Role of the Complement System in Geographic Atrophy


David Lally, MD describes the association of the complement system with geographic atrophy and how the 2 FDA-approved therapies for GA work to block the complement system.

David Lally, MD: The year 2023 has been a landmark year for the treatment of geographic atrophy. For the first time ever, we now have two FDA approved treatments for slowing the progression of geographic atrophy. The first one is called SYFOVRE, also known as pegcetacoplan, which was approved in February 2023. We also have a second therapy called IZERVAY, also known as avacincaptad pegol, which was FDA approved in August of 2023. Both of these therapies are injections into the eye called intravitreal injections of medicine that block the complement system. The complement system is a system part of our innate immunity, which traditionally we think of fighting pathogens and infectious things in our body. But, the complement system is also used to help clear out dead or dying material within our bodies.

The reason we got to thinking about looking at the complement system for the treatment of geographic atrophy was actually a surprise. A couple of decades ago, retina specialists would have never thought that the complement system played a role in this disease. What keyed us in to the complement system in this disease was really two things. The first was when we looked at histopathologic studies of patients with macular degeneration, meaning patients who passed away, and we looked at their eyes under the microscope, we saw that in the components of drusen, which is the hallmark feature of macular degeneration, there was the presence of a lot of complement, and the proteins of the complement system within the drusen. That gave us a signal that the complement system may be playing a role here in macular degeneration.

The second finding that we saw, was looking at what we call our GWAS studies, or our genomic wide association studies, where we look at populations of people who have macular degeneration versus populations of people who do not have macular degeneration. We look at all the genes of both groups and we see if we can identify common variant mutations in certain genes that may be different in the macular degeneration group compared to that that does not have macular degeneration. Interestingly, in the genes that we found associated with macular degeneration, a large number of them are associated with the complement pathway. Really, it was those two things, the genetic studies and the histopathologic studies, that got us looking and saying, the complement system may have a role that's at play here.

With knowing that, then the next strategy would be to block the complement system. The first drug that was FDA approved, SYFOVRE, blocks a part of the complement system called the complement C3. The complement system is made up of three pathways, they're distinct pathways, but they all converge onto what's called the protein C3. From there, the pathway continues in a common pathway. And the pathway ends with the development of what we call the MAC complex, which is a complex of proteins that injects itself into the cell membranes and causes cells to burst and die. By blocking C3, you're blocking really the entire complement system where it becomes the common pathway in hopes of preventing cell lysis or death at the end of that pathway.

The other drug, IZERVAY, also blocks the complement system a little further down then SYFOVRE. It blocks what's called C5, which is also part of the common pathway of the complement system. And by blocking C5, you also will block the formation of the MAC complex and cell lysis. The two drugs are in essence trying to do the same thing, generally speaking, block cell death. These drugs were both studied in two large global phase 3 trials and they were successful in showing that by injecting this medicine, when you look one and two years out, you slow the death of more cells over time.

These patients with geographic atrophy, we don't make them see better with these treatments, we also don't stop the progression of the disease. But, what these drugs can do is they slow down the progression, they slow down the loss of the death over time. That's important because now for the first time ever, physicians have some tool in our tool belt that we can offer to patients that will have some interaction in the course of the disease of that patient. We look at these therapies as an opportunity to slow the progression of their disease down over time.

We hope that that will afford them more time with the vision they have in today's world, than what they would have had without this treatment. The treatments don't stop the inevitable. If the patients live long enough, over time, their disease will significantly progress. But, permitting that patient to have more time, more hope, in keeping the vision they have for as long as they're possibly able to have, offers that benefit to that patient.

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