David R. Lally, MD

David Lally, MD highlights the safety signals observed with GA therapies and the future of the treatment landscape. 

Risk-Benefit of Treatment for Geographic Atrophy

: What we've seen from both of these complement inhibitors that have been FDA-approved is that they have a treatment effect for patients and to the benefit of slowing progression of disease. Albeit, the treatment effect of the rates of what they can do and lowering the progression are not as high as we'd like to see, it's still a landmark time, as we have for the first time in our history, a tool that we can use that can alter the progression path of geographic atrophy.

These treatments do have small, but important side effects that I counsel with my patients that they need to be aware of. We saw that complement inhibition can be associated with increased risks of developing the wet form of macular degeneration called choroidal neovascularization. This is when new blood vessels can grow in the retina and leak fluid and/or blood into the retina. It can negatively impact the central vision if that occurs. If that occurs, I tell my patients, the good news is that we have good treatments to treat wet macular degeneration. They're good effective treatments that we've been treating patients with wet macular degeneration for over 10 years now. So it is a complication that we can do something about to help patients.

In terms of the other risks we think about there's always a risk of inflammation with any drugs that we inject into the eye. That's something to that I counsel patients on, there's always a risk of infection anytime we inject a needle into the eye. Then, the other thing we saw is that there were rare reports of what we call ischemic optic neuropathy, which can negatively affect vision. These were rare cases. And in the the SYFOVRE trial, there was only one case seen with the every-other-month dosing arm. The other cases were seen in the monthly arm. And in the IZERVAY trials, there was only one case observed in the first trial. We don't really know if these drugs cause that problem yet, because the numbers were still small. These numbers were not seen in the sham group, so we consider it as a possible side effect at this point.

Those are the side effects that I counsel my patients on, they're all low side effects. For the vast majority of patients, the treatment benefit would outweigh those risks. In terms of where I see the landscape going in the future in the treatment of geographic atrophy, the first place we would see it going would be the development of complement inhibitors that have more durable treatment effects that lasts longer for our patients. So our current treatments are either monthly or every-other-month intravitreal injections, with no stopping. That's indefinitely with the patient. That's a high treatment burden for patients to come in so frequently for eye injections.

There are a lot of companies already that are out there in early development, working on medicines that we can deliver to patients eyes that release complement inhibition for a longer period of time. Some of those therapies being developed aren't even injections in the eye. There are some companies out there looking at subcutaneous injections, or other routes of administration to last longer for patients to reduce treatment burden for patients. The other place is where people are looking is just a different mechanism of action. You know, we saw the complement in inhibition has a treatment effect but not to the level we would hope for, there's still a long way to go in treating this disease.

There's many other types of mechanisms of action that are likely involved in this disease that have yet to be discovered. A lot of companies are out there working on treatments, hoping that we can get better slowing of progression of geographic atrophy with the ultimate goal being someday to restore the vision and restore that tissue to get patients seeing better. We've come a long way with these new therapies. That was a big landmark change in the field of treating geographic atrophy, but we still have a long way to go.

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David Lally, MD highlights safety signals observed with GA therapies in clinical trials and the future of the treatment landscape. 

Risk-Benefit of Geographic Atrophy Treatment

David Lally, MD describes individual phenotypic features in geographic atrophy and determining patient response to treatment

Patient Characteristics in Geographic Atrophy

: For my patients with geographic atrophy, traditionally I would see those patients in my office every 6 months. When they would come to my office every 6 months, they would undergo certain visual assessments. I always check their visual acuity, I check their eye pressure, I do a dilated eye exam to look at the eye and look at the geographic atrophy. I also like to get imaging, and standard imaging would be to get a picture of the center of the retina, called an optical coherence tomography (OCT) picture. That OCT picture is almost like an optical biopsy of the retinal tissue, where I can see on a very microscopic level, what the health of the retina is looking like. I like to follow that picture over the years. That gives me understanding of what type of progression rate the patient is showing with their geographic atrophy.

I also many times like to get another imaging picture called a fundus photograph, which is just a photograph of the back of the eye. That's another way that I can follow the change in the size of the atrophy over time. The final picture I like to get often would be called a fundus autofluorescence picture, which is similar to the fundus photography picture, although it uses a different technique to look at the geographic atrophy in a different manner. And that also is a third way that I can assess how the geographic atrophy is expanding over time. With those three different types of imaging modalities, it gives me the best understanding of the patient and counseling the patient in terms of how that atrophy is progressing over time.

Historically speaking, we have not had any treatments where I could offer any treatment but that has changed in the year 2023 with our two new FDA-approved treatments. Depending on how the characteristics of their geographic atrophy appear, and by that I mean, is the geographic atrophy lesion located in the fovea? Is it located outside the fovea? Is it located outside the fovea, but close to the foveal center? Is it one lesion of geographic atrophy or is it many lesions I'm seeing appear in the macula. Depending on that appearance, I may or may not have a discussion with the patient about the option of treatment with our new FDA-approved treatments.

The other thing I want to look at is the progression rate of the atrophy over time. Some patients, their atrophy lesions can expand and progress very slowly over time. In those patients, I may be less hesitant to want to discuss treatment with our FDA-approved therapies. On the other hand, many patients will show me signs of progression over time at a moderate or significant rate, where I'm observing the atrophic lesions expanding over time. In those cases that I see moderate to significant progression rates, I will be likely to counsel patients on the option of starting one of these two therapies in an attempt to slow down that progression rate.

The other thing I look at is the visual acuity of the patient. If the patient has very advanced geographic atrophy with very large subfoveal geographic atrophy lesions in both eyes, and their visual acuity is poor, they can only see the E on the chart, and that perhaps they're an older patient in their 80s or 90s. The idea of starting and initiating these FDA approved therapies to slow progression when they're already close to the end of the progression. They're close to the end of the road. That treatment burden of coming in for frequent injections monthly or every other month, does not, in my opinion, have great benefit for that individual patient.

With that being said, I don’t use visual acuity as a make or break if I will counsel the patients for these treatment options. Certainly I have patients that have 2200 vision with large atrophic lesions that have been progressing over the years, those patients are still noting progressive, continuous vision loss. For these patients. I know they're not at the end of the road yet. I know that over the next few years, their disease is going to continue to progress. And these can be motivated patients who are looking for some treatment that can impact the progression rate of their disease. And in those cases, I will discuss the treatment options with our FDA-approved therapies.

I think the important take home message is there's a wide variety of different phenotypes of this disease that we see. There's different age ranges of patients that we see. There's different motivating factors within patients that we see. Some patients are noting unrelenting vision changes. Other patients do not notice changes in their vision, even though I'm detecting the atrophy lesions grow on my imaging. I think it's really a case-by-case decision in my practice on what I see the value of these therapies for and the counseling is really individualized for my individual patients.

David Lally, MD describes individual phenotypic features in geographic atrophy and determining patient response to treatment.

David Lally, MD describes the association of the complement system with geographic atrophy.

Role of the Complement System in Geographic Atrophy

: 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.

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, discusses biomarkers for the progression of geographic atrophy and the lack of previous treatment options for the disease. 

Biomarkers in Geographic Atrophy

: Historically speaking, we have not had good therapies to treat geographic atrophy. The reason we have not had these good therapies is traditionally in our interventional clinical trials, we use visual acuity as our endpoint, as our measuring stick to determine if a treatment we're using has any effect of helping the patient with disease. We've learned over the years that visual acuity is a poor endpoint for studying geographic atrophy. And that's because this disease is a heterogeneous disease.

If a patient has a non-foveal geographic atrophy lesion, that patient might maintain really good central visual acuity for a prolonged period of time, for many years, until that atrophic lesion expands into the fovea. Only when that lesion expands into the center of the retina will we be able to detect a decline in visual acuity. That's different than patients who present with fovea. geographic atrophy lesions at baseline, where their vision is going to be negatively impacted at the baseline. And we would anticipate their vision to decline as that atrophy lesion progresses over time.

So, visual acuity really has not been a good endpoint. That's one of the reasons why we've not had good therapies for this disease. And we've really struggled with finding other endpoints that we can use in our clinical trials, that can be good biomarkers for studying whether our interventions are meaningful to help patients. Fortunately, we have discovered one, and it's an endpoint that's on an imaging test called a fundus autofluorescence image, which is basically like a photograph of the macula taken in a specific manner. We've been able to discern that the changes in the size of the atrophic lesion on fundus autofluorescence, over time, can be a good biomarker for progression of geographic atrophy. That is currently what has been used in recent clinical trials and is being used in ongoing clinical trials.

Besides fundus autofluorescence, we're still looking for other biomarkers that we can use to to find treatments. So currently, the mainstay of treatments is to recommend things such as good nutritional diet, we recommend patients maintain a healthy green leafy vegetable diet, eating like the Mediterraneans do. We also recommend that patients wear UV protected sunglasses while outdoors. We think exercising a few days a week, getting your heart rate going a few days a week, causes good metabolic changes in the retina to slow progression. And we recommend not smoking. So, doing things that are good for your cardiovascular health, we also think are good at lowering the progression rates of geographic atrophy.

David R. Lally, MD

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