An Overview of VEGF Inhibitors

W. Lloyd Clark, MD: Hello and welcome to this HCPLive® Peer Exchange titled, “Roles of VEGF Inhibitors in the Management of Retinal Diseases.” I am Dr Lloyd Clark. I specialize in the treatment of vitreous and retinal diseases, and I practice at the Palmetto Retina Center, located in Columbia, South Carolina. Today, joining me in this discussion are 3 of my expert colleagues, first Joseph Coney of the Retina Associates of Cleveland, in Cleveland and Akron, Ohio; Dr Diana Do, of the Byers Eye Institute at Stanford University School of Medicine in Palo Alto, California; and finally, Dr Ehsan Rahimy of the Palo Alto Medical Foundation of California. We have Palo Alto well represented here. Today, we are going to discuss several topics pertaining to the role of VEGF inhibitors in the management of retinal diseases. We will also provide an overview of diabetic retinopathy, specifically nonproliferative diabetic retinopathy, and discuss therapy with VEGF inhibitors. Welcome everyone, let’s get started.

We’re going to spend the first section of our talk today in an overview of VEGF inhibitors. I am going to start out with Dr Rahimy to lead us off. Give us an overview of the mechanism of action of VEGF inhibitors.

Ehsan Rahimy, MD: Thanks, Lloyd. As we all know here, VEGF inhibitors are basically standard of care for most of the conditions we take care of on a day-to-day basis in our clinics. This class of medications are monoclonal antibodies. They bind to and sequester circulating VEGF. VEGF as you know stands for vascular endothelial growth factor; this is an important signaling protein that’s involved in production of new blood vessels known as angiogenesis. By sequestering VEGF levels, they prevent it from binding to its receptor and exerting its downstream effects. We know that VEGF levels are significantly elevated in several retinal vascular diseases, notably diabetic retinopathy. They’ve done numerous studies showing levels to be elevated in the aqueous and vitreous of patients. It’s important to understand VEGF’s contribution to the pathophysiology of diabetic retinopathy. We know that underlying tissue hypoxia stimulates VEGF production. From there, VEGF is a critical player in the molecular crosstalk between 2 pathways. One is angiogenesis, or the neovascularization cascade; due to progressive tissue malperfusion, the growth of new blood vessels, this gives rise to proliferative diabetic retinopathy, which we will discuss. And the second pathway is inflammation. We know that VEGF also stimulates leaky blood vessels, breakdown of your inner blood-retinal barrier level, so endothelial cells aren’t as tight. And this results in leakage of fluid into the retina, resulting in diabetic macular edema, which is the No. 1 cause of vision loss for people with diabetes. These 2 pathways are obviously very complex and multifactorial, but VEGF is a very important component of both of them.

W. Lloyd Clark, MD: That’s a great opening discussion of the mechanism of VEGF inhibitors. Diana, first welcome, great to see you. Talk to us a little bit about the role of VEGF inhibitors in macular edema. Vision loss and retinal disease is due to swelling in the retina or macular edema. We treat a wide array of indications of retinal disease with VEGF inhibitors. Are they all the same? We use the same agents. How does this work in terms of treating multiple different diseases with a single class of drug?

Diana V. Do, MD: Lloyd, over the past 15 years there has been a large body of scientific evidence that has shown both the safety and efficacy of these intravitreal VEGF inhibitors for variety of retinal vascular diseases. As you mentioned, the common theme with these retinal diseases is that they are vision threatening because they affect the center of the retina, the macula. VEGF inhibitors are FDA approved for wet age-related macular degeneration [AMD], diabetic macular edema, and macular edema due to retinal vein occlusion. The patients who have these conditions present with blurry central vision, and we have seen through numerous phase 3 randomized clinical trials that when VEGF inhibitors are given appropriately and dosed regularly that patients can experience significant vision gain. These medicines have revolutionized the visual prognosis for our patients, and it’s exciting that these medicines have also been approved for nonproliferative diabetic retinopathy.

W. Lloyd Clark, MD: As a follow-up, clearly there are disease states where the target protein, VEGF, or vascular endothelial growth factor, is significantly upregulated, particularly in retinal vein occlusion. In AMD, we use an anti-VEGF agent, but it’s not necessarily because we have wildly elevated levels of VEGF in the eye. Explain that, how does that make sense to use a VEGF inhibitor in a disease state where we don’t have dramatically elevated levels of the target protein?

Diana V. Do, MD: That’s a great point, that in different diseases there may be different levels of VEGF expression. For example, in wet age-related macular degeneration, the culprit is choroidal neovascularization, which is abnormal blood vessel growth underneath the retina. We know that VEGF, the molecule, plays an important role in both angiogenesis, which is the formation of new abnormal blood vessels, or excessive vascular permeability, which is the leakage from damaged blood vessels. In wet AMD, VEGF inhibitors are effective because they help to shrink the choroidal neovascularization that leads to the vision loss in wet AMD. Therefore, these VEGF inhibitors are very effective because they can help target multiple disease states.

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 inbox.

Transcript edited for clarity.