Anti-VEGF Therapy for Wet AMD

Arshad Khanani, MD: In terms of treatment for patients with neovascular AMD, anti-VEGF agents are the primary treatment. We have 3 FDA-approved agents for treating neovascular AMD: ranibizumab, aflibercept, and brolucizumab—and an off-label agent, bevacizumab—are utilized for the treatment of this condition. Essentially, what happens in neovascular AMD is you have upregulation of VEGF, or vascular endothelial growth factor. VEGF-A leads to leakage, and of course chronic leakage leads to damage to the retina, whether it’s from fluid or bleeding. Our goal is to use anti-VEGF agents to control this disease.

These patients get treatment in their eyes with an intravitreal injection. Essentially, all these agents that are available have shown great efficacy in terms of controlling neovascular AMD, decreasing the risk of blindness, and improving visual acuity. Ranibizumab was the first anti-VEGF agent, approved in 2006 based on the pivotal ANCHOR and MARINA studies. Aflibercept was approved in 2011 based on the VIEW1 and VIEW 2 trials. The aflibercept studies were designed to see if patients can be treated less frequently. After 3 months of the dosage, there were every-8-week and every-4-week arms to see if we can go longer in terms of treatment intervals, and then the recently approved brolucizumab in 2019. The trials were also designed to see we can go every 8 to 12 weeks. All these agents worked. There were some differences in terms of drying retina, especially with brolucizumab, which is a very small molecule, with 6 mg dosing, that dries the retina better based on the trial and real-world experience compared with aflibercept, which dries the retina slightly better than ranibizumab. Safety has been an issue lately with brolucizumab, with rare events of retinal vasculitis and retinal artery occlusion, which is not what we see with other agents. There has been a lot of work done to learn more about that and to see how this agent can be used in the future. Bevacizumab, as I mentioned, is an off-label anti-VEGF agent, but it also works well in patients with neovascular AMD, which is compounded by a pharmacy. We have to balance the benefits and risk of any of these agents for treatment of our patients.

Looking at the different agents, all of them work well in our patients. There are some durability differences among these agents as well as safety differences. Bevacizumab, ranibizumab, and aflibercept—we have a lot more experience with those agents than we do with brolucizumab. Based on the trial and based on real-world studies, we can see that these agents work well. Aflibercept dries the retina better than ranibizumab and bevacizumab, so the patients can go a few weeks more if they’re treated with aflibercept. Ranibizumab has been approved for longer than aflibercept. We have more long-term data in terms of safety with ranibizumab compared with aflibercept, but aflibercept has been out since 2011, so we still have a lot of data there. In terms of safety, all these agents are comparable. When aflibercept came out, there were some reports of intraocular inflammation, but that was addressed.

Then a couple of years ago, there were some cases of intraocular inflammation with aflibercept. They were correlated to syringes but also resolved, and in my opinion all 3 agents have similar safety profiles. Brolucizumab dries the retina better than all 3 of the other agents, with a 6-mg dosing and a much smaller molecule, but the safety profile is different. It has a much higher rate of intraocular inflammation, and in the pivotal HAWK and HARRIER studies, the rate was about 4% of IOI [idiopathic orbital inflammation]. Once the drug was available in the real world, when we had thousands and thousands of injections, we saw events of retinal artery occlusion as well as retinal vasculitis. These are still rare events, but these events can lead to permanent vision loss in a subset of patients looking at the analysis done by SRC [Optometry Victoria’s Southern Regional Congress], which was safety review committee that looked at patients with intraocular inflation. With brolucizumab, they found the rate of severe vision loss associated with these events about 1 in 200. But we are learning more about patient profile and baseline characteristics that are leading to this inflammation. We’ll learn more about it, but the bottom line is that ranibizumab, bevacizumab, and aflibercept have a comparable efficacy and safety profile while brolucizumab is different in terms of safety but is a better drying agent.

When I’m seeing a patient, I discuss the risk and benefits of all the agents, their FDA approval, and off-label bevacizumab. Then we come up with a decision with what agent the patient is interested in trying, but in my practice most of the patients have good insurance coverage, so they choose an FDA-approved agent. I usually start my patients with ranibizumab or aflibercept. After treating them for 3 to 6 months, if I feel like there is persistent disease activity or there is vision loss associated with disease activity, then we consider switching to another agent, and then brolucizumab comes into the conversation if the patient is losing vision with aggressive monthly anti-VEGF treatment. We have to talk about the safety because it is different from ranibizumab and aflibercept.

Initially when anti-VEGF agents came out, there was a concern about systemic absorption leading to systemic adverse events, thromboembolic events, and other issues. But we have done a lot of work in a host of studies that have shown that there is no difference in systemic adverse events among these agents. Of course, we follow patients closely. We keep in mind that we are paying attention to their systemic safety, but in general, these agents are very safe. In terms of intraocular profile, there is not much in terms of differentiating 1 agent from another except for brolucizumab. The recent work we did shows that patients with a history of inflammation with other agents or having inflammation from other causes had a higher rate of inflammation with brolucizumab. Other than that, there are no differences in terms of picking a patient or looking at their comorbidities trying to select 1 agent or the other.

Transcript Edited for Clarity