ASRS 2024: Geographic atrophy, lesion growth and outer retinal tubulation

Srinivas Sai Kondapalli, MD, is presenting at the American Society of Retina Specialists (ASRS) meeting in Stockholm, Sweden this year. Ahead of the conference, he sat down with Sydney M. Crago, Assistant Managing Editor of Ophthalmology Times and Modern Retina, to discuss his presentation topic, outer retinal tubulations in lesion growth for subfoveal and non-subfoveal geographic atrophy.

Editor's note: The below transcript has been lightly edited for clarity.

Sydney M. Crago: Hi. I'm Sydney Crago, Editor of Modern Retina, and I'm here today with Dr Kondapalli to talk a little bit about his upcoming presentation at ASRS. Dr Kondapalli. Can you share a little bit about what you'll be presenting?

Srinivas Sai Kondapalli, MD: Sure yeah. Thanks for having me, Sydney. I'm really glad to be here. So our presentation this year is the predictive role of what's called outer retinal tubulations in lesion growth for subfoveal and non-subfoveal geographic atrophy, which is basically a long title to describe a pretty simple concept. What we're looking at is what's called outer retinal tubulations, and outer retinal tubulations are a sign that we see on an OCT. And I never really knew what they were until I got involved in this research, but what they are...These things called outer retinal tubulation, they look like tubes, right? They are in the outer retina. They have this really hyper-reflective, or really bright white, kind of rim and the dark center. And outer retinal tubulations are seen, not just in geographic atrophy, but other disease states of the macula, especially kinds of atropic disease lesions. But our case, we specifically looked at geographic atrophy because we really weren't sure what that outer retinal tubulation was, and its relationship to geographic atrophy lesion growth. And so that's kind of what we were hoping to find out in this study.

SC: How exactly did you get involved in this research and kind of what has the process looked like?

SSK: So the way that we got involved with this research is that, I was curious to see the natural history progression of patients that had geographic atrophy, and I was able to work with some partners at Apellis, because they were looking at treatment of geographic atrophy with pegcetacoplan, which is a complement inhibitor for the treatment of geographic atrophy. But in the sham arm of these clinical trials, they obviously had a great ability to follow patients' natural history. So what we looked at initially was the FILLY trial; we presented that last year. And what we saw that initial trial was that those patients that had outer retinal tubulations, or ORTs, actually grew at a slower rate than those patients without. This was a relatively small study, because obviously, FILLY was a phase 2 trial. And so in this trial, or at least, this research, what we're hoping to do was look at a larger population study. And that's what we were able to accomplish by looking at both OAKS and DERBY, which was their phase 3 clinical trials. In this study, in particular, what we looked at was the patients that were receiving sham treatment, so we really follow the natural history. And what we're able to find was those patients that had outer retinal tubulations in the sham arms. In total, what we looked at was 300 patients that had geographic atrophy, secondary to macular degeneration, and what we found was that about a third of the patients in the subfoveal lesions had outer retinal tubulations at baseline, and about 20% of patients in the non subfoveal lesions had outer retinal tubulations at baseline. And so what we looked at was both outer retinal tubulations presence and absence, regardless of lesion location, whether that was subfoveal or now subfoveal.

SC: Where might ophthalmologists go to learn more about ORTs, and specifically what they look like on OCT images?

SSK: Yeah, absolutely! So ORTs can definitely be a little bit...it's one of those things that once you see one of them, you'll have a good idea in terms of what they look like for you. I think one of the great resources that we could provide would be showing our examples of ORTs that we were able to show in our clinical trials. And so what I'm happy to share those with you, Sydney, and I get them out to the readers as well. I think that would be a great way to kind of just identify the biomarker of an outer retinal tubulation for sure.

SC: Overall, what would be some key takeaways from this research or things that people may be able to apply in practice?

SSK: Absolutely, I think that there are really two great results that we came out of the study in the 300 patients that had geographic atrophy. And when we looked at the patients that had outer retinal tubulations, on average, they grew about 20% slower than those without outer retinal tubulations. So those patients with ORTs actually have some sort of protective, or kind of safeguard, against geographic atrophy lesion growth. What's really interesting to note, though, is that we also looked at the incidence of those patients with ORTs in the sham arms of these 3 clinical trials: OAKS, DERBY, as well as FILLY, the phase 2 trial. Those patients that had ORTs actually had a greater incidence in the sham arm of DERBY compared to OAKS, and this could explain the reason why that this imbalance kind of led to an underestimation of the treatment effect and may explain the reduced treatment effects seen in DERBY compared to OAKS. Essentially, what we saw is that there was a greater percentage of patients that had ORts in the sham arm in DERBY, and that would explain the reason why, if you're trying to show a treatment effect, that it wouldn't be as significant when you're looking at patients that actually grow, grow slower, right? And that the overly enriched population of ORTs in the DERBY sham arm allows it for legions to grow a lot slower, therefore the treatment effect maybe not as prominent. And so, I think for clinicians, it's useful to know, because going forward as we investigate other clinical trials and medications to help patients with geographic atrophy, we want to make sure that there are not these imbalances of ORTs, because it can really lead to kind of imbalances in terms of treatment effect or efficacy of treatment as well.