Current and Emerging Therapies for Wet Age-Related Macular Degeneration (AMD) - Episode 5

Safety and Efficacy of Available Treatments in Wet AMD

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Experts compare the safety and efficacy of agents currently available for wet AMD treatment and emphasize the importance of post-marketing surveillance.

Diana V. Do, MD: We were used to having such excellent safety profiles with the 3 most commonly used anti-VEGF agents: bevacizumab, ranibizumab, and aflibercept. More recently, the retina community faced some challenges with a new agent, brolucizumab, which was very efficacious. It had FDA approval, but later in the post marketing surveillance of this drug, we noticed some episodes of intraocular inflammation and severe adverse effects, such as retinal vascular occlusions. This is a good example of the surveillance that we still need with new agents because this new adverse effect did change my consent process if I were to use that particular agent because it poses a different risk that these other agents did not.

Charles C. Wykoff, MD, PhD: Great comment. Glad you brought that up. Let’s dive into that. Mark, give us the mechanism of action. If you think about it historically, there’s actually, right, there are 5 anti-VEGF agents that are FDA approved. We really use probably 3 of them, maybe a little of a fourth. We have aflibercept, bevacizumab, ranibizumab as Diana beautifully just said, and also pegaptanib as the first one on the block. Then brolucizumab also as Diana mentioned. Mark, give us your description of the mechanism of action, overall efficacy, and safety profiles.

Mark P. Breazzano, MD: The first 1 on the table of the 5 was pegaptanib. I don’t think anyone really uses that 1 anymore, but it’s extremely important in ushering in the 3 we use now. There are bevacizumab, ranibizumab, and aflibercept, as you said. Bevacizumab basically follows being approved for colorectal cancer treatment and follows the mechanism of pegaptanib, which was basically an inhibitor just specifically for VEGF164 molecule. But it is more effective at getting the VEGF isomers in that, it has higher binding affinity and clinically has stronger results in treating the components of wet AMD. After that, we have ranibizumab, which is a monoclonal fragment that is FDA approved for wet AMD and is very similar in its efficacy and profile for treating as well. Then we have aflibercept. All 3 are similar, but there could be a slight edge to aflibercept in certain cases. However, the visual outcomes data aren’t super compelling in terms of being superior. But in terms of thickness levels, they achieved slightly better outcomes in certain cases. That is a common infusion protein to accomplish that. It effectively binds VEGFA, VEGFB, and placental growth factor. As Diana mentioned, we have brolucizumab, and that’s an even smaller antibody fragment that was exciting in a lot of these trials in drying up the retina in these wet AMD patients with really long intervals. But as we found out, in its post marketing surveillance, the incidence of intraocular inflammation and retinal vascular occlusive disease had alarm bells going off in terms of safety profile that we need to keep a better eye on.

Charles C. Wykoff, MD, PhD: That’s a great summary. Sophie, I’m curious about your perspective because you do a lot of clinical trial work. When HAWK and HARRIER came out, both Mark and Diana have discussed that they had this predefined secondary outcome in HAWK—one of their trials—of looking at improved drying of brolucizumab over aflibercept. We can all agree, aflibercept is a great medication, as is ranibizumab. They both are highly effective at drying the retina. Then in this study we saw highly statistically significantly better drying with brolucizumab compared with aflibercept. Then we have this safety signal. Is there is a role for brolucizumab in the practice of retina across the country, Sophie? What do you think?

Sophie J. Bakri, MD: That’s a great question. Like everyone on this panel, I was very excited about the brolucizumab data. The better drying, whether it’s intraretinal fluid or subretinal fluid is really compelling. We were all looking forward to converting some of our patients on other drugs to brolucizumab to see if we could extend treatment. I treated several patients and then COVID-19 hit. We heard about the intraocular inflammation, and some of us have cases. That made us think because COVID-19 plus the combination of intraocular inflammation meant that perhaps patients couldn’t come in like they normally would. Then you have somebody with an intraocular inflammation sitting at home, losing vision, and not being treated. I know some ophthalmologists who use brolucizumab and will see their patient back at 1 week. Some will see them back weekly. But we all know that, not only is there COVID-19, but there are convenience issues, burden on the family, costs to patient visits, etc. All those reasons combined, as well as obviously our concern for the patient losing vision, have had most retina specialists back off from brolucizumab, at least for the time being. Certainly, I know the company is making great efforts to get to the bottom of this and understand what’s going on.

Transcript edited for clarity.