Veeral Sheth, MD, MBA, FASRS, FACS

Veeral Sheth, MD, MBA discusses the 3 improvements needed for the future of treating patients with geographic atrophy. 

The Future of Geographic Atrophy Treatment

: I think with geographic atrophy, we're in the beginning stages of therapeutics. This is like inning number one of the last game of the World Series. We're finally at a point where we have a therapeutic, that does something, right? After years and years of looking for therapeutics, in clinical trials that just didn't pan out. As a clinician who's been involved in a lot of those clinical trials, I'm very excited about the fact that we got something past the finish line, but we know that this is the first step.

While we have something that's efficacious, it requires a heavy treatment burden, right? We can slow the disease down, but I would love to be able to slow the disease down with maybe a more durable agent, something that doesn't need to be given every month or two. That’s, I think, what patients are going to demand over time. We've seen that with our wet AMD and DME patients, and I think this is no different.

I think that in the future of treating geographic atrophy, we're really going to look for kind of three improvements. One is going to be efficacy – we need agents that are going to further slow down the damage being done, and maybe one day even reverse the damage, but that's even further down the road. But, better efficacy. Right now, we're talking 20 to 30% slowing down, maybe we get to 40 or 50%, maybe we get to 70 or 80%. I think it's something that we have to aim towards.

The second thing is durability. How can we achieve these types of endpoints, but with fewer injections, or maybe even alternate routes? Right now, there are people out there looking at gene therapy as an example. This is a perfect place for gene therapy because you can treat potentially one time and get a prolonged treatment effect from that. That’s one of the things that we're looking at, and potentially something that's not as far down the road.

Then, safety. The third thing we look for is safety. We want to make sure that whatever treatments we continue to push forward that they are as safe, if not safer than whatever kind of bar has been set. Right now the bar has been set by SYFOVRE and IZERVAY. We have got to continue to kind of push those three factors and come up with good solutions for patients. We've done it before with neovascular AMD and DME, and I have no doubt we're going to do that for geographic atrophy as well.

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Veeral Sheth, MD, MBA discusses the clinical trial data that led to FDA approval of SYFOVRE and IZERVAY for geographic atrophy

Clinical Trial Evidence in Geographic Atrophy

: I'll take a second just to dive into some of the clinical trial evidence that allowed these treatments to get to us with the FDA approvals. And so for the first drug SYFOVRE, we had mentioned OAKS and DERBY. OAKS and DERBY were the big phase 3 studies that really looked at patients with both central and non-central geographic atrophy. And what we saw in both of those studies is a significant reduction in GA lesion growth and we saw that in one of the studies, we saw a significant P value, and in the other one we did not, not at the one-year mark.

But the good news is that at 24 months, we seem to find that the divide between the patients that aren't treated and the patients that are treated, continues to grow. What does that mean? So in the two-year data, we saw that in the OAKS study, for example, there was a 22% reduction in GA lesion growth versus the sham. And in DERBY, we saw a 19% reduction. But what we see is that the delta between those two groups, the study treatment group, and the sham group continues to separate over time.

The way I think about that, and the way I talk to my patients about that is with treatment, we're going to shift the course of your disease. And so what I tell people is, there's a likely chance that a year from now after starting treatment, or two years from now, that we've potentially allowed you to have less vision loss, less spread of that atrophy, then if we were to not have treated you. That’s the way I positioned kind of the treatments and the benefits of these treatments. And so that's the SYFOVRE data.

If we talk about the IZERVAY data that came from two studies, the GATHER1 and GATHER2 study, in the GATHER1 study, we saw that there was a 35% reduction in the treatment group versus sham. In the GATHER2 study, we saw about 17.7%, that's 12-month data, we should be finding out about the data beyond that pretty soon. And this study was a little different. This looked at patients who did not have central GA lesions and so there is a difference there. I think one thing that is very important to note with both of these clinical trials, is not only the efficacy but the safety, right? Safety is so important and again, is really an important bullet point that we talk to our patients about. In both of these studies, we sign an increased risk of choroidal neovascularization (CNV) rates when you treat patients with these agents. I do counsel my patients about that, in fact, I have patients in the clinic who do some research on this, and then come to me and ask me specifically about this increased CNV rate that we see with treatment. And I do tell them look, there is a chance that if we do start treatment for your geographic atrophy you may develop wet macular degeneration. Now, we know that that can happen without treatment because there is an increased risk in patients with GA to develop CNV, but there's potentially a slightly higher risk with these treatments and so again, that is something that I counsel patients about.

Veeral Sheth, MD, MBA, discusses the clinical trial data that led to FDA approval of SYFOVRE and IZERVAY for geographic atrophy.

Veeral Sheth, MD discusses the two newly FDA-approved therapies for geographic atrophy: pegcetacoplan injection (SYFOVRE) and avacincaptad pegol (IZERVAY).

New Therapies for Geographic Atrophy

: We've had thankfully, 2 new drugs approved for geographic atrophy. This is after having nothing clinically available for these patients who suffer from geographic atrophy. Back in February of 2023, we had SYFOVRE approved, and that came from two studies, the DERBY and OAKS studies, which I can talk about in a second. Then, more recently, in August of 2023, we had IZERVAY approved, again, for patients with geographic atrophy. And that was FDA-approved after two positive clinical trials, the GATHER1 and GATHER2 studies. They’re similar but slightly different, right? They both attack the complement pathway. We know that the complement pathway is kind of a natural pathway that we have in our bodies, it can help fight bacterial infections, and things like that. It's kind of an immune response.

But, we also know that there's this genetic tendency for patients to to have an overactive complement pathway. And that can lead to kind of uncontrolled inflammatory reactions, especially in the retinal pigment epithelium. When you look at some of these patients, or you take, for example, some of their tissue and you look at that tissue under a microscope, what you can see is high levels of things like C3 and C5, which are kind of towards the end of that complement pathway. As we started to identify those as potential targets in the retina, we obviously started looking at therapeutics that could potentially block some of those pathways. The first drug that we had approved, SYFOVRE, looks to inhibit the C3 pathway or the C3 molecule and that will help kind of lower the inflammatory damage being done in the RPE cells and photoreceptors. And then IZERVAY targets just slightly downstream of that, which is the C5 pathway. Again, they're similar in that they're both addressing kind of this complement inhibition, but they're different enough that they're actually targeting different parts of the pathway.

What does that mean clinically? They both have had studies that show slowing down of the damage that's done with GA, in other words, they've slowed down the spread of those geographic atrophy lesions to the order of between 20-30% depending on which study you're looking at. And there's a little bit of a range in the studies. And so from a therapeutic standpoint, we're not talking about stopping the disease dead in its tracks. And we're certainly not talking about reversing the disease. But what we are talking about for the first time is at least having some impact and slowing down the rate of damage that's being done in that patient's retina. And that's something that we are very clear with patients about because a lot of times, even if you start treatment, six months later, a year later, they may notice that, hey, my vision is still getting a little worse. And again, we kind of reiterate that, at least not yet, we don't have anything that will stop that disease dead in its tracks. But we do have these two treatments that can slow things down.

Veeral Sheth, MD, MBA describes the presentation of geographic atrophy in patients and how they are first affected by the disease. 

Symptoms and Manifestations of Geographic Atrophy

: When we talk about geographic atrophy, one of the interesting things is, for the longest time, we really didn't talk much about geographic atrophy in our clinics, especially not with our patients. Because it's this nebulous type of dry macular degeneration, we didn't have treatments, so it wasn't really worth a lot of conversation because it didn't go anywhere with patients. And so, we're talking a lot more about it now, obviously, because we have a couple of new therapeutics that were introduced in 2023. 

We're a lot more excited about talking about it, we're talking to patients about it because there's a potential of offering them a therapeutic. And so when we do talk to patients, how do I describe geographic atrophy, atrophy for that patient? I say, look, it's a form of dry macular degeneration because I think patients are still pretty familiar with the fact that there is a wet type and a dry type. And I tell them it's an advanced form of dry macular degeneration, for which, for the longest time, we had no therapies. For us, as clinicians, what we've noticed is that, or at least what we've thought, historically is that this is a pretty slow-moving disease. 

And I think part of that is because when you don't have treatments for these types of things, you don't pay as much attention to it, or you don't see these patients maybe as often. And not just that, when we measure patients' vision, for example, we could have patients that have geographic atrophy, that's progressing pretty significantly, that are still 20/20 or 20/30. And so when we're quickly going through patients in our clinic, and we're just looking at vision, and we're making sure that there's no fluid on the OCT, we're not often kind of appreciating the fact that this disease actually may move a little more quickly than we thought. And if you look back at the data now, it does look like it moves in many patients pretty quickly. 

That's something that I think we need to recognize as clinicians and then, when we talk to patients about it patients will come in 20/20 and they'll complain about having more trouble driving, more trouble reading. Someone was walking across the crosswalk, and I didn't see him right away. So things like that, that actually affect their daily life, but that we don't necessarily see in the measurements that we do in clinic, but we're starting to recognize the fact your to your question, which is, how does it affect patients? 

Before they lose central vision, they're still becoming symptomatic and then sometimes that means just as the quality of vision is degrading so there again, like I said, having more difficulty doing daily life activities, reading and driving being two of the more common ones, things like being able to see the ticker on the television or see someone's face from across the room. Things like that are the things that you'll hear pretty routinely in the clinic, from the patients that are suffering from this disease.

Veeral Sheth, MD, MBA, FASRS, FACS

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