Management of Wet Age-Related Macular Degeneration - Episode 7

Anti-VEGF Agents for Wet AMD Treatment

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A panel of eye care specialists review the 4 currently available anti-VEGF agents available for the treatment of wet AMD.

John W. Kitchens, MD: Presently, there are 4 main anti-VEGF therapies utilized here in the United States. We’re going to start with them in the order in which we started to use them. It was back in 2004 and 2005 that we began to use off-label bevacizumab, or Avastin as it’s known, in the eye. Dante, your group in California did a lot to innovate with this being used in an off-label fashion. Tell us about how you all helped the development of this.

Dante J. Pieramici, MD: Phil Rosenfeld, MD, PhD, had given a talk where he was using IV [intravitreal injection] bevacizumab because bevacizumab was a cancer drug. If you look at a lot of the agents that were used, they were initially used for cancer therapy because Judah Folkman, MD, came up with the idea that you could restrict cancer growth by getting rid of the vascularization in the tumor. So we used this agent that was being used for cancer therapy, and they showed a response in patients given IV, but there were a lot of complications, things like hypertension and potential strokes. Phil had done 1 or 2 patients, he had done an intravitreal injection, and I thought it was brave, but it was remarkable. One of my partners, Bob Avery, MD, came back and said, “We should start doing this.” We were thinking about doing IV therapy, so we just started using it in our patients. It was one of those treatments where the effect was so large that you almost don’t need a clinical trial to know that it’s working. You need a trial to make sure it’s safe in the long run and such.

This drug was a one that the company didn’t want marketed for this use because it was being used off label, and it was very inexpensive compared to the ones that they were developing. But it quickly took hold like wildfire, not only around the United States, but around the world, with no marketing dollars spent trying to get this drug in use. It was used worldwide, that was the large effect of it. It was one of those things in my career that, we had been through PDT [photodynamic therapy], and we did submacular surgery, and some of the things Roger talked about, for example, laser. It was unsatisfying for the patients and for the doctors. When you gave this patient an injection, they came back a month later and they said, “I’m seeing a whole lot better doctor.” You looked at the pictures and they were much better. It was a big effect, and it’s continued to be so.

John W. Kitchens, MD: Absolutely. And as Dante pointed out we’re still using bevacizumab to this day. It’s an affordable option for our patients. Next up in 2006, ranibizumab was approved for the treatment of exudative age-related macular degeneration. Lloyd, talk to us a about the effect of ranibizumab and the place it’s found in your armamentarium.

Lloyd Clark, MD: Ranibizumab was the first FDA-approved drug for use in the eye for wet macular degeneration. It was the first anti-VEGF agent that was specifically studied in the eye for treatment of these common retinal diseases, including age-related macular degeneration. It shares many similarities with bevacizumab, but it has a higher affinity to the target protein than bevacizumab, and it’s also significantly less stable in the serum. It has a serum half-life of around 5 hours compared to almost 3 weeks with bevacizumab. That makes it a drug that’s ideally suited for use in the eye. It has a higher affinity, so that it sticks tightly to the target protein, but once it’s expelled from the eye, it’s rapidly metabolized in the systemic circulation. What it was designed to do was have a stronger effect inside the eye than bevacizumab but have a limitation in systemic cardiovascular events, as Dante discussed.

There was a full, robust, 3-phase clinical research development program that Genentech underwent with ranibizumab. It showed about a 10- to 12-letter improvement of vision in patients with wet macular degeneration compared to the current standard of care. The overall delta between this drug and the standard of care was approximately 4 lines of vision. As Dante described with bevacizumab, even though we were masked in these clinical trials, and we weren’t allowed to know what they were getting, it was clear early on in the first few months that these patients were receiving something that was completely different. These trials were remarkably positive in terms of favoring ranibizumab as a superior drug in wet macular degeneration, and ultimately it was approved in 2006. It became the gold standard for treating wet macular degeneration, both in the clinic as well as a gold standard comparator for the clinical trials that would follow the approval of ranibizumab.

John W. Kitchens, MD: Roger, a decade ago we had approval of a third agent, aflibercept, for the treatment of exudative age-related macular degeneration. Talk to us about aflibercept and how it's different from ranibizumab or bevacizumab.

Roger A. Goldberg, MD, MBA: Aflibercept, the brand name is Eylea, it’s made by Regeneron. Back then Regeneron was a relative start-up biotech. It’d been around for a long time, but it never had a big commercial success. We now know Regeneron as one of the major biopharmaceutical companies that have been very involved with the COVID-19 treatments with an antibody treatment, and they have multiple other drugs. Eylea is what put them on the map with aflibercept. Aflibercept is what’s called a fusion protein, and it’s more akin to a full-length antibody in terms of its size. They call it a VEGF trap because it binds soluble VEGF, and it has a tight binding affinity and soaks up all the free VEGF that’s there. Based on some work that they did early in the clinical development pathway, it seemed to have a longer half-life in terms of its potential for efficacy. When aflibercept was developed, by 2011 when it got FDA approved, it wasn’t ethical anymore to have a sham or a PDT [photodynamic therapy] control. It was a controlled trial against ranibizumab, which is what we said was the gold standard. They were able to show that patients who were treated every other month after a series of loading doses did equivalently as well as patients treated monthly with ranibizumab. It offered the prospect of longer time in between treatments when it came to market.

John W. Kitchens, MD: Last, we had approval about 2 years ago of a medication called brolucizumab. Dante, talk to us about the type of molecule that brolucizumab is, how it may have some differences from the drugs we’ve talked about previously.

Dante J. Pieramici, MD: It’s another molecule design, a very small peptide molecule. You could have a large concentration molar equivalent of the drug, it had a very high binding affinity. We thought one of the ways to extend the durability of a drug is to put more of it in there. That was part of it with brolucizumab, and the high binding affinity. This drug came out, and was looked at in clinical trials, and it was compared with the standards of care at the time and shown to be equivalent and perhaps having a longer durability. We were excited about the drug, and we started using it, a number of our patients were part of the clinical trials. We were enthusiastic about the possibility in patients who didn’t seem to dry up completely with the other agents, that this would be a better drying agent. In some cases, anecdotally it seemed to be that way.

It turns out, unfortunately, there were some increased risks of complications, intraocular inflammation, and rare occlusive arterial occlusions that occurred in these patients that are inflammatory related. These caused very abrupt and severe loss of vision. These are rare events, but in the environment where you have other agents that are working close to the same efficacy and durability, it was hard for a doctor to choose this type of agent. For the most part we, at least in my practice, don't use brolucizumab much. We still have some patients who were placed on it and seem to be doing pretty well. If you don’t overuse it or use it on a less frequent basis, the risks are less. That’s the latest one that got FDA approval, but the use of it has been less.

John W. Kitchens, MD: It had a lot of excitement when it first launched, and we were all disappointed to see some of these as you mentioned very unusual events, and not a class effect. We don’t see these vascular occlusions with other drugs in these classes. It gave us a lot of pause before we jumped in wholeheartedly. It has caused a big pause among our community in utilizing this.

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Transcript Edited for Clarity