In this MD Newsline exclusive interview with vitreoretinal specialist Dr. Michael Singer, we discuss treatment strategies for wet AMD and the latest research.
What is your treatment strategy for wet AMD and how is it tailored to each patient? How do these treatments work? How do you decide when to switch treatments?
Dr. Michael Singer:
“In terms of treatment strategies, most therapies are based on targeting abnormal blood vessels and causing them to shrink. There’s a chemical called VEGF, which is vascular endothelial growth factor, which causes new blood vessels to form.
Essentially think of it as is if you’ve got problems in your circulation. There’s a chemical that is secreted to help generate new blood vessels. Well, this is a great idea if you’re a baby. It’s a great thing for your heart. It’s not such a great thing for your eye. The problem with these blood vessels is they grow in the wrong place, and they bleed very easily. Similar new blood vessels are often seen in cancers, especially when they’re growing.
There are a number of medicines that have been developed over the years to take care of these new blood vessels, but they all work by the same concept. They’re called anti-VEGF medications. They try to block or soak up the vascular endothelial growth factor not only to close the blood vessels down but to decrease the leakage they’ve got. The technology is based on cancer therapies.
There are four medicines right now that are being used to treat wet macular degeneration. The first one [that] was approved that’s still being used is ranibizumab or Lucentis, made by the company called Genentech. It’s been around since 2005.
The second medicine that’s been around even a bit longer is called bevacizumab or Avastin. It’s also made by Genentech. Bevacizumab, however, is an existing cancer drug that is currently being used off-label. It’s not been FDA-approved for the treatment of macular degeneration but is commonly used because it’s significantly less expensive. As I said, it initially was a cancer drug, and it’s really given in tiny amounts that you can inject in your eye to close down abnormal blood vessels.
The third medicine is called aflibercept or Eylea, made by Regeneron. It works slightly differently. It is something called a VEGF-Trap, that traps the VEGF molecule. It works slightly differently than the first two but essentially does the same thing. What it does is it causes new blood vessels to shrink and swelling to go down. And it’s been around since 2011.
The newest medicine is called brolucizumab. It’s made by Novartis. Essentially it’s a very small molecule. It’s the smallest anti-VEGF, and what they do is they concentrate it into a very small dose, so you have a lot more power in a given dose, and it was approved in 2019.
When my patients present to the office with wet macular degeneration, it’s usually one of three scenarios. First, the patient noticed [it] themselves. They say, ‘doc, I just don’t see so well. Something has changed.’ The other way they come in is they’ve seen an eye doctor, and they were given an Amsler grid, and they noticed the change in the checkerboard and came in. Or the third, they were referred by an optometrist or primary care doctor.
In any of these three scenarios, what we typically do is we measure their vision, we examine their eyes, and dilate their eyes. When you look at a dilated eye, think of it as a camera. You’ve got a lens, and you’ve got film. The macula is the bullseye of vision, or the center of the wallpaper, or the film in the retina. In macular degeneration, you are going to see some changes in this bullseye. If the macula has fluid, it’ll be a little out of focus. If the macula has bleeding, you might even see frank blood.
During the visit with the patient, I’ll order a fluorescein angiogram, which is a photography test based with vegetable-based dye, to look at the circulation, to see what I’m dealing with. After it’s confirmed that it’s wet macular degeneration, we start having a conversation with the patient about treatment options.
The problem with all therapies for wet macular degeneration is all these medicines are injected into people’s eyes. So obviously, there’s a bit of a shock when you’re going to tell them, ‘Mrs. Jones, I’m going to treat you with this medicine, but this medicine is going to be injected in your eye.’ This becomes a very significant and lengthy conversation.
A lot of patients are concerned about pain. It obviously runs parallel to what your mother told you not to stick something in your eye, so we spend a great deal of time [explaining] how we numb the eye, and it shouldn’t hurt much at all.
Along with testing with the fluorescein angiogram, we do a test called an OCT or optical coherence tomography. Basically, fluorescein angiogram maps out a two-dimensional picture of the circulation of the eye, and the OCT measures topographically [how much] swelling or thickness there is. The OCT is much more quantitative, and the fluorescein angiogram is more qualitative. The reason it’s important we use an OCT is the OCT is what we’re going to assess how our therapies are working over subsequent visits.
We then have a conversation about different treatments. Like I said before, there are a number of treatments that have different efficacies and safety profiles and different costs. In 2021, you have to have issues concerning costs because insurance companies dictate what patients are going to have, and as a result, patients may have to start with bevacizumab or Avastin because it’s significantly cheaper. If the patient has Medicare, which allows more choice, then more options are available.
Personally, if I’m given my choice, I’d rather start with branded medicines because branded medicines do a better job of decreasing swelling on OCT than Avastin or bevacizumab. As I said before, I’d rather use branded medicines, but if I have to, I will inject the patient with bevacizumab first and then change to ranibizumab or aflibercept, depending on whether or not I’m getting a good response.
This algorithm of switching medications from bevacizumab to a stronger medication is what’s being used by most retina doctors throughout the country for them to change from unbranded to branded medications.
In general, as I said before, for most of my patients that I use branded medicines, I use ranibizumab or aflibercept. Rarely, I use brolucizumab. Brolucizumab was probably the strongest anti-VEGF medication, but the problem is it recently had reports of inflammation and loss of vision, and these were first detected last year. As a result, I reserve it to a very small percentage of my patients who I can’t get dry on the OCT after using other medicines like aflibercept or ranibizumab.
So, in summary, each of these medicines has their place, but in general, they all work on the same mechanism.”
Which of the latest research studies on wet AMD are you most interested in regarding treatment safety and efficacy?
Dr. Michael Singer:
“In terms of the latest research, I’ve been involved with most of the phase three clinical trials for anti-VEGF medicine, which is a nice way of saying I’ve been around a while. There are two things in the near future I’m really excited about.
The first is a medicine with a different mechanism of action. It’s called faricimab. It’s made by Genentech. It’s not only an anti-VEGF medication. It’s also combined with something called anti-ANG2. Angiopoietin-2 is a pathway that destabilizes blood vessels or causes them to leak. Anti-ANG2 medicines cause vessel stabilization, so they don’t leak at all.
With [an] anti-VEGF portion of a molecule and an anti-ANG2 portion of a molecule in one medicine, you basically can close the blood vessels and stabilize them and stop them from leaking, and decrease potential edema. What does this translate to? It translates to medicines potentially being stronger. In addition, it also translates to medicines lasting longer. They may be able to be given every three to four months, leading to less clinic visits and hopefully more compliance.
This medicine recently had very positive results in phase 3 clinical trials, and the data will be reported this year in greater detail for both diabetes and wet macular degeneration. I am excited about the trials that have been performed comparing it to aflibercept, which most doctors think is the strongest medicine at this point for wet macular degeneration.
The other therapy made by the same company Genentech is basically called a port delivery system. What a port delivery system is is a pump for ranibizumab. It’s a surgically implanted device that acts as a reservoir that gives the medicine slowly over time and shows [that] greater than 80% of people didn’t need a refill for up to six months in the phase two trial.
In the recently reported phase three trials, 98% of patients did not need to be rescued by six months. However, it is a surgical procedure in the operating room. Still, it is of value for patients because of the fact that you don’t have to see them or give them more injections once you’ve got the pump in. Essentially you fill it twice a year in the office. And these therapies that I just mentioned are probably going to be approved by the end of the year or the beginning of next year.
In the more distant future, there’ll be other medicines with different mechanisms of action as well. An example of one of these is developed by a company called Kodiak [Sciences] called antibody binding complex, or ABC. ABCs are very big molecules that stay in the eye for a while but have shown in early phase studies that the duration of action may be as long as six months between injections. This is very nice because you potentially get six months of therapy without having to insert a device in the operating room.
Another therapy on the horizon is gene therapy. One [therapy is produced by] REGENXBIO, in which a gene vector is placed under the retina in the operating room. And this gene therapy works by making ranibizumab in the eye. It’s like a ranibizumab-type factory. This trial was performed on people who had hard-to-treat lesions and needed significant injections to control their swelling. And the therapy allowed them to remain dry on their OCT with few or no injections.
The other medicine in [the] gene therapy space is [made by] Adverum [Biotechnologies]. It mimics Eylea, or it’s like an Eylea factory or an aflibercept factory. It’s given by injection in the eye, so no operating room is required. Similar to [the] REGENXBIO [therapy], the Adverum gene therapy decreased the number of extra injections needed to stabilize patients with high-need wet AMD.
Both of these therapies have promise, but each has its drawbacks. [The] REGENXBIO [therapy] requires surgery in the operating room, and currently, Adverum’s therapy is associated with intraocular inflammation.
In terms of dry macular degeneration, there’s some new therapies in development. Currently, if you have dry macular degeneration, there’s not much we can do. You can take vitamins, get good UV protection, and have a diet [high] in green leafy vegetables, control your blood pressure, don’t smoke, but that’s pretty much it.
So right now, therapies [are] kind of focused on lifestyle changes, but there are a number of companies working on medications that basically attack these molecules in the inflammatory cascade or complement cascade.
Some of these are in clinical trials. One is [made by a company] called Apellis, which is doing a phase three trial that is fully enrolled, and the goal of the Apellis medicine is to slow the growth of dry macular degeneration over time. Another company called Iveric bio is also working on a therapy with [a] similar mechanism of action.
Similar to the therapies of wet macular degeneration, these medicines do require injections in the eye, but they work by slowing the natural history of the disease. So the vision gets worse more slowly but doesn’t get better. This is not a reversal. It’s basically a preservation over time. These two studies probably will have results in the next two to three years. But the goal of all these therapies is to preserve [vision for] patients, allowing them to remain independent longer.”
Responses have been condensed and lightly edited.