VEGF Inhibitor Trial Data in Macular Edema Following Retinal Vein Occlusionanti-VEGF therapy


Shared insight on clinical trial data in macular edema following retinal vein occlusion that support use of VEGF inhibition.


Rishi P. Singh, MD: Now we have the approved therapies that are available. We have ranibizumab and aflibercept. We have off-label utilization of bevacizumab, and I mentioned to you obviously the steroids. Let’s talk about the interesting findings. What did you think was interesting from the ranibizumab or the aflibercept studies? There was GALILEO and COPERNICUS with the aflibercept trial, and BRAVO and CRUISE with the ranibizumab studies. What did you find interesting in those studies?

Jayanth Sridhar, MD: There is such a wealth of data to come out of those trials, and for perceptive, all these drugs, we know and for the listeners to know, they need to go through certain trial phases to get approval. For ranibizumab we had BRAVO and CRUISE, which were BRVO [branch retinal vein occlusion] and CRVO [central retinal vein occlusion] trails, to obtain approval, phase 3 randomized controlled trials. For aflibercept, we had GALILEO and COPERNICUS. I’ll focus on BRAVO and CRUISE because those were the first ones. They are very similarly designed, and patients were randomized to either the standard of care or to receiving monthly treatment with ranibizumab. For branch retinal vein occlusion, you referenced the BVOS trial, the standard of care was focal laser. For central retinal vein occlusion, CVOS showed no benefit to focal laser, the standard of care was a sham. That’s the critical difference if you look at how they were designed, but otherwise they were very similar in terms of the design.

There is a wealth of data. I am going to focus on the 3 big takeaways. No. 1, anti-VEGF therapy when compared to the gold standard in both trials was substantially more effective at achieving a greater than or equal to 3-line improvement and sustaining that over time. The second major takeaway was that if you follow these patients past the year, that benefit continues to be maintained. The third major takeaway when you look at some of the analysis is that if you delayed therapy, if there was a delay in therapy or patients did not receive anti-VEGF earlier, then later were enrolled, they achieved vision gains but not equal to the patients who were there at the beginning. We can go into other things to talk about prognosis, how patients with worse vision versus better vision did, but if I am talking to a trainee, those are the 3 big takeaways. It works, it works better if its earlier, and again, just understanding the 2 differences between the trial design.

Rishi P. Singh, MD: Jay, one of the comments was around the branch retinal vein study, in fact, and whether it was valid. I’ll tell you why that thought process is there. At day 0, patients in the BRVO study were not randomized to receiving focal laser, they were receiving no treatment for the first few months. That was a controversy at the time because of the fact the people felt that you were stacking the deck for the anti-VEGF to work better. Clearly, it worked way better than we ever expected, but there was a concept around the fact that they were patients not necessarily being treated with the standard of care on day 0 versus month 3. And again, the caveat to that is that even in the BRVO study, they did wait 3 months before treating patients because they were waiting for the hemorrhages to clear before they started focal laser treatment. That was the reason for the wait.

I will summarize COPERNICUS and GALILEO, and VIBRANT. VIBRANT was the BRVO study, COPERNICUS and GALILEO were the CRVO studies for aflibercept. There were some major differences in comparison to BRAVO and CRUISE. First was that they were treating patients at baseline, so you received focal laser at baseline if were in BRVO study versus anti-VEGF therapy. And in the CRVO study, you didn’t get anything except for sham treatments as you mentioned before. But again, you were receiving the anti-VEGF, in this case aflibercept, for the first period with loading doses as well. What the study essentially found was comparable improvements in visual acuity with regard to anti-VEGF treatment in VIBRANT in comparison to BRAVO and the same for CRUISE versus COPERNICUS and GALILEO together showing that outcome. The 2 major take-home messages from these studies were, first, the randomization of patients with the appropriate standard of care, which showed you that there was maybe slight improvement in visual acuity, albeit it wasn’t at this level of anti-VEGF in the patients with branch retinal vein occlusion.

For the patients with CRVO, in COPERNICUS and GALILEO, there were some great substudies that were conducted, and one in particular helps drive me from a treatment decision standpoint. This is a study that looked at the 12 disc areas of nonperfusion analysis. What this did essentially is looked at patients with and without significant nonperfusion of both the macula, as well as the retinal far and mid periphery, with 12 disc areas being the cutoff. What it found is regarding macular perfusion, yes or no. The answer was that regardless of the perfusion status, the patients did equivalently well regarding visual acuity. With regard to the overall state of nonperfusion and whether you had 12 disc areas of nonperfusion or not, your visual acuity was the same at the end of the trial. It helped to solidify this idea that even though you have nonperfusion, it doesn’t mean you need to do something with it. It just means that it’s there, it’s an annoyance factor because it could cause more recurrences and the need for anti-VEGF over time. But ultimately, the final equity outcome was the same in the 2 arms.

Jayanth Sridhar, MD: Those are great points. There are a lot of things we could talk about. Your point about BVOS in the BRAVO trial and that 3-month waiting period, it’s always interesting to think about what happened to those patients in those 3 months in BVOS. This will tie into our conversation later about prognosis of anti-VEGF and how we treat these patients over time. About a third of those patients at the end of 3 months did not need focal laser. The macular edema improved, and that’s always interesting to think about prognostically. We can talk about how we manage this. None of us would delay therapy to wait those 3 months, but maybe it changes what we think about prognosis at 3 months if they are doing well. What does that mean? Can they come off therapy or not? But we can touch on that a little later.

Rishi P. Singh, MD: Thank you all for watching this HCPLive® Peers & Perspectives. If you enjoyed this content, please subscribe to our e-newsletter to receive upcoming Peers & Perspectives and other great content right in your inbox. Thank you for watching.

Transcript edited for clarity.

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