Roles for VEGF Inhibitors in the Management of Retinal Diseases - Episode 9

A Review of Clinical Trial Data in Non-Proliferative Diabetic Retinopathy

December 8, 2021
W. Lloyd Clark, MD

,
Joseph M. Coney, MD

,
Diana V. Do, MD

,
Ehsan Rahimy, MD

A panel of experts reviews data on nonproliferative diabetic retinopathy treatments from the PANORAMA, Protocol W, RISE, and RIDE studies.

W. Lloyd Clark, MD: Joe, I’m going to start with you talking about the role of the available anti-VEGF agents in the treatment of DR [diabetic retinopathy]. We’ve got 2 approved agents, ranibizumab and aflibercept. How do you use these agents overall in managing patients with diabetic eye disease?

Joseph M. Coney, MD: Both are great drugs. Both have turned back the hands of time in terms of their disease. When I was in a residency or fellowship not long ago, everyone had progression of the disease; they were all getting lasers. They would still bleed; you’ll have these tractional components. I just don’t see that with the current landscape. It’s also true for when you have nonproliferative disease. When we did our clinical trials for DME [diabetic macular edema], I don’t think any of us thought about what we were doing to the level of retinopathy. We noticed this as a by-product of how we were treating patients in clinical trials and, obviously, what we saw in our clinics day-to-day.

We have great studies that have shown—PANORAMA being the most recent—that if eyes have come in at the severe nonproliferative state, you can reduce their level of disease 2-fold 65% to 80% of the time. This was by customizing doses that they received injection after loading doses, even if it was at 16, 18, or 8 weeks. You have the flexibility to use these agents how you see them fit into that particular patient. In the long term, I don’t know how long I need to maintain these patients. Those are questions that someone on the panel can ask.

Once I get that improvement, how often should I follow patients? I typically use a widefield angiogram. Sometimes I’ll skip an injection, and I’m surprised when I see the neovascularization come back. That if it was severe or maybe had early PDR with low-risk characteristics, I’m very surprised on the changes I see. I’m starting to treat patients a little longer but space them out further. This is a landscape I’m still getting more comfortable with. The more I see these patients do well, the more I’m a very big proponent that if they have disease states that I know that over the next 4 years can have sight-threatening problems, then I tend to start therapy earlier.

W. Lloyd Clark, MD: Diana, we’re going to lean on you for some clinical trial results. Joe alluded to the PANORAMA study, talking about a 65% to 80% rate of 2-step reduction in diabetic retinopathy severity. Can you give us your thoughts on the PANORAMA study as well as the recently released data from Protocol W? Both trials evaluated aflibercept for the treatment of nonproliferative diabetic retinopathy [NPDR]. Give us the lowdown on these trials and your thoughts about how they were performed and what the results look like for you in clinical practice.

Diana V. Do, MD: Over the past few years, we’ve received an abundance of clinical trial data providing level 1 evidence that demonstrates that intravitreal VEGF inhibition with aflibercept is effective and safe at treating moderately severe to severe nonproliferative diabetic retinopathy. Both the PANORAMA study and Protocol W were randomized clinical trials that looked at different dosing regimens of aflibercept compared with sham treatment. They followed these patients over time to see what the benefits and risks would be for the treatment of moderately severe to severe NPDR. Recall that any patient in these clinical trials did not have diabetic macular edema at the time of enrollment. The results of these trials showed that intravitreal VEGF inhibition with aflibercept was safe and effective, and it decreased the risk for vision-threatening complications.

What does this mean? In the sham treatment arm, if you were observed over the 2-year period, you had a 50% risk of developing a vision-threatening complication such as diabetic macular edema or progression to proliferative diabetic eye disease. On the other hand, if you were randomized to aflibercept, this risk was dramatically decreased to less than 15%. It shows that prophylactic proactive treatment with VEGF inhibition could decrease the risk of vision loss over time. This is exciting for the field, and we can see that practice patterns are beginning to change and retina specialists are thinking and treating patients earlier in their disease state.

W. Lloyd Clark, MD: What’s the most important data point from these studies? PANORAMA was a study where the primary outcome was a 2-step progression in diabetic retinopathy. That was the primary outcome. We’ve been programmed to pay attention to primary outcome data in level 1 trials. Is that the most important data point, or are some of the secondary data points—such as vision-threatening complications—more relevant to us in clinical practice?

Diana V. Do, MD: The reduction in vision-threatening complications is the most clinically meaningful for us and for the patients. As you said, the primary end point was looking at severity scale of their diabetic eye disease and the reduction, and these studies met those primary end points. But when we’re talking to patients and we’re understanding how we can preserve their vision, vision-threatening complications is where the money is. That’s where we can help patients preserve their central and peripheral vision.

W. Lloyd Clark, MD: Diana, we observed these reductions in diabetic retinopathy severity when we were all involved in the clinical trials evaluating anti-VEGF agents for DME. We saw similar reduction rates, slightly less, reduction rates in patients treated for DME. Can you talk about the data we saw in RISE and RIDE, as well as VISTA DME and VIVID-DME that informed these primary treatment of retinopathy clinical trials?

Diana V. Do, MD: If you recall, when we first used VEGF inhibitors in diabetic eye disease, it was for vision-threatening diabetic macular edema. When we were treating these patients every month or every 2 months, investigators also noticed that there was an additional benefit because these agents also improved the diabetic retinopathy severity score in these eyes. Because of this evidence, additional clinical trials were launched, specifically looking at eyes who had moderately severe to severe nonproliferative disease at baseline in the absence of diabetic macular edema. The key point with these new clinical trials is that the treatment burden for treating eyes with nonproliferative diabetic retinopathy is less. We don’t have to treat them intensively every month or 2. We saw that aflibercept in these clinical trials could be given every 4 months and still have a beneficial effect.

W. Lloyd Clark, MD: To our audience, thank you very much for watching this HCPLive® Peer Exchange. If you enjoyed this content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box.

Transcript edited for clarity.

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