Lecture: Dry Age-Related Macular Degeneration (AMD) Update: New Therapies

DR KAISER: My name is Peter Kaiser. And I am very happy today to give you an overview of dry macular degeneration. I’m a professor of ophthalmology at the Cleveland Clinic Cole Eye Institute. And I’m very active in clinical research. Here are my financial disclosures because of that involvement.

If there’s a clinical study going on in retina, I’m probably either designing it or part of the scientific advisory board.

So today we’re gonna be talking about age-related macular degeneration. And this is one of the most common causes of irreversible vision loss worldwide.

And this is a huge problem. About 200 million people have age-related macular degeneration, worldwide. And it’s projected to increase to close to 290 million in the year 2040.

In the United States, approximately 11 million people have age-related macular degeneration.

This issue is huge, because age is one of the major risk factors for all macular degeneration. About a third of patients over the age of 75 will have some form of macular degeneration. And that risk continues to increase dramatically with age.

So that patients will eventually develop issues. It’s estimated about 50% of patients eventually living long enough will develop late macular degeneration. And may have geographic atrophy.

So let’s start the first poll, so we get to know each other. This first poll is: Who are you? What is your specialty? Are you in training? Are you an ophthalmologist? Optometrist? Retina specialist? Or other?

Why don’t you go ahead and vote, and that way we can get to know each other a little bit.

All right. So the next poll is going to be…

Let’s just talk… See your knowledge. What are the most important risk factors for developing age-related macular degeneration?

Is it genetics? Smoking? Body mass index? Or age?

Good. About 75% got it right. It’s age. Genetics certainly plays a large role. But if you look here, sort of if you look at macular degeneration, pathogenesis, there’s a lot of factors that are involved.

Obviously genetics are certainly involved. And it’s thought to be about 70% of the contribution.

In terms of your risk. Age, of course, is the greatest risk factor. As was correctly, in a poll, answered. But we’ll talk about some of the other physiologic, systemic issues that can lead to macular degeneration.

And finally, your lifestyle and your environment. Smoking, et cetera. Your diet. These are all involved. But the vast majority is actually genetics. There’s not too much one can do about your genetics.

And this is shown in many GWAS. Genome-wide association studies. Found that many different nucleotide polymorphisms, SNPs, so to say, led to macular degeneration. In fact, this was one of the first ways that we found what was involved in macular degeneration.

Looking specifically at the complement system. But also some of the other genetic factors included. Inflammatory markers, as well as reactive oxygen species.

As I mentioned, environmental factors are very involved. High body mass index, high lipid levels, chronic HPV infection has been correlated. If you have systemic inflammation, that is related.

And interestingly enough, other cardiovascular diseases are also correlated, including diabetes and heart disease. Environmental, though, is one of those ones that you can have your patients change.

And the majority of the environmental is related to smoking. And certainly this is something that all of us would hope that our patients would stop. But it is very involved. So if I see a patient with early dry macular degeneration, I’m gonna ask them to stop smoking.

I’m gonna ask them to change their diet a little bit. High intake of saturated fats, low — I want them to have a high intake of things like Omega-3 fatty acids and lower their saturated fats and cholesterol. So French fries aren’t a good thing for macular degeneration.

High alcohol intake has been correlated. And high sunlight exposure. And that’s a good reason why we all should be wearing sunglasses when we’re outside. Or wearing a hat to protect our eyes both from cataracts, as well as macular degeneration.

So if we look at the stages, and it’s a progression from no macular degeneration to advanced or late macular degeneration. You know, patients come in oftentimes diagnosed with macular degeneration, and only have a few small drusen and no pigmentary abnormalities.

This is actually not yet macular degeneration. To develop macular degeneration, to be called early macular degeneration, you have to have some drusen, more than 63 microns. So these are relatively medium sized. They’re not large.

So large would be more than 125 microns. Which is about the size of the retinal vein, as it leaves the optic nerve. And at that stage, you would be considered to have intermediate age-related macular degeneration.

Why is that important? Well, the intermediate stage is when we would start to recommend the AREDS formulation or the AREDS II formulation of high dose vitamin supplementation.

Any pigmentary abnormalities would also qualify you as intermediate. Now, the late stage is either choroidal neovascularization, the wet macular degeneration, or geographic atrophy.

So there’s two forms of that advanced stage. And what is very interesting to note is: In that advanced stage, on slide right, you know, about a third of the patients will have the opposite form. So if you have wet macular degeneration, you’ll develop geographic atrophy.

If you have geographic atrophy, you can develop neovascularization. So the late form — about a third of patients could have one or the other types. CNV or geographic atrophy.

So what is geographic atrophy? Because that’s what we’re really gonna be concentrating on in this discussion. Well, that’s a thinning and eventually a loss of the photoreceptors, retinal pigment epithelium, and choriocapillaris. You can see this on the fundus autofluorescence image on slide left.

Now, most patients have dry macular degeneration, when you look at the prevalence rates of AMD that we talked about. But about 30% to up to 50%, depending on your age, will eventually progress to some form of geographic atrophy.

Now, that may not affect the vision. It may be off to the side of the fovea. But they do have GA on their image. So if we look at what macular degeneration is, in terms of worldwide numbers, it’s estimated about 5 million patients worldwide — so this is a big problem — will have geographic atrophy.

Of which about a million are in the US. Now, the problem is: This is an aging issue, and the prevalence quadruples every ten years of age, from the age of 50 years.

So if you say — you look at your 90-year-old patients in your practice, a very large proportion will have some form of geographic atrophy, and that accounts for about 20% of the legal blindness that we see due to age-related macular degeneration.

Now, this incidence is actually even greater in patients who are Caucasian. So this incidence in the Caucasian population is even higher. It’s even higher, interestingly enough, than the incidence of neovascular age-related macular degeneration in this population.

So this is something that in the United States in particular we’re looking at very closely.

So what are the symptoms? Well, we all know that if you have extrafoveal geographic atrophy, those areas that are extrafoveal will actually be scotomas. You will have trouble seeing. But it’s only when the fovea is involved that you will really have significant visual loss.

But many studies have shown how geographic atrophy affects a patient’s quality of life. And this leads to many problems. For instance, when you have poor vision, your exercise and engagement with friends goes down.

Chores and social interactions are decreased. Patients become isolated and depressed, because they may not be able to drive, and that causes them to rely on others. Many of their hobbies, reading, using the computer, et cetera, are gonna become more difficult.

So this truly is a problem that affects our patients’ quality of life.

And if you look at some surveys that were done amongst patients who had geographic atrophy and those who didn’t, about half the patients who have GA and a driver’s license, so they haven’t lost their driver’s license, said: We don’t feel confident during the day, and almost 90% felt they didn’t feel confident at night.

We know that dry macular degeneration decreases your dark adaptation. So nighttime driving is gonna be even more difficult. Interestingly enough, if you really ask those patients how they’re doing over the past year, the vast majority, almost 80%, will tell you: We’re getting worse.

Compared to patients who don’t have geographic atrophy, who don’t really note that type of problem. So again… Geographic atrophy is a big issue.

So how does geographic atrophy develop? So here’s a patient of mine. You can see over time they started off with some drusen. And some drusenoid pigment epithelium detachment, back in ’97. And eventually they developed this central geographic atrophy, as shown in 2004.

And have lost their central visual acuity. So how is this visual decline? So many people really don’t think that geographic atrophy is a big problem. But the visual decline that we see — first of all, it’s highly variable. So you can’t really predict it. You can’t tell a patient: Oh, you have x amount of years before you’re gonna start to have a vision decline.

But when the vision decline occurs, it’s rather rapid. So about 30% had about a 3 or more line loss of vision in a two-year time point in this study. And about 30% had a 6 line loss of vision over 4 years.

Just showing you that geographic atrophy, from a visual acuity standpoint, is a significant problem. So if you’re examining a patient with intermediate age-related macular degeneration, what are some of the lesions that you can look for, in their clinical exam, that precede GA development?

Well, you can look for large confluent drusen. So intermediate AMD alone. And the average time it takes before GA — any GA — forms, about 6 and a half years. If you have hyperpigmentation or hypopigmentation of the RPE, these are even more of a risk factor.

So hypopigmentation, for instance, there’s only about 2 to 3 years before geographic atrophy, on average, will appear.

In addition, look for these crystalline deposits. They’re oftentimes near drusen that will eventually form into geographic atrophy. So if you look at these crystalline deposits, and then look at a color photograph maybe two, three years later, you’ll start to see that where those deposits were, geographic atrophy occurs.

So what do we first see in geographic atrophy? Well, 70% of cases will present as a unifocal lesion. And these unifocal lesions in general do not involve the center of the fovea.

It’s off to the side. It may actually be outside the macula. But they’re there. And they do need to be followed. So when you start to notice the appearance of geographic atrophy, you may want to increase the frequency of your examinations.

So what do we use to distinguish geographic atrophy from other problems? And to follow patients with geographic atrophy?

Well, the key feature of geographic atrophy is the very sharply defined border. And you can see this on your clinical exam, on color fundus photos. The historical way of following it is fundus autofluorescence.

But more recently, we’re using OCT, either the near infrared image on bottom right, or the en face or B scan. So let’s look at these different imaging modalities in a little bit more detail.

So let’s do a poll. What imaging device do you think is best to follow your patients with geographic atrophy? Is it your exam, fundus autofluorescence, OCT, or color photographs? What do you do to follow your patients with geographic atrophy?

All right. Well, OCT won. In close second was fundus autofluorescence. At 36%. But more than half of you said OCT.

So let’s see what I thought about that. Well… The old way, and the historical standard, was of course color photographs. And this is what was used in the AREDS study, for instance, as well as the AREDS II study. But there’s limited reliability to follow patients, because a color photograph, just like a clinical exam, it’s very difficult to see the edges of atrophy.

For instance, in that picture there, you can’t really see where the atrophy ends and where normal retina occurs. So because of that, fundus autofluorescence largely replaced color photographs. At least in a regulatory acceptance. So all the clinical studies we’ll talk about later uses fundus autofluorescence as the primary endpoint. Because you’re able to very easily see the area of the geographic atrophy.

They’re dark, right? Now, the problem here is: Can you tell if there’s involvement of the fovea in that picture? Because of that, other areas are being looked at. So one is near infrared reflectance. This is built into all OCT devices. So you can get infrared evaluation of a patient. You don’t need to go out and get an autofluorescence image. But there’s very little validation studies as to how this compares to fundus autofluorescence.

You can use a confocal or multifocal color imaging. The nice thing about that is it allows you to very easily see reticular pseudodrusen. And it contrasts between atrophy and fibrosis very easily. But it’s not really a true color image. And many people don’t like the appearance of a multicolor image.

Which leads us with OCT. Which more than half of you said: I follow my patients with OCT. Which is what I do myself. The reason I like OCT is because recently we’ve had a group of us got together, called the CAM group. And we defined what was the best way to follow atrophy.

And we all felt it was OCT. Because you could see some of the pre-atrophy features on OCT that you really don’t get a good feel for with fundus autofluorescence.

The issue with OCT, of course, is the automatic segmentation. Which we would need to be able to tell if our diseases, our drugs for this disease, were working. They’re really not great yet. And it’s something that’s being worked on and will get better with time.

As I mentioned at the beginning, the rate of progression of geographic atrophy is very variable. And it depends on many things. And we’ll talk about some of those things in a moment.

But in general, you know, there is about a two and a half millimeter square per year growth in geographic atrophy. Now, it’s hard to say to a patient: Hey, you know, your GA is gonna grow 2.5 millimeters a year.

It’s almost an irrelevant number. There’s no way to quantify that number. So in general, I like to talk to patients sort of about what are some of the things that increases their risk of geographic atrophy progression.

So let’s do a poll. What do you think is the most important risk for geographic atrophy progression? Is it the size of the lesion? Is it the location? Is it the fundus autofluorescence pattern at the junction to the GA? Is it the presence of reticular pseudodrusen or subretinal drusenoid deposits?

So let’s see what everybody thinks.

Well, we got a wide variety here. The two leaders were location in relation to the fovea, about a third of you, and about a third of you said the presence of reticular pseudodrusen.

And then lesion size and fundus autofluorescence pattern. So let’s take a look. Now, all of these things matter. So size, configuration, location, patterns.

Presence of reticular pseudodrusen. As well as junctional zone. But… If you look at it, these are what these look like. So we know that reticular pseudodrusen are very high risk for progression of geographic atrophy.

And what the difference between reticular pseudodrusen versus a true drusen is shown on the top left there. A true drusen is sub-RPE, which you can see in the little asterisks there. A true drusen is below the retina. That’s why we call it a subretinal deposit. You can see these on this image but also on OCT very easily.

So OCT is a good way to follow these patients. The location matters. If it’s a non-subfoveal lesion, extrafoveal lesion, increased risk of progression. Size matters. The larger the lesion, the faster it grows. And different types of fundus autofluorescence patterns will grow quicker or slower.

We’ll go over that in a second. So these are the different types of patterns of the fundus autofluorescence that you can see in a junctional zone.

Slide left shows just the geographic atrophy. There’s nothing around it. And that is the slowest growing lesion. On slide right, you can see those white little spots. We call this diffuse and trickling, from the edges of the geographic atrophy.

And that has the largest rate of lesion growth. And in between, the diffuse, patchy, and banded are all things to watch out for. So look at your fundus autofluorescence image, if you see it, and check to see if this diffuse trickling pattern is present.

Because that foretells a very poor prognosis. But if you look at some of these wide field fluorescein fundus autofluorescence images, which you can get from the Optos wide field fundus autofluorescence, peripheral lesions are present in these patients and the peripheral lesions also progress. We don’t follow them all that much. Because it’s kind of irrelevant.

It doesn’t really affect the central vision. But it is something to note. That the geographic atrophy progression is not just in the fovea. It’s in the periphery also. Now, I personally like to use OCT to follow patients. I look both at the near infrared images, as well as the B scan images.

The B scan tells me a little bit more. Especially the location of the geographic atrophy, compared to the fovea. And this was part of what we looked at in the CAM classification, and the CAM classification came out with these two new terms. Which is kind of important to understand, these terms.

The term that you should start with is complete RPE and outer retinal atrophy, or cRORA, which is on the bottom there. So the definition of cRORA is that that white hypertransmission, beyond the level of the Bruch’s membrane, should go more than 250 microns, or about the thickness of the retina, into the choroidal space.

So that’s first. And number two, the width of that disruption, that more than 250 micron disruption, should be more than 250 microns. So if you see that, that is called cRORA. Now, cRORA is technically geographic atrophy. So if you did a fundus autofluorescence in that area, it would be completely dark.

Because there would be absence of the RPE in that area. But prior to developing cRORA, you develop something called iRORA. So iRORA is incomplete RPE and outer retinal atrophy. iRORA basically means you haven’t met yet the criteria for cRORA.

Why is that important? Well, our drugs that we’ll talk about in a moment really treat — prevent the progression of cRORA. But we know that if a patient has iRORA, they’re gonna develop cRORA very quickly. And so… Should we be using them earlier?

Maybe. We don’t really have results from the clinical studies yet to guide us there. As I mentioned before, most of the commercial OCT software allows automated atrophy measurement.

This is for research use only. It’s not used… It’s not FDA approved or EMA approved. But it is something you can use to kind of follow your patients’ atrophy.

This is a good example of why OCT is so beneficial. So here’s a picture of a patient. Fundus autofluorescence shows the hypoautofluorescence. But does this patient have foveal involvement? It’s really hard to say.

Well, an OCT of this patient shows very nicely, number one, the near infrared image shows it’s not. And the OCT B scan, again, shows the cRORA off nasally there.

But it does not involve the fovea, which is the green line. Here’s another example. A more unifocal GA lesion. Does it involve the fovea or not? That’s hard to say. The OCT shows very nicely… Well, it actually does.

You can see the cRORA actually involves the central fovea. So you can see how OCT would be very important to follow patients with geographic atrophy. And I mentioned this before. The reticular pseudodrusen? This is something to look out for in your patients, if you’re looking at the intermediate AMD stage. Because if they have reticular pseudodrusen, they have an increased risk of progression.

Well, I mentioned to you in the beginning about 70% of patients start off with unifocal, unilateral geographic atrophy. How often does this become bilateral? And how long does it take? Well, on average, in the AREDS study, bilateral geographic atrophy occurred within about 7 years.

So you can be pretty assured that this is a bilateral disease in most of your patients. Now, when we always in the past… Especially when we didn’t have a treatment, we really didn’t think of how much and how quickly geographic atrophy causes decrease in vision and central geographic atrophy. In the AREDS study on average, it took about 2.5 years, when a non-foveal GA proceeded to central GA.

In IRIS Database, a US database of multiple practices in the United States, it was a little quicker. About 1.5 years. So this is a problem. On average, you can call this about 2 years. Before central atrophy occurs. Just summarizing this introductory portion: Geographic atrophy starts off earlier, as unifocal and non-central.

The fundus autofluorescence patterns can predict the growth. Larger lesions grow fastest. And thankfully, geographic atrophy grows towards the periphery. But don’t forget: Central involvement is when we lose vision. And that usually occurs within 2 to 2.5 years.

So how does geographic atrophy develop? Well, if I could tell you the answer to that question, I could tell you how to treat it best. The problem is: The pathophysiology is very poorly understood.

As I mentioned, there are many different aspects of risks, both environmental and genetic. We do not have an animal model to test our drugs. So we have to test this in humans. That’s our animal model.

And there are a variety of pathways that have been implicated. So let’s just ask: What is the best way to treat geographic atrophy? Is it using the AREDS vitamins? Is it complement modulation? Neuroprotection? Gene therapy? Or none of the above?

All right. So the answer: 40% are AREDS vitamins. 30% said none of the above, and a few others said some of the things we’ll talk about in a moment.

So first of all: And this is a point that most people don’t realize — the AREDS vitamin supplementation has no effect on preventing geographic atrophy. So AREDS was only shown to reduce the formation of choroidal neovascularization.

So although I do want your patients to consider the AREDS vitamins when they have intermediate AMD, they do not prevent the progression of geographic atrophy.

So right now… 2023 January… We have no treatment for geographic atrophy. So what are the areas that we’re testing right now?

And there are multiple. One, neuroprotection. Two, reducing toxic by-product accumulation. So reducing drusen formation. Visual cycle modulation. Which again sort of works on 2. Because that decreases toxic by-product accumulation.

You could use stem cells. You could use other approaches that we’ll talk about. And finally, suppressing inflammation. Particularly complement modulation. Is being tested. So let’s look at each one of these in turn.

The number one is reducing oxidative stress. We know that patients with macular degeneration have dysfunction of their mitochondria, and this dysfunction causes problems. And one company called Stealth Biotherapeutics has a drug that reverses this mitochondrial damage. It binds to the damaged cardiolipin, restoring its function.

And in a phase II study that was recently announced, the use of Elamipretide, which is a subcutaneous injection, so not intravitreal, those patients had a significant visual gain in low luminance vision.

And so we’re gonna hopefully see a phase III study with this drug in the future. Another drug by Allegro, called Risuteganib, also reduces oxidative stress and improves mitochondrial function and cell survival.

And in a phase II clinical study with this drug, which is an intravitreal injection delivered every three months, a significant proportion of patients had a gain of 8 letters of visual acuity at month 6, compared to the sham.

And this was statistically significant. So a phase III clinical study with this drug is also being organized.

Now, reducing toxic by-product accumulation was something that was being tested by many companies. And the idea here is that we know that drusen, and particular β amyloid in drusen, is a problem. Now, amyloid β is something you may all have heard of, when you talk about Alzheimer’s disease. And there’s been a lot of research attacking amyloid β. In particular oligomer formation.

Because both in Alzheimer’s disease as well as macular degeneration, we see these amyloid β oligomers. In the plaque formation in Alzheimer’s, but in the core of drusen. So it’s thought that this amyloid β acts as a scaffold for drusenoid accumulation.

And this leads to inflammation, and these proinflammatory changes eventually lead to geographic atrophy. As well as choroidal neovascularization. So amyloid β, as a target, is a good one. And there are a couple of companies that are targeting amyloid β. A company called Galimedix has an oral molecule that binds to the monomers, preventing formation of the toxic oligomers.

Again, as a pill, this would be really very interesting for patients with macular degeneration. And it’s about to begin testing. Alzheon has a prodrug, ALZ-801. This is right now in a phase III clinical study in Alzheimer’s disease.

But what ALZ-801 does is it metabolizes to Tramiprosate, which prevents the metabolization and blocks oligomer formation. As I mentioned, it’s in phase III as we speak in Alzheimer’s disease. It had a positive phase II study. And since this is a pill, again, it would be very easy to use this as a treatment for dry macular degeneration.

Now, in the past, we were worried about… When the visual cycle is overactivated, that leads to toxic by-products accumulating, and damage to the photoreceptors in RPE. So if we can slow the visual cycle down, we can reduce these toxic by-products from accumulating.

Two drugs tested this in phase III clinical studies. Both Acucela and Fenretinide were tested in phase III studies. Unfortunately, both of them failed. We know the drugs were working, because patients had dark adaptation problems in the study, as you would expect. If you’re taking a visual cycle modulator that slows your rod function in particular. But there are a couple of companies testing the idea of a visual cycle modulator.

Either with vitamin A or a visual cycle modulating pill. And those are still in the works. Now, interestingly enough, on a daily basis, I have my patients come to me and talk to me about stem cells and how stem cells are gonna cure their macular degeneration.

Now, that may be in the future. But currently, stem cells are very experimental. And largely, the ones that appear to be the most beneficial are those that use some sort of scaffolding to recapitulate the area of RPE or RPE and photoreceptor.

So in the past, we started with just injecting stem cells underneath the retina, and that didn’t really work as well as we would like. Nowadays, you can see these PLGA biodegradable scaffolds or Parylene scaffolds are being tested, and the results of those clinical studies so far have been better.

But I would like to warn you and warn your patients: This type of research is really in its infancy. Other companies are using a different approach. Which is that we know that some of these human retinal progenitor cells can release good trophic factors.

And so if you inject this either into the intravitreal… With an intravitreal injection, or subretinally, the trophic mechanism can save the cells. And this is being tested by many companies, as we speak.

Both in macular degeneration but more so far in retinitis pigmentosa.

The area of greatest research is suppressing inflammation through complement modulation. So it’s important to kind of understand the complement system.

So the complement system starts with activation. There’s three ways to activate it. The classical pathway is normally activated by antibody binding to the bacteria. But C1q, which is the key activator of the classical pathway, is also activated by amyloid β.

And this leads to formation of C3 convertase, and then C5 convertase, and that C5 convertase basically makes C5a and C5b. And C5b basically aggregates to form a thing called a membrane attack complex.

So the MAC forms these pores or holes in the bacteria’s cells, causing extracellular fluid to pour into the bacteria, essentially causing the bacteria to explode.

In addition, C3a and C5a produce an inflammatory factor. That basically leads to macrophage recruitment and other aspects of the inflammatory cascade.

The lectin pathway is another way that the complement system is activated. And this is activated by the binding of mannose binding lectin to the oligosaccharides on bacteria and viruses. So if you don’t have a bacteria that’s recognized by an antibody, the lectin pathway will then lead to cell death.

The most active pathway, however, is called the alternative pathway. And the alternative pathway is designed, such that our body doesn’t know what bacteria and viruses are out there.

So we don’t have antibodies to all the drug… The viruses out there. Say, for instance, COVID. Right? So to protect our body, the body is constantly spontaneously hydrolyzing C3. So C3 becomes C3a and C3b, and the C3b then attaches to both bacterial cells throughout the body — so the C3b, when it’s on a bacteria, then causes C3 convertase and C5 convertase to form.

Again, killing the bacteria. So the alternative pathway is thought to be the most active aspect of the complement cascade. The problem, however, is that in the alternative pathway, the C3b that’s being spontaneously produced is being deposited on the bacteria, but it’s also being deposited on our own host cells.

And we need to have a way to turn off all this host cell activation. And that’s where complement factor H and complement factor I come into effect. So CfH and CfI basically inactivate that C3b that’s being deposited on our own host cells.

Preventing damage to our own cells. So here you can see the three activation pathways. And the thought, then, is that what causes macular degeneration or one of the causes of macular degeneration is lifelong oxidative stress.

The eye is very active from the light. And this leads to deposition of complement. Patients who have a genetic predisposition or who smoke or have a poor diet are at higher risk of this. But this complement deposition at the level of the Bruch’s membrane can lead to both CNV, as well as geographic atrophy.

So this is really the ongoing hypothesis as to what’s happening in macular degeneration. If we look at the genetic association of the complement system, with AMD, many aspects of the complement cascade are involved.

If we look at histopathology specimens in patients with macular degeneration, many of the complement factors have been found in drusen and around geographic atrophy. So it’s pretty obvious that the complement cascade is involved in macular degeneration.

In fact, if you look at the complement pathway, there are abnormalities in the complement pathway in patients with early and intermediate macular degeneration, as well as advanced macular degeneration.

So we really know that this is involved. As I mentioned, the overactivation of complement leads the RPE photoreceptors and other neurons open to damage from complement activation.

And that’s what we think leads to geographic atrophy.

So let’s talk about targeting aspects of the complement cascade to treat it. Well, one company is targeting C1q. And as I mentioned, C1q is the main activator of the classical cascade. But what’s important to know is that the classical cascade is activated by amyloid β.

So some of the parallels between Alzheimer’s disease and macular degeneration are actually uncanny. So blocking C1q with a FAB fragment seems to be a reasonable way to target macular degeneration.

C1q, if you do histopathology, is found around drusen as well as around geographic atrophy. So Annexon has a Fab fragment that’s injected intravitreally, that binds to and inactivates C1q. And this is currently in phase II testing.

Well, we know that the alternative pathway is very, very involved. And it’s spontaneously activated. One of the rate limiting steps is modulated by complement factor B. So if you can block complement factor B, you can turn off the alternative pathway.

In a subcutaneous antisense is being used to block complement factor B. And this is currently in phase II clinical testing in the GOLDEN study. This is a subcutaneous injection, so much easier on patients. And it causes inactivation of complement factor B.

Now, complement factor D is also one of the rate limiting steps in the alternative pathway. And factor D was looked at in a very large phase III study, using Lampalizumab. But that study failed, unfortunately. Other companies are looking at targeting factor D, however, and those are starting clinical studies as we speak.

Now, Properdin is part of C3 convertase and C5 convertase. So blocking it would block both C3 and C5 convertase. This is currently being looked at in other systemic diseases, including PNH. And is likely going to start testing in macular degeneration. Novartis has a similar molecule that blocks complement bb, an important part of C3 and C5 convertase, again, being tested systemically, and will hopefully be brought to macular degeneration in the future.

Now, I mentioned to you before that complement factor H and complement factor I are the key regulators of the alternative pathway. And we know that complement factor I levels are strongly associated with the development of macular degeneration. So those patients who have an abnormality or mutation leading to CFI reduction have a much higher risk of advanced macular degeneration.

So a company is looking at targeting complement factor I, both Novartis and Catalyst. Now, what’s important to understand about these molecules, and why it’s in green, is they’re not trying to block complement factor I.

You want complement factor I. What you’re trying to do is: If you have the mutated complement factor I, you want to give a patient the normal or wild type complement factor I, so you’re giving back what is mutated. And to do that, you need to do that for a very long period of time.

So this Novartis product, GT005, is using gene therapy to deliver a normal complement factor I to the body, long-term. So essentially forever. And this is being tested both with subretinal injection, as well as suprachoroidal injection. In a phase II clinical study.

The early results from the phase I study showed excellent reduction in some of the overactivity — so complement factor I reduces factor Ba and C3b et cetera. And this was shown that the vitreous level of complement factor I increased with the gene therapy, and all the negative aspects decreased.

And so we’ll hopefully see the results of this phase II study in the future. Complement factor H supplementation is also being tested. Both with intravitreal injection, which is how Gemini is doing it, as well as gene therapy, to deliver complement factor H, to normal complement factor H, to the eye.

The area that has gotten the most sort of press, shall we say, is blockade at the level of C3. And you notice that if you block C3, you block all three of the activation pathways.

And the results of the Apellis study were what really spurred all of this development. Because they showed positive phase II and phase III results, by blocking C3. But there are many, many companies that are now in this space, trying to block C3, or the production of C3b. So there’s areas around C3 that are being looked at.

And it really came about because of the DERBY and OAKS study by Apellis, using Pegcetacoplan, a monthly or every other month injection in patients with geographic atrophy. And the primary outcome was preventing the growth of geographic atrophy.

As you can see here, the gray bars are the sham patients. And the blue and orange bar showed the reduction in geographic atrophy growth, and here at month 24. But notice how that slope, that angle, between the sham treated patients and the Pegcetacoplan treated patients is increasing. So we would expect that this would increase over time.

Now, this drug is not yet approved in the EMA or FDA. But it is currently in front of the FDA and EMA. So maybe we’ll see this drug get approved some time this year, if we’re all lucky.

This shows you the difference in the RPE and photoreceptor death between the study eye on slide left and the fellow eye, slide right.

With a dramatic decrease, reduction in the growth, in the study eye, versus the fellow eye.

See how that grows so much greater, slide left, versus slide right? And this just really brings home the point, that treating these patients becomes very, very important to prevent that progression.

NGM621 is also a C3 inhibitor. It’s an antibody. So because it’s an antibody, it’s thought to last longer. In a phase II clinical study called the CATALINA study with an intravitreal injection was performed. But unfortunately, unlike the phase II study with Pegcetacoplan, the phase II study with NGM621 was negative.

And so further development is called into question. With this drug. The other area with very high excitement is around blockade of C5. And that is largely around the results of the Avacincaptad Pegol drug or Zimura. The GATHER1 and 2 studies took patients with geographic atrophy outside the fovea, and either treated them with sham injection or an Avacincaptad injection monthly. And a second study, rerandomized to monthly or every other month injections.

So the results of both GATHER1 on the right and GATHER2 on the left, were statistically seen to be significant and positive to reduce the rate of geographic atrophy progression. Interestingly enough, there was a better safety profile of this drug versus Pegcetacoplan. And this drug, just like Pegcetacoplan, is currently in front of the FDA. So maybe we’ll have two drugs for the treatment of geographic atrophy in the future.

But this drug, because of the efficacy being positive in two studies, with excellent safety, has a higher likelihood of success for approval. We’ll have to see, of course. Because neither of these drugs is currently approved.

One of the post hoc analyses that was done in the GATHER studies was: Could you prevent progression from intermediate macular degeneration, so just drusen, to iRORA or cRORA? Something I talked about at the beginning of this lecture.

And just like we would expect the GA progression to be reduced, the progression to iRORA or cRORA was also reduced with the use of Avacincaptad Pegol. So this is really where we would want to use these drugs, before geographic atrophy actually occurs.

But again, more testing will need to be done. This is just a post hoc analysis.

The final common pathway of geographic atrophy is the formation of the membrane attack complex. And CD59 has been shown to be reduced in patients with macular degeneration. CD59 prevents the formation of MAC.

So Hemera is using gene therapy. This is now a Janssen product. A single intravitreal injection of gene therapy produces this soluble CD59. And this was shown to reduce GA progression. And a phase II study is about to start with that drug.

Well, outside of complement activation, are there other things we can do? Well, HtrA1 has been shown that patients who have overexpressed HtrA1 have an 8-fold increase in macular degeneration.

So the goal of treatment would be to block HtrA1, and this is currently in phase II testing with intravitreal injections. We know that inflammasome activation leads to damage to the RPE. So several companies are looking at the idea of inhibiting inflammasome activation.

And what happens if you develop geographic atrophy in the fovea? Can you do anything for those patients who have already lost vision? And that’s where this idea of optogenetics is coming in.

And optogenetics is interesting. Basically what you use is gene therapy to deliver a light sensitive protein to cells in the eye. Specifically the ganglion cells and the bipolar cells.

So you’re basically producing photoactive molecules on the cell membranes, so that if you’ve already lost your photoreceptors, other cells that are not yet dead, like ganglion cells and bipolar, can then be activated by light.

And this is being tested in retinitis pigmentosa currently. But many of these companies are looking at the idea of using this in central geographic atrophy.

So in conclusion, dry macular degeneration is a uniquely human disease. We don’t have any animal models to test any of the drugs that I’ve mentioned.

When we look at these current treatment strategies, there are several. One is preventing oxidative damage and mitochondrial dysfunction. Two is preservation or replacement of photoreceptors and RPE. Maybe with stem cells.

And finally, the one that seems to be having the most effect so far is suppression of inflammation, of which we have two drugs with positive phase III studies.

So we are very close to a treatment. And hopefully in the future we can talk about how we can treat this devastating disease.

So thank you for listening. And now I’m gonna open the floor to some of the questions that we may have had. So I’m not sure how to open the floor for questions. But let’s open the floor for questions.

>> Thank you, Dr. Kaiser. You can go ahead and open up the Q and A. It should be right next to the green “share”.

DR KAISER: All right. So some of the questions. Let’s see… One of the questions is: Can we prevent macular degeneration once detected? Can it be stopped?

Unfortunately at this point, even the drugs I talked about really are not able to be stopped. We don’t have a cure for macular degeneration. We have ways to slow it down.

But certainly we can’t cure it at this stage. Which is why if a patient has early macular degeneration, it would be very important to try and sort of reduce their risk of progression with lifestyle management, diet management, stopping smoking, for instance.

One of the questions says: The majority of cases of macular degeneration are due to genetics. Would multivitamins really help in management? And the answer is: For the prevention of choroidal neovascularization and late macular degeneration, we do have two studies, AREDS I and AREDS II, that show that vitamin supplementation does help.

So you do want patients to take their vitamins. But specifically, for geographic atrophy, it doesn’t really help all that much.

One of the questions is about the idea that light and light toxicity and reactive oxygen species are involved, and that’s true. And the question is: How does oxygen play a risk for GA? Well, we don’t know exactly what it is.

But we know that patients who have thinner choroids, poorer blood levels, poorer oxygenation, those patients who have higher mitochondrial dysfunction, which we now have ways to image, are at an increased risk of macular degeneration. And as I mentioned, there are some companies working on ways to treat it.

One question is: What is the current line of therapy? Well, unfortunately, as I mentioned, we really don’t… We really don’t have a way to treat this at this point. We’re working on it. But we don’t really have a way to go into the current treatment landscape.

There is nothing currently. So if you walk out of this talk today, you can’t treat it today. We hopefully will have stuff in the future.

Let’s see. One question is: Should we be looking at multispectra imaging in patients with early macular degeneration, because we know that this can image some of the peripheral lesions a little bit better?

Which is absolutely true. The question is: Should we be using multispectral imaging? And the answer is yes. If you are fortunate to have multispectral imaging, it does very nicely. It shows pseudodrusen, it shows small areas of atrophy.

So you can show that to your patients and follow them. Unfortunately, it’s expensive. So most of us don’t have it. And in that case, OCT can show many of these abnormalities that you would see also on multispectral imaging.

OCT imaging can show some of the photoreceptor and ellipsoid abnormalities. But that’s absolutely true. The issue, of course, is: Can you use your current OCTs to show this and these abnormalities? And the answer is not really. It really requires some of the research level OCT algorithms. They’re not currently available in the standard machines.

So, for instance, at the Cleveland Clinic, we have an algorithm using artificial intelligence to analyze the EZ zone and photoreceptors, to follow for thinning of that area, which precedes geographic atrophy. And we can show very nicely that that thinning precedes the geographic atrophy.

So we can predict it. But this is not yet commercially available.

There is a question on slowing the rate of progression — is what we’re seeing with some of these geographic atrophy drugs. How about the use of subthreshold laser? Well, subthreshold laser, as well as photobiomodulation, as well as microcurrent stimulation of the retina, have all been proposed as treatments for dry macular degeneration.

Some of these devices are actually… Have received CE Mark approval, for instance. But as of yet, no randomized clinical studies have been performed using microcurrent or photobiomodulation.

And so once we see if these treatments — so light or microcurrent — works, then that certainly would be a way to treat it. But like all these other drugs that are being tested, they need to be tested in a randomized clinical study.

Arshad asks if there’s a role of saffron in treating macular degeneration. I don’t know the answer to that. I love saffron in my food. But I don’t know yet if there’s a way for saffron to treat macular degeneration. There’s been no clinical study that has shown that. There have been some case reports and case studies that suggest it may be beneficial.

So certainly it can’t hurt a patient. But whether it helps patients, we don’t know the answer to that just yet.

One of the questions is: Some of these emerging therapies, studies, have inclusion criteria of intermediate AMD. How are we doing in terms of treating intermediate AMD? And the problem is this: So the regulatory agencies, EMA, FDA, et cetera, and the countries that follow those two regulatory agencies, for late macular degeneration, we have an outcome. Which is prevention of GA progression.

For intermediate AMD, we don’t have an outcome. The only outcome that the regulatory agencies allow us to use is visual acuity outcomes in intermediate AMD. And the visual acuity outcome that they require is a 15 letter delta between the treated patients and the sham patients.

So a 15 letter delta is a very high bar. In fact, a much higher bar than geographic atrophy — prevention of geographic atrophy progression. So although we do have drugs, both the Stealth product and the Allegro product, treating patients with intermediate AMD, it is a high bar for their phase III studies to get approved.

So we’ll see. Are other systemic disorders risk factors? Of course. Both diabetes and higher lipid levels increase risk of macular degeneration.

In early macular degeneration, can blue blocking or sunglasses help? We think the answer is yes. There hasn’t really been a good study to show that. We do know that blue blocking, as well as sunglasses, reduces the risk of cataracts. And cataract progression.

And we would assume it would also work in preventing dry macular degeneration progression.

But again, no study has conclusively showed that.

Another question is: How often should OCT be done? Follow-up examinations? I like to follow up my patients with dry macular degeneration about once every six months.

And I get an OCT every time I see them, for a couple of reasons. One: I want to follow for progression or formation of geographic atrophy.

Two: I want to make sure that these patients don’t have some sort of low level or occult choroidal neovascularization. So it’s very useful to see if there’s a double layer sign, for instance.

Or something that I would want to see the patient more frequently. They’re about to develop exudative CNV. And finally, for research purposes, we do a lot of research at the Cole Eye Institute, that I like to follow up patients with OCT.

Let’s see. We talked a little bit about multivitamin supplementation. So yes. I would recommend it. And if a patient has geographic atrophy, I wouldn’t stop their AREDS formula. I would continue it.

I don’t think it hurts geographic atrophy. So it’s a really important thing to continue to do. I would never ask my patients to stop their AREDS, once they develop GA, even though it doesn’t prevent progression.

Low vision aides for patients with central scotoma — that’s an excellent question. Patients who have particularly central scotomas, using low vision solutions is a very important part of “treating” your patient. Whether that be magnifiers, a lot of the iPhones, iPads nowadays can read.

If you shine your iPhone at, say, a label in the shopping mall, it will just read what it is. So a patient can go shopping. A lot of my patients have large magnifiers that they carry with them, with lights. But it is important that if you have a patient who has lost vision in both their eyes, to get them hooked up with low vision specialists.

And we have an excellent one here in Cleveland that I do use, and have them evaluated for. Let’s see. The rest are kind of not really… Lycopene — it’s been asked: Is there any role of Lycopene in macular degeneration? And while, again, there’s been some anecdotal evidence of its benefit, it’s yet to be proven in a clinical study.

There’s a question about microperimetry. Absolutely. Microperimetry has been shown to be very nice. It’s showing if a patient’s GA is causing problems, and if you do the microperimetry around the area of geographic atrophy, some of these drugs have been shown to reduce microperimetry deficits.

It’s not currently used in clinical studies, because as an outcome measure, the bar to use microperimetry is actually higher than using visual acuity as an outcome measure. So the FDA requires a 7 decibel change at 5 prespecified points in the retina.

And so that’s a very high bar to meet. So although microperimetry can be used to follow patients, and certainly is a good way to follow patients, it’s not really used in regulatory studies.

So I think we’ve reached the end of our discussion here. I really thank everybody for sticking around.

And for being involved in this Cybersight webinar.

And hopefully it’s given you something exciting to be able to share with your patients, that we’re on the cusp of a new treatment for age-related macular degeneration. So thanks for attending this Cybersight webinar.