Scott Krzywonos:

Can a single molecule treat both GA and Stargardt disease? And if so, how far along is the research?

Greg Nothstein:

I'm Greg Nothstein, and he's Scott Krzywonos, and this is New Retina Radio, from Retina Today and Bryn Mawr Communications.

Dr. Jay Chhablani joins New Retina Radio to share data from ArMaDa and GARDian, which assessed OCU410 and GA in Stargardt disease, respectively.

Scott Krzywonos:

And Dr. Jordan Deaner sits down to discuss his research on real-world retinal tears and detachments, following YAG capsulotomy. What are the actual incidence rates, and what risk factors were identified? Stick with us to find out.

Greg Nothstein:

Gene therapy has been a promising possibility for years, but just how close are we to having a treatment that could be used by a large population?

Scott Krzywonos:

Dr. Jay Chhablani is here to give us an update on OCU410, which is a novel modifier gene therapy for both geographic atrophy and Stargardt disease. Dr. Chhablani is a Professor of Ophthalmology and the Director for Clinical Research at the UPMC Vision Institute at the University of Pittsburgh. Dr. Chhablani, welcome to New Retina Radio.

Jay Chhablani, MD:

Thank you so much, guys. It is an honor to be part of this podcast. Thank you so much for inviting me.

Scott Krzywonos:

Let's talk about OCU410. This targets the complement cascade. Where exactly on the cascade are we focused? Because there's so many targets on there.

Jay Chhablani, MD:

OCU410 seeks to over-express iRORA, which is an important modifier protein, which in turn inhibits CD59, and therefore mac formation. Eventually the mac formation, which is now reduced due to this gene modifier of protein, it can lead to reduced disease activity for both geographic atrophy and Stargardt’s. But to remember that OCU410 is administered via subretinal injection.

Greg Nothstein:

OCU410 was assessed in the phase two ArMaDa trial. Can you tell us about that study please?

Jay Chhablani, MD:

Absolutely. I think that this trial has shown us very exciting data, particularly for GA. So for the ArMaDa phase two trial, we enrolled patients with geographic atrophy secondary to dry age-related macular degeneration. Because it was a phase two study, that's why the focus was very much on the safety. The patients were randomly assigned into one-to-one ratio to medium dose, high dose and control. The endpoints were at month 12. As I mentioned that the safety was the primary outcome, so the safety was looked very carefully.

In addition to the safety, we also looked into the change in GSI lesion on fundus autofluorescence as well as ellipsoid zone area loss on optical current tomography that is OCT. Patients were given oral steroid prophylaxis and a postoperative topical steroid per surgeon's discretion.

Greg Nothstein:

All right, you mentioned it a little bit ago, but let's talk efficacy first here. What did you see on OCT at 12 months?

Jay Chhablani, MD:

We did see the significant benefit in both structural damage in regards to fundus autofluorescence as well as on OCT. We noticed the medium dose performed the best with 23% slower ellipsoid zone loss versus control. We also saw 41% reduction in RP loss for the medium dose group versus control. This was among all patients. When we only look at patients whose lesion size fit criteria used in other GA pivotal trials that is less than 17.5 maximum size, we saw a 27% reduction in ellipsoid zone versus control for the medium dose. Similarly, we saw 45% reduction in RP loss in the group which was treated by medium dose compared to the control arm.

Scott Krzywonos:

That's some encouraging efficacy. Were there any safety signals of note?

Jay Chhablani, MD:

We did not notice any safety signals in this study.

Scott Krzywonos:

All right, and let's shift gears. Let's look at Stargardt disease and OCU410. You were part of a phase one study. What did you and your colleagues find in that study?

Jay Chhablani, MD:

This was a GARDian trial which enrolled Stargardt patients with ABCA4 mutations with bilateral lesions. This was a dose escalation study with three doses similar to GA. Overall, this was a safety study. Did not see any reports of serious adverse events or adverse events of special interest in any of the arms.

Scott Krzywonos:

There's always the temptation to look at efficacy even in a phase one study, and I understand that you did. What did you find on the efficacy front?

Jay Chhablani, MD:

We only treated one eye in each patient and we compared that eye with the fellow eye. When doing so, an independent reading center saw 116% decline in the ellipsoid zone rate in the treated eye, which is a quite significant number. However, we understand that this was a small study considering the early phase of the study, but we look forward to see such excellent results in the upcoming trial phases as well.

Greg Nothstein:

In your opinion, what are the biggest takeaways from both ArMaDa and GARDian?

Jay Chhablani, MD:

I would say that the best thing which I learned was the great safety. We did not see any serious adverse events in both these studies. We did see an encouraging efficacy profile in both geographic atrophy and Stargardt's. What we are looking forward is that ArMaDa global GA study phase three is about to start very soon, and GARDian study for Stargardt phase three study is already fully enrolled with the data in the first half of 2027. So I'm looking forward to hear more about both their studies.

Greg Nothstein:

Dr. Chhablani, thank you so much for joining us here on New Retina Radio.

Jay Chhablani, MD:

Thank you so much for having me. Looking forward to meeting again.

Scott Krzywonos:

Retinal tears or detachments will happen in some degree of patients undergoing YAG capsulotomy, but how many? And are there any predictors that can tell us if a patient is at risk?

Greg Nothstein:

Dr. Jordan Deaner looked into it, shared data about it at ASRS, and is kind enough to join us here today. Dr. Deaner practices at Wills Eye Hospital and Mid-Atlantic Retina in Philadelphia, where he's also an Assistant Professor of Ophthalmology at Thomas Jefferson University. Dr. Deaner, welcome to New Retina Radio.

Jordan Deaner, MD:

Greg, Scott, thank you so much for having me.

Scott Krzywonos:

Let's start at the top. Keep in mind that some of our listeners are trainees. Why do patients undergo YAG capsulotomy?

Jordan Deaner, MD:

I think we start at the beginning. When we do cataract surgery, we try to remove all of the cloudy lens from our senile, usually senile patients' eyes, but we're never able to remove all of the lens from the eye. We always leave small particles. These cells, they're living things. They do what all living things, when we leave them alone, they grow, they replicate. They don't understand that we left them with a nice clear plastic lens. And so, sometimes these cells grow and create a smudge on the back of the lens that needs to be cleared up.

We can clear that up surgically, or more standard of care or more modern day therapy is using what's called a YAG laser. That stands for a Yttrium Aluminum Garnet Laser. We use that to carefully polish out that smudge on the back of the lens. We know that there is some risk for retinal detachment whenever we do this laser polishing procedure, but the literature's been pretty mixed on the outcomes, and we really wanted to look and see what is the true rate of retinal tears and retinal detachments following a YAG capsulotomy.

Greg Nothstein:

Dr. Deaner, where do we look if we want to find those answers?

Jordan Deaner, MD:

Yeah, so I think we can look in lots of different places. We could do prospective studies, we could do retrospective studies. I think for this phenomena, we think that this is a very rare occurrence or very rare risk of YAG capsulotomy. This is where our giant databases come in handy, and so we looked into the AO IRIS registry. We looked at data. We ran an analysis looking at the IRIS registry from 2014 to 2023, and we found that during that period, 7.8 million cataracts were performed.

For this study, we included eyes of patients that were 40 years of age or older and had had a YAG capsulotomy following a successful cataract extraction with intraocular lens implantation. We made that definition by CPT code, and then they needed to have at least one year of follow-up. We also excluded eyes with other vitreoretinal pathology, including things like diabetic retinopathy, a history of prior retinal tear or retinal detachment, a history of vitreoretinal surgery, or a history of panretinal photocoagulation.

Greg Nothstein:

So now let's turn to the biggest picture then and discuss overall incidents here.

Jordan Deaner, MD:

Yeah, and so when we were looking at this study, we identified our primary outcomes. We looked at retinal tears, retinal detachment, and then we looked at the combined score of retinal tears or retinal detachment, and we identified those by ICD-10 codes. We also looked at some secondary outcomes, risk factors for retinal tear, retinal detachment, or both. Ultimately, applying our inclusion and exclusion criteria, we were able to identify 2.1 million eyes of 1.4 million patients. The overall one-year incidence of retinal tear was 0.22%. The overall risk of retinal detachment following a YAG capsulotomy was 0.29%. The overall risk of a retinal tear or retinal detachment following a YIG capsulotomy was 0.49%.

That's about one in 200 eyes that will have a rhegmatogenous complication following a YAG capsulotomy. I think it's important to know the raw numbers. Those are the incidents of this rare occurrence following YAG capsulotomy, but probably more important was how these events were distributed over time. They didn't all just happen at once. Importantly, the risk over time wasn't uniform. The highest risk of rhegmatogenous pathology here occurred within three months. It peaked at three months, and then it steadily declined over the follow-up period with about two-thirds of all retinal tears and retinal detachments occurring within six months. I think this is actually one of the most important findings.

Scott Krzywonos:

You mentioned risk factors that could be associated with retinal detachment or a retinal tear. What did you find?

Jordan Deaner, MD:

Yeah, so we looked into multiple different risk factors that could be associated with retinal tear or retinal detachment following a YAG capsulotomy. The strongest risk factors we found was the comorbid presence of lattice degeneration and a new posterior vitreous detachment that occurred following the eye capsulotomy. Both of those increased the risk of having a retinal tear or retinal detachment following the eye capsulotomy by over tenfold. Some additional risk factors that we found that weren't nearly as severe included younger patients, men, highly myopic eyes, and then those eyes that had a preexisting PVD prior to the eye capsulotomy were also all at increased risk for retinal tears and retinal detachments.

Scott Krzywonos:

These data are fascinating, but what do they mean for clinical practice? Are they going to change your decision-making when it comes to post-YAG monitoring? Do you think that there are broader implications? I'm curious where you think they fit in a real sense.

Jordan Deaner, MD:

I love doing studies that have a true clinical impact, and have a true meaning, and change the way that we should practice medicine and ophthalmology in particular. I think this is one of those studies. And so right now, a lot of patients that go in and have a YAG capsulotomy after cataract surgery, the doctor does the YAG capsulotomy, and sometimes they never see that patient again. And now, we know the true rate of this occurring. It is low, but not zero. It's one in 200 eyes, and we're talking about millions of cataract surgery being done over this period.

I think it really illustrates to us that not only should we be following our patients that we do routine YAG capsulotomies to, we should be reading them the rule book on, "Hey, if you have 20 to 100 new floaters, flashing lights that wouldn't go away for a few hours, a dark curtain that would come over the eyes, those would be very meaningful things that should bring you immediately to my office so that we can take a look. Those are symptoms of a retinal tear or retinal detachment."

Beyond that, I think we need to advise our patients that are getting YAG capsulotomies a little closer, particularly when they have high risk features like lattice or they develop a new posterior vitreous detachment after the YAG capsulotomy, that not only do those patients need to be advised of this risk, but they need to be followed closely after these events to watch for retinal tears and retinal detachments. I think that both falls on the performing comprehensive ophthalmologist doing the YAG capsulotomy and also falls on retina specialists for these high-risk patients because we should be seeing them in consultation maybe before and after YAG capsulotomy as well.

Greg Nothstein:

Dr. Jordan Deaner, thank you so much for joining us here on New Retina Radio.

Jordan Deaner, MD:

Greg, Scott, thank you so much for having me.

Greg Nothstein:

That concludes New Retina Radio's coverage of the ASRS meeting that happened a few weeks ago in Montreal. But don't you worry, we'll be providing coverage from AAO this fall from New Orleans.

Scott Krzywonos:

And if you missed our first episode of coverage, go back in your feed. You can hear us talk to Carl Danzig and Dilsher Dhoot about their presentations at ASRS.