FLORetina ICOOR 2024: Charles Wykoff, MD, PhD, discusses diabetic retinopathy and reperfusion

Ahead of this year's FLORetina meeting and International Congress on OCT Angiography, En Face OCT and Advances in OCT (ICOOR), David Hutton of Ophthalmology Times spoke with Charles Wykoff, MD, PhD. Throughout FLORetina ICOOR, he's presenting on a number of topics, including diabetic retinopathy—the subject of his conversation with the Eye Care Network.

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

David Hutton: Hi. I'm David Hutton of Ophthalmology Times. The FLORetina International Congress on OCT, Angiography and Advances in OCT is holding its annual meeting in Florence. At the meeting, Dr Charles Wyckoff is presenting Diabetic Retina Imaging: New Biomarkers. Thanks for joining me today. First, give me an overview of what you'll be presenting.

Charles Wykoff, MD, PhD: David, great to be here with you, and excited for the FLORetina meeting. It's a great, great meeting in Europe. So, talking about retinal non-perfusion in the context of diabetic retinopathy, and it's a simple presentation. We're addressing three sorts of questions that come up a lot about retinal non-perfusion, and I'll just go through each of those three with you.

So, the first is our understanding and awareness of the presence of retinal non perfusion. Is that clinically useful information? And I think the answer is yes. And the brief summary of that is, you know, originally we had the ETDRS [Early Treatment Diabetic Retinopathy Study] which is our prognostic scale for diabetic retinopathy. We also learned from the original ETDRS trial that angiographic risk factors, including retinal non-perfusion, provide additional prognostic information. And more recently, DRCR AA and PANORAMA trial have shown us that a greater amount of retinal non-perfusion at baseline correlates with a higher likelihood of disease progression through 1 in 2 years of followup. So, the answer is yes. From a prognostication perspective, the presence of non-perfusion, the amount of non-perfusion is important.

And then the second question is, is reperfusion possible? Right. That's sort of the Holy Grail here in diabetic retinopathy. And while the clinical reality is that it is very uncommon to see reperfusion, absent perfusion, with or without anti VEGF therapy, you know, the clinical reality is progressive retinal non-perfusion that accumulates over time, and I'll show some images of that. But it's interesting, because if you look in the literature and you take a deep dive, there are multiple papers going back to the 1980s that have beautifully documented areas of non-perfusion that are then revascularized, with or without treatment of different kinds. And so it's certainly possible, although not common clinically with our anti-VEGFs. What is interesting, though, about all of our clinical trials—RHINE and RISE ... VISTA showed this—all of them, in posthoc analyses, they showed that more frequent anti-VEGF dosing led to a slowing of disease progression. So, you accumulated less retinal non-perfusion when you dose patients frequently with renovisumab or afflibercept. This was studied directly in the RECOVERY trial. That was a prospective trial that randomized 40 patients to either monthly or quarterly aflibercept, all with PDR and large areas of non-perfusion. And we saw that with monthly dosing through 1 year, the primary endpoint of retinal non-perfusion was stable between the baseline and year 1 endpoint, showing you could stabilize retinal mono perfusion with monthly dosing, whereas in the quarterly group dose patients, we saw a meaningful increase in the area of retinal non-perfusion by about 29%. So anti-VEGF therapy does not frequently cause revascularization, but it may slow progressive retinal non-perfusion when dosed frequently.

And the final question is, you know, what could the future of retinal non-perfusion look like? And fortunately for patients, there are a lot of pharmacotherapies that are being considered and being explored in a development perspective, for reperfusing areas of non-perfusion would be the most amazing thing. But they're really being overall, pursued to decrease ischemia by increasing local perfusion, and a few of those are in human development. The one that's furthest along is actually a biologic targeting a pathway called the semaphorin pathway. It's targeting a molecule called Semaphorin 3A, which is an anti-angiogenic, vaso-repulsive cytokine. And the thought here is that if you block Semaphorin 3A, you may be able to allow intraretinal revascularization through a VEGF-induced VEGF-dependent pathway. So there's a controlled Phase 2 trial, ongoing, pursuing that new fastening molecule. That's what I'm touching on at Floretina, an exciting space in diabetic retinopathy.

David Hutton: What can all this mean for patients diagnosed with diabetic retinopathy?

Charles Wykoff, MD, PhD: I think the most important thing from a patient perspective is make sure you're getting a routine eye exam with diabetes. If you have diabetes, we know most people with diabetes, probably worldwide, are not receiving appropriate eye care screening. And then when there is pathology—diabetic retinopathy, I think has a low threshold to at least consider initiation of therapy, right? There are pluses and minuses initiating therapy at all the different stages, but it's worth being able to have that conversation with someone that can adequately treat you if needed.

David Hutton: And you kind of touched upon this, but where do you see this going in the next, say, 3 to 5 years?

Charles Wykoff, MD, PhD: We have some very good therapies for the vision-threatening complications of diabetic retinopathy, right? Diabetic macular edema and proliferative diabetic retinopathy. All of which work better, in my opinion, when you treat the diseases earlier in the disease course. But I think we're still missing a key component of the treatment of diabetic retinopathy, which would be a treatment of the underlying pathophysiology. And I think retinal non-perfusion is at the core of that pathophysiologic drive in this disease process. So, it'd be great to have therapeutics that can directly treat that core pathophysiology. And it's still a dream of finding a medicine to cause reperfusion of damaged areas of retina. But I think it's possible. There's a few biologically possible mechanisms here that are being explored in humans, and I think over time, we'll hopefully find new therapeutics that can help us in that regard.