Advances in treatment for geographic atrophy

This podcast provides a review of some of the key highlights from the Controversies in Modern Eye Care meeting held in April 2023. The program is designed for those who did not attend the live meeting and to help reinforce learnings for those who did.

Editor's note: This transcript has been lightly edited for clarity.

David S. Boyer, MD:

At the present time, we really have no idea of what causes geographic atrophy, but a lot of attentions being played to the alternative pathway in the complement cascade, as everybody knows, there's three complement pathways. There's the classical, the lectin, and the alternative pathways. There is evidence drusen and in other histopath pathologies that there are complement factors that are involved in drusen, also in the pigment epithelium. There are certain complement changes that will potentially cause these changes to progress. So a lot of attention is being played in the alternative pathway. There is one drug, Annexon, that's being used in the classical pathway. It has some rationale because it's down-regulating C3, but from a different angle. C3 unfortunately, or fortunately, I guess, is the commonality of all three of the pathways, the alternative, classical, lectin pathway. But there is some evidence that C1q, which is found in the classical pathway, will have a role. It does play a role in synapses. It's also found on drusen.

Most of the work is being done in trying to reduce the alternative pathway from even starting. So down-regulation of the alternative pathway is the goal from almost all these drugs. If you start the alternative pathway and it goes through from C3 to C5, all the way to C9, you get what they call apoptosis. So the little cells at the edge of your atrophy begin to have holes, pores put into them, and the cells die. So by treating and trying to reduce the progression, we're hopefully going to reduce the apoptosis that occurs as the final event. So there are many different factors that are being looked at. We have factor I, factor B, factor D, all which down-regulate the complement system. Factor D happens to be a oral medication very similar to lampalizumab, which failed. We have factor I, which is a gene therapy that also down-regulates the system.

Factor B down-regulates the system. Well, there's also the ability to put in complement factor H that may be not present and some patients, and if they can do that, may slow it down. There's a new company that just started. There are some good factors that stop neovascularization from occurring on a genetic basis and they're being placed into the eye and hopefully can reduce progression. But the two major areas are inhibition of factor C3 and C5. C3 is a drug known by Apellis. This drug has been approved by the FDA and showed a fairly significant improvement in the extrafoveal geographic lesions. The extrafoveal lesions basically grow faster and they grow faster, and by reducing them, you can hopefully stop the lesions from growing into the center of the fovea and losing vision.

In fact, in their study, they showed about 27% reduction in these extrafoveal lesion growths, and they recently, just a few weeks ago at ARVO presented that if patients are 250 microns or greater from the center of the fovea, that those patients at two years had five letter better vision than they did in the group that was in the sham group that wasn't treated.

They also have shown that the lesions by visual field tend to not grow as much and you save off more retina. Lesions that are sub-foveal tend to grow at a slower rate in general, and it's only about a 16-18% reduction in the growth rate in that. There's no free lunch in medicine. There's always safety, which is the biggest concern that we have. We've had very excellent drugs recently for treating AMD, but because of the side effect profile and the safety, have never really been utilized to any great degree. The safety is good, but there was about 8% of patients that did go on to developing wet macular degeneration. Inflammation was about 1.5%. There's a small incidence of infection, but that goes along with almost every drug you put into the eye. The C5 is the next drug that will probably be approved.

It is basically, I think in July or August is their PDUFA date. So we'll know in July or August if the approval comes forward. But they should be approved. They have had two phase three trials that both showed statistically significant improvement, whereas in the Apellis drug, it took the C3 inhibitor, it did take 18 months before they started to show an improvement in one of the trials. And at 24 months, both trials were clinically and statistically significant. C5 is downstream from C3 and again, blocking it will decrease the ability for C5b to go on to activating the MAC complex at C9. Another drug that's being tested right now is CD59. It's a drug that actually, CD59 is a natural occurring protein that is in the eye. It goes up when you have AMD and if you can down-regulate that... I'm sorry, it goes down when you have goes down when you have wet AMD, and if you raise that, it will be a natural inhibitor of the progression.

It's a gene therapy. So one and done. Also has been shown to reduce progression of geographic atrophy, again, by the fact that it stops the progression to the MAC complex, it doesn't allow it to form, but we have a lot of unanswered questions. What starts the complement pathway? Is it amyloid? Because amyloid is found in drusen? Is that what stimulates and causes the pathway to begin? Do we have to treat forever? Can we treat just acutely and stop the process? How long do we have to do it? Is it forever? Is this something that we have to do forever? Or once you get the patient righted and you're not having any further inflammation in that pathway, can you back off? And would combination therapy be a more benefit? You've got a C3 inhibitor and a C5 inhibitor both showing about 27% decrease in the extrafoveal lesions.

If you put them together, would that equal an improvement? If you added C3 to CD59, would that cause a bigger improvement? And those are things that'll have to be worked out in the future. Certainly, gene therapy or longer-acting delivery systems are going to be the answer to this. It's not very sustainable to give monthly or even every other month injections to these patients. And the other thing that I'm really amazed about is the number of patients who have dry AMD. When you look at autofluorescence or look at their OCTs or look at their photographs, have geographic atrophy present. It's a lot larger population than I originally thought.

Tina Mac Donald, OD, CDCES, FAAO:

So first, you can have direct damage, which is through the membrane attack complex, which directly targets the RPE cells, and you can also have the indirect damage, which is to the photoreceptor cells where you get that abnormal protein deposition, which directly leads to the mortality of photoreceptor cells.

Host:

Evidence supporting the contribution of the complement system to progression of AMD and GA has accelerated the development of therapeutics targeting complement protein C3 and C5. Drugs being investigated include avacincaptad pegol, which inhibits C5 and C5 cleavage, pegcetacoplan, which prevents C3 activation, ANX007, which inhibits C1q, and GEM 103, which controls the complement cascade. Let's listen to Dr. Boyer review these agents.

Boyer:

At the present time there are a number of companies that are investigating the complement pathway as a means of slowing down the progression of geographic atrophy. The thought being that the geographic atrophy occurs and progresses due to dysregulation of the complement system. We don't know what starts it. We don't know if it's started by amyloid, oxidative stress can start this, but there are a variety of different causes that activate the complement pathway. Why the complement pathway? Because a lot of complement factors that are being investigated are found within drusen, and drusen are a hallmark of dry macular degeneration. We also can see that complement factors that are involved in genetics also play a major role.

So if we go to the GATHER 1, 2 trial, which is a C5 inhibitor, basically at this time it's PDUFA date or the day that the FDA has to announce whether they'll allow us to use it or not or approve it is in late July, early August, and it probably will be approved because they've had two 12 month phase three trials that both showed an improvement. In this trial the patients had have to have extra fovea lesions, meaning that the area of geographic atrophy was not centered and was not under the center of the fovea. It could be one micron away, but that was considered non-central involvement. And in that case, in the first GATHER 1 trial, there were about a 27% reduction in progression. In the GATHER 2 trial, it was much more modest, about 16 to 18% reduction.

They were both statistically significant. And when you looked at the GATHER 1 trial data over a long period of time, 18 months, that held, and we don't have the long-term GATHER 2 data. In the second year of the GATHER 2 trial, 50% of the patients went to every other month, and some continued on a monthly basis. Now, there are other differences between the trials, but the safety of the C5 inhibitor was excellent. They had no signs of uveitis. They had a very small incidence of conversion to wet macular degeneration, about 6%.

They seem to have excellent response. They've showed a reduction in the three line loss of vision by patients being treated over the period of time. So we don't have that drug available yet, but at least for non subfoveal lesions, extrafoveal lesions, this appears to be a good alternative. The drug that has been approved recently is a C3 inhibitor by a company called Apellis. It's called SYFOVRE. And this drug acts within the complement system and is central to all the complement pathways. There are three complement pathways. There's the classical, the lectin, and the alternative, and they all meet at the C3 and then go on to C5. And the C3 blockage eliminates C3b from activating the alternative pathway and allowing it to not go to the MAC complex. They've done two trials, DERBY and OAKS. The OAKS trial was positive at 12 months showing an excellent reduction in vision.

The DERBY trial did not meet its primary specified endpoint, but at 18 months, both of them did, then at 24 months the results were excellent. For the extrafoveal lesions, which were about one third of all the lesions in their trial, they showed about a 27% reduction, very similar to the C5 inhibitor I just discussed. They also, however, had a very large percentage of patients who had the lesion under the foveal area, and those the results again, were positive compared to the sham and as well in growth. However, the growth rate was much less, in the range of about 16 17%. The growth rate was significantly decreased. In their trial again, the safety was good. There was slightly a higher incidence of inflammation, though the inflammation was mild and was treated with topical steroids. Also in addition to that, there was about an 8% risk of developing the wet MAC degeneration, having exudative form of Mac degeneration, that form.

There also had eight patients in the trial that went on to developing ischemic optic neuropathy, which seems to be a puzzle that nobody has been able to figure out. There was one patient, I think, in the GATHER trial, and there was one patient omalizumab, which was a very large trial. So this showed a definite change that's been investigated, and two neuro ophthalmologists that are world renowned could not find a correlation, and they found that all the patients had a disc at risk. They all had some other vascular episodes at a similar period of time, whether it be hypertensive crisis or some other change, and felt that this was based on that. But that is still something that needs to be discussed. There are several other complement factors that are being evaluated all again, to slow down the process of the alternative pathway. There's factor B, factor D, factor I.

There's patients who are receiving a CFH. There are also people that are now treating and trying to improve the genetics by giving proteins, or I'm sorry, giving the genes that are positive that actually can overcome the negative genes. There's one in the classical pathway called C1q that's being blocked that they feel is important. It plays a role in synapses and it's also found on drusen, so there is some reason to do it. By blocking it it does reduce C3 further down. Now, as you go down the complement pathway, you eventually end up at C9. And C9 is the MAC complex. It's composed of 5, 6, 7, 8, and 9, and it causes a pore formation, which causes cell to rupture and die. CD59 is a natural occurring protein that reduces the progression. It's found to be decreased in patients with macular degeneration.

And by gene therapy they can add CD59 as a protective mechanism. This protective mechanism may reduce the progression of the geographic atrophy and also reduce the progression of the wet MAC degeneration. So this also is being studied. There are a number of other drugs not in the complement pathway that are being studied to hopefully reduce the onset of the problem. One of them has to do with macrophages and trying to reduce the macrophages from becoming active and activating the complement pathway. Inflammasome are another substance that will cause the activation of the complement pathway and is being treated way upstream to hopefully stop the complement pathway from being activated. There are a number of other factors that are looked at. We know that our mitochondria go down as we get older, but in patients with macular degeneration, it goes down even more in the eye. So several companies are looking at treatment to try to improve the mitochondrial function over a period of time.

And as it improves the mitochondrial function, hopefully it will improve the low luminance vision, the poor vision that we get at night or just age related macular degeneration causes patients to have more difficulty with night vision. Reading needs more light. Driving at night is not very easy to do for patients with macular degeneration. So there are a number of other factors that are being evaluated to try to reduce the onset of the alternative pathway, and also to try to slow it down and hopefully in the near future, some combination of these will give us better results than we have today.

Host:

Visual loss associated with advanced GA affects many aspects of patients' lives. Daily functions like household chores become more challenging. Patients may engage in fewer social interactions and may be isolated from family and friends. Let's listen to Doctors Boyer and Macdonald discuss how GA affects patients' quality of life.

Boyer:

Geographic atrophy is an area of loss of the pigment as well as the photoreceptors that lie above them. So everywhere that you have an area of geographic atrophy, you actually have an area that's a blind spot or a scotoma. And obviously as a scotoma comes into the foveal area, patients lose the ability to read, drive, see people's faces clearly. Prior to that though, in both dry macular degeneration as well as wet macular degeneration, patients begin to have more difficulty with night vision. They have a lot more difficulty. They may come in to see you and they're 20/20, and the biggest complaint is, they can't read anymore. Doctor will say, well, you're 20/20. I gave you some reading spectacles, you should be able to read. The biggest problem is the loss of the ability to see. They need a lot more light and they have a hard time driving at night.

They don't feel comfortable driving at night. And even though their vision may be 20/20, their dark adaptation really suffers very early in the course of this condition and continues on. So it would be wonderful to have a drug that would improve that because that's the major complaint that I hear when I see the patients in the clinic. These patients come in and they've gotten the best spectacle correction possible, and sometimes they are 20/20, but still have bitter complaints about reading and everything.

I remember one patient specifically when I told them to buy a light that goes over their shoulder or to get a Kindle, and the patient with the light came back and said, I can read. I can read. It was like a miracle, just having more light and the Kindle has been a big boon. I think patients who want to read and try to read, the Kindle with back lighting is much better than a lot of the other machines that are out there to allow them to read. So I think that it really makes it very difficult for patients to drive and to see people's faces clearly. And again, depending on where the scotoma is, it can be devastating if it's in the center.

Mac Donald:

It affects it drastically. First, you can have direct decrease of vision. So the visual impairment can affect everything that would require detailed vision. So reading, self-care, detailed vision. And it can also affect contrast sensitivity, which is being able to see shades of gray. So looking at something that wasn't high contrast, very black on white, for instance, looking at facial features of somebody or expressions or navigating in dimmer illumination. So this can lead to a decrease in self-care and activities of daily living, which then can make somebody feel like they are more dependent on others, and that can directly lead to decreased social interaction for people. And decreased social interaction is obviously going to lead to an impact on mental health for these individuals. So it affects them very severely.

Host:

Low vision aids and vision rehabilitation services may be especially helpful for patients with GA. Among individuals with low vision, an estimated 90% have useful residual vision that could be optimized from rehabilitation services. Many patients are unaware that these low vision services are available. Doctors Boyer and Mac Donald outline these services.

Boyer:

I think one of the things that we as physicians and eyecare professionals in general, really don't pay enough attention to is the wonderful advances that have been made in low vision. It's very frustrating for me as a doctor for many, many, many years to not have a treatment available for these patients, many of which are very active and except for their dry macular degeneration, geographic atrophy, really want to do things that are in good health. They want to travel, they want to do whatever they can. Some of them are professors and they like to read and they want to continue reading. So I refer a fairly large number of patients to low vision specialists because there are a lot of devices out there, and there are more to come. There are a lot of devices, unfortunately are very expensive, but there'll be glasses that will magnify and will be able to help them read, be able to read to them if they can't read.

There are certain devices that can actually read to them. You can take your iPhone and blow it up also. Just if you were shopping and you couldn't read a label, didn't know how much something costs, you can take a picture on your iPhone and just blow it up and be able to see what the price is so you don't go expecting a $15 item and it's $150 item. So I think that that low vision specialists really help the patients a lot. They teach them little tricks. In the home what they can do, they teach them about navigation. You won't see very many of the patients come in with a white cane, even though they may be legally blind from macular degeneration. It just doesn't happen in my experience. So they have to be very careful when they're outside. My mother, as I indicated earlier in the conversation, had severe macular degeneration, and I took her to a wedding.

My wife was out of town. My sisters were going somewhere else, and I realized that just going down an escalator was difficult for her because she couldn't see where it started and where it ended. Going to the restroom, everybody's got fancy restrooms, little things that sometimes I have to look three times to make sure I'm going into the correct one because the little models that they have on the door are sometimes questionable when I look at them for a while. So I think that there's so many things that low vision can help, just extra lighting. When you go to read a menu, they'll be embarrassed to pull it out. But I send a lot of patients to get low vision, and I think the low vision devices in the very near future will improve greatly.

Mac Donald:

So when somebody has a vision loss, supplementing that by going to a low vision specialist, looking at what your vision is and how much magnification you need or filters or lighting to help somebody improve their quality of life and daily living tasks is important. A low vision doctor will look at various assistive technology devices or regular optical devices to assist somebody, and they may even do specific training for the patient and have adaptive strategies for them, as well as being able to coordinate with all the other eyecare professionals and other interdisciplinary professionals to help the patient navigate this condition.