic macular edema, post-surgical cystoid macular edema? Again, I'm speculating, but it's an entirely new pathway, the first novel mechanism in decades to show efficacy in retinal vascular conditions, and therefore it deserves to be studied alone, in combination, in sequence, before, after, during, as many ways as we can possibly look to exploit the promise of this new agent.

Greg Nothstein: Dr. D'Amico, thank you so much for joining us here on New Retina Radio.

Donald J. D'Amico, MD: Oh, it's been a pleasure. Thank you so much.

Scott Krzywonos:

The LUGANO and LUCIA trials are assessing the safety and efficacy of the vorolanib intravitreal insert or DURAVYU for the treatment of wet AMD. The LUCIA data are due out soon, but the LUGANO data are in. Dr. Carl Regillo shared data from LUGANO at AAO Retina Subspecialty Day, and he's on mic today to tell us more about it.

Greg Nothstein:

Dr. Regillo is the director emeritus of the Retina Service at Wills Eye Hospital and a partner at Mid-Atlantic Retina, both located in Philadelphia. Dr. Regillo, welcome back to New Retina Radio.

Carl D. Regillo, MD, FACS, FASRS: Thanks so much for having me. Pleasure to be here.

Greg Nothstein: So Dr. Regillo, remind us how vorolanib addresses exudative disease.

Carl D. Regillo, MD, FACS, FASRS:

So what vorolanib is is a tyrosine kinase inhibitor, small molecule that works intracellularly to block the downstream effects of a variety of receptors, cell membrane receptors, particularly all three VEGF receptors, in addition to others that may also help in terms of having a favorable effect or some efficacy such as blocking IL-6 in particular. So it's a true pan-VEGF blockade effect plus some other cytokines, IL-6 and even PDGFR. And so, they all could be playing a role in neovascular AMD, diabetic macular edema, and other retinal conditions. More specifically, well, that's what the TKI is and vorolanib is one of many out there.

Scott Krzywonos:

EYP-1901, that's the other name for this vorolanib intravitreal insert, which is bioerodable. It's being studied for both wet AMD and DME. The wet AMD studies are coming across the finish line right now. As we mentioned in the opening, LUCIA data are almost ready, but the LUGANO data are in. Before we get to it, just remind us how LUGANO was structured.

Carl D. Regillo, MD, FACS, FASRS:

Before we get to that, one more point about what EYP-1901 is, because it's more than just vorolanib. It's vorolanib as a small molecule packaged in a bioerodable polymer that's injected intravitreally. So this insert stays in the vitreous cavity and delivers therapeutic levels of the vorolanib intravitreally for at least six months. So it's sustained delivery giving us indirectly an anti-VEGF-like effect.

Now onto the clinical trials, because the clinical trial program in general for 1901 is large and robust, looking at both neovascular AMD and diabetic macular edema, both of which have been through Phase 3 testing successfully, including the DAVIO 2 wet AMD study. So now we're into the Phase 3 program for both wet AMD and DME. And LUGANO and LUCIA are ongoing Phase 3 trials testing EYP-1901 for the treatment of neovascular AMD.

And what are they? So LUGANO in particular, but they're again identical. These are head-to-head non-inferiority trials comparing 1901 injected intravitreally and dosed every six months, versus on label every eight week aflibercept 2 milligram injections in the maintenance phase after both arms have had three monthly doses, three monthly loading doses as you would say, with the aflibercept.

And from there, both arms in the maintenance phase or after week 8 could be supplemented with aflibercept meeting specific criteria. And the primary endpoint of the clinical trials, LUGANO again specifically, is the mean change in BCVA from baseline to weeks 52, 56 averaged with a standard 4.5 letter non-inferiority margin? And then secondary endpoints included anatomical assessments by OCT, treatment burden and safety.

Greg Nothstein: Did the study hit its outcomes here?

Carl D. Regillo, MD, FACS, FASRS:

Well, actually it fell short of hitting the primary endpoint. So it was not non-inferior in terms of mean change in BCVA out to the primary endpoint. What we saw was good vision gains in both groups in the loading phase, and it held on pretty nicely up until about months 9 through 12 when we saw some decline in the BCVA, the vision, mean vision in the EYP arm, falling short with the plus two letter endpoint visual acuity gain versus about six letters in the aflibercept arm. So statistically that was not non-inferior, so it didn't meet the primary endpoint.

But what it did show, however, was excellent anatomical control when you look at mean change in CST from baseline. So the OCT anatomic analysis showed excellent reduction in mean CST from baseline, and that was relatively well-maintained with a flat OCT curve in the maintenance phase for the 1901 arm for the course of the study and comparable to the aflibercept arm dosed every eight weeks.

Scott Krzywonos:

Now this study had an asymmetric cohort of nine patients that have been a big topic of discussion. Can you talk us through that asymmetric cohort, help us define it and understand who was in that cohort?

Carl D. Regillo, MD, FACS, FASRS:

We had a successful Phase 2 study, very similar design, except it was just one injection of EYP, but it was compared to on-label aflibercept. That was the DAVIO-2 study. And it actually was successful in meeting its primary endpoint of being non-inferior BCVA.

So this came as a surprise, and we had to explain it. Why did we get some vision decline in the 1901 arm and yet we saw exudative control holding up very well in comparable to aflibercept? So there's a bit of a disconnect, and obviously this was hard to explain.

So a deeper dive into the data did reveal that there was a total of nine cases unique to the 1901 arm that lost three or more lines of vision from non-wet AMD causes. So those nine patients, six had geographic atrophy into the fovea, resulted in decreased vision, two advanced cases of glaucoma, and one retinal attachment with a poor outcome. Collectively, these nine patients had a poor vision outcome and there's evidence now with a post-hoc analysis that it definitely influenced the mean. Because if you exclude them in a post-hoc analysis that was performed, you do see more comparable visual outcomes to the degree in which non-inferiority would've been met.

Greg Nothstein:

But surely patients lose vision for all sorts of reasons in clinical trials. Doesn't this all come out in the wash in the end?

Carl D. Regillo, MD, FACS, FASRS:

Well, ordinarily or normally it does, meaning both arms will typically have non-wet AMD if it's an AMD trial, not a AMD-like vision loss. For example, both arms had a retinal detachment. It happened to be in the aflibercept arm. The patient actually gained letter, had a great outcome, yet 1901 had a poor outcome.

So usually you're right, it's random, it's balanced. But here, there was an unusual and unexpected imbalance. The aflibercept control arm actually performed even better than expected. Usually, we see rates of 3 to 4% with three or more lines lost with a mix of reasons or causes, wet AMD and non-wet AMD. Here we saw 1 patient out of over 200 at 0.5% that had three or more lines lost in the aflibercept arm, and that was from wet AMD. There were no non-wet AMD causes or cases of vision loss, and that was surprising because we've seen that in other trials. In fact, we saw that in DAVIO 2, some GA causing vision loss in the aflibercept arm. So ordinarily it is balanced, but occasionally unusual things happen purely by chance. So in essence, some bad luck with some asymmetric distribution of these types of events.

Greg Nothstein:

Presumably, there were fewer injections for patients in the EYP 1901 group. What did that mean for treatment burden?

Carl D. Regillo, MD, FACS, FASRS:

Well, when you look at all the secondary outcomes, the study was actually very successful in showing that 1901 had some advantages over aflibercept. Treatment burden was among their top of the list as a secondary outcome. It achieved superiority in terms of injection burden up to week 56. So there was a 42% reduction in treatment burden.

So comparably exudative control with less injections, both the 1901 plus any aflibercept supplements over the course of the year. Put it in other ways, that 1901 arm averaged 1.1 supplemental injections, and 79% received either 0 or 1 supplement injection up to week 56. So that means the product alone performed very well in terms of disease control with not a lot of additional treatment needed.

Scott Krzywonos:

There are a lot of moving parts in a study like this. It can be hard to know what to pin down on. So from your perspective, what are the major take home points and what do we need to keep an eye on in the next couple of months?

Carl D. Regillo, MD, FACS, FASRS:

Sure. The major take home points was it surprisingly did not meet non-inferiority. Everything up till now pointed to a very effective product to control wet AMD. And in fact, we did see that when you look at the anatomic analysis with OCT outcomes, and it lived up to what we expected with regards to decreasing treatment burden by 42% over a one-year timeframe. And also throw in a very favorable safety profile.

So when this product is dosed every six months in the maintenance phase of neovascular AMD, there's strong evidence to show that it actually performed very well. But missing its primary endpoint is a potential issue with regards to FDA approval. But we have a second study to draw upon, and that's the LUCIA trial. [inaudible 00:22:43] should read out. It's an identical study, and so it'll help the support and give us the big picture here.

Scott Krzywonos:

Understood. Well, Dr. Regillo, thank you for coming on New Retina Radio and sharing all this information with us.

Carl D. Regillo, MD, FACS, FASRS: Thank you for having me once again. Appreciate it.

Scott Krzywonos:

That concludes our AAO 2026 coverage on New Retina Radio. We had one other episode. If you missed it, go back in your feed and take a listen.

Greg Nothstein:

And to be sure that you get all of our coverage from meetings in 2027, make sure that you subscribe to your favorite podcatcher of choice.