Ryan Haumschild, PharmD, MS, MBA: We’ve given a background of geographic atrophy [GA], but now let’s delve into the management and discuss some of the upcoming treatments and the current or historic management of GA. Dr Khanani, we know we’ve had a recent FDA approval, which is really exciting for patients with GA. But a lot of these patients have had to be treated differently because there were not approved agents in this space. If you could, maybe speak about how you’ve been treating patients before this FDA approval, how these patients have been cared for, and what if anything can be done to prevent or slow the disease.

Arshad Khanani, MD: Ryan, that’s the million-dollar question because we had no treatment until now, so we were giving the bad news to the patient that this disease will progress over time, we will monitor it. I’ll have patients with GA in my clinic who I’ll see every 6 months just to make sure that they don’t have neovascular AMD [age-related macular degeneration]. Or if they have any acute changes, they will call me, trying to see how much damage they’re having over time, measuring fundus autofluorescence pictures to see the area of the lesion. But there is nothing there, so we are seeing these patients twice a year, and all they do is every time they come in they say, “My vision is getting worse, do you have anything for me?” The answer was no, obviously until now. As I said, many of these patients are being followed in general ophthalmologist and optometrist offices also because everybody knows there was no treatment, so nobody was referring these patients to us. In a retina clinic, they may have to wait longer, but we had the same answer that we had nothing. For intermediate dry AMD, there are AREDS2 vitamins that we recommend, but once you hit GA, there is really nothing else other than quitting smoking and making those lifestyle changes. But again, as I said earlier, that doesn’t stop the disease. It’s exciting now that instead of telling our patients that we have no treatment, we can tell our patients that there is some hope, and there’s some light at the end of the tunnel.

Ryan Haumschild, PharmD, MS, MBA: It’s definitely an exciting time, especially with some of these new approvals because we’re giving patients hope. I think otherwise our ophthalmologists and retina specialists have done everything possible to preserve [patient] quality of life, but I know it’s been difficult and challenging. I appreciate everything you’re doing and am excited about the future as well. Dr Lally, I know you’ve done a ton of work in this area. If you think about upcoming treatments for GA and those that have been approved, [they] act through complement inhibition. I know we’ve touched on this a bit, but what is the role of the complement system in GA, and if you could, what are the potential advantages of targeting the complements at different steps within the GA pathway?

David Lally, MD: Sure, so our first identification that [the] complement [system] may be involved in GA, we started homing in on it for 2 specific findings. The first was when we looked at the histopathology of patients with GA and macular degeneration, and we looked at these retinas under the microscope, we started seeing the presence of complement proteins in the drusen that we were seeing under the retina. As I mentioned previously, drusen is the hallmark finding of macular degeneration, and within drusen, we started seeing the presence of C3, C5, the MAC [membrane attack complex], we also see C1Q. That was a sign that complement, we’re seeing this under the microscope. We were not seeing that in just aging eyes without macular degeneration, so that was the first clue. The second clue was the genome-wide association studies, looking for common variant mutations in single polymorphisms in genes in large populations of patients. We started identifying that multiple complement polymorphism mutations, that increased the risk of patients developing the advanced form of GA. From there, that’s where trials were initiated looking at blocking complement, and I think we’ve seen success there. We’ve kind of confirmed that complement does play a significant role in the development of GA.

What is the complement system? The complement system is one of the oldest systems in our body, it’s part of the innate immune system, and there are 3 pathways. There’s the lectin, the classical, and the alternative pathway. All 3 of these pathways converge on a common molecule called C3. From C3, it becomes a common pathway where further reactions occur and lead to the development of what we call the membrane attack complex, or the MAC complex, which is a complex that inserts itself into the cell and can cause cell death. There are a lot of different companies out there looking at blocking different parts of that complement pathway and the different pathways. To be honest, we don’t know which is the best one to block or not. We don’t know if it’s good to block as much of the complement system as you can, or only block part of the system. I think a lot of that we’re going to determine over the next 10 years. Some companies have tried the strategy of blocking C3, which is the convergence point of all 3 pathways. Theoretically, you’re going to be blocking as much of the complement system as you can. Other companies are looking at blocking a bit upstream of C3. One company is looking at blocking C5, which is specifically within the alternative pathway. But then there’s another company looking at blocking the classical pathway, C1Q.

Until we get all of the clinical results, we don’t know if it is best to block the entire system or block part of the system because this is part of our innate immunity. It’s a constitutively active system, it’s always active. We just know in GA that it’s overactivated. If we can get it back to at least the homeostatic level of a patient who does not have GA, that may be all that’s required. Or maybe it’s better to block as much as you can. I think time will tell. But where to block in the system, we don’t know yet in terms of what’s best. We just know that blocking the system, at least so far with our results from the C3 and C5 blocking trials, the data we’ll talk about, that does seem to slow the progression of GA over time.

Ryan Haumschild, PharmD, MS, MBA: That was a great overview of the complement system. I appreciate you going through that. It explains a little more about why we are seeing C3 and C5 in a lot of these clinical trials, and hopefully more are coming.

Transcript edited for clarity.