Macular Degeneration Research

New Year - What’s New in AMD

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Featuring: Joshua Dunaief MD, PhD

University of Pennsylvania

BrightFocus Foundation held this Access Live Event to speak with participants about living with age-related macular degeneration. The event featured Dr. Joshua Dunaief from the University of Pennsylvania Medical Center to provide tips on how to keep eyes healthy in the new year. Specific topics of discussion included stem cell research, new treatments, and dietary/vitamins that may be helpful to aid in this disease.

  • January 26, 2022
    1:00 p.m. EST

    Please note: This Chat may have been edited for clarity and brevity.

    MICHAEL BUCKLEY: Hello, I’m Michael Buckley with the BrightFocus Foundation. Welcome to today’s BrightFocus Chat, “What’s New in AMD.” If today is your first time joining us, welcome. I’ll give you a brief overview of who we are and what we’ll do today. The BrightFocus Foundation is a nonprofit based in Maryland. We fund some of the top researchers in the world. These are scientists that are trying to find cures and better treatments for macular degeneration, glaucoma, and Alzheimer’s. And what we try to do with the Chat and with the materials on our website is to share the latest updates from science and in best practices in medicine with families that are impacted by these diseases. So, in addition to today’s Chat, you can learn more at BrightFocus.org. What we do on the Chat is we have an opportunity to talk to some of the top researchers and other experts in the field of macular degeneration.

    Let me tell you about today’s guest. It’s Dr. Joshua Dunaief from the University of Pennsylvania Medical Center in Philadelphia. If the name sounds familiar, he’s been a frequent guest at the BrightFocus Chats and has written some really helpful articles for the website, BrightFocus.org; and he is one of the leading experts on macular degeneration, particularly the development of possible treatments and things that could lead to cures. So, Dr. Dunaief is a great person to kick off the new year with a very simple question, and that’s, “What’s new in AMD?” So, Dr. Dunaief, welcome.

    DR. JOSHUA DUNAIEF: Thank you very much, Michael. It’s good to be back with you, and I’m happy to get some information out to patients.

    MICHAEL BUCKLEY: January is the time where a lot of people take stock of where things are and how far we’ve come and what’s left to go. So, kind of in that vein—almost a State of the Union—how would you compare where we are with AMD—diagnosis and treatment, and new research? How do you think we are now in January 2022 compared to how things were, maybe, 5, 10, 15 years ago?

    DR. JOSHUA DUNAIEF: Sure. We’ve come a long, long way. So, back when I started seeing patients with macular degeneration in the year 2000, we really didn’t have much to offer other than some laser treatments that didn’t work that well. And then in about 2005, we got Lucentis® and Avastin®, and these are drugs that we can inject into the eye to slow the progression of wet macular degeneration and sometimes even reverse it and get patients better vision. And then, in … about 5 years later, we got Eylea®, which can be given somewhat less frequently than Lucentis and Avastin in many patients. A lot of patients complain about the frequency of injections in the eye, understandably, and one goal for all these years has been to decrease the

    frequency of injections but still get the same benefit. And there are some interesting developments in that that we can get to a little bit later when we talk about some newer treatments, but I think that has been the major advancement over the past 15 … 20 years.

    There are also patients who suffer from the advanced form of dry macular degeneration, which is called geographic atrophy, and there are some treatments that look … are looking promising for that form of macular degeneration, too. We’re not quite there yet, but I think we may have something coming along even later this year that’s being reviewed by the FDA. In terms of diagnosis, the imaging technologies for macular degeneration have improved dramatically, and we now have this imaging device called OCT—optical coherence tomography. Patients who go in for their visits every month or every few months I’m sure are familiar with that. It’s a way that we can scan the retina and get a cross-section view at very high resolution, and that can show us what’s going on in the retina. This OCT lets doctors and patients look carefully at what’s going on in the retina and seeing if there’s any sign of wet macular degeneration, any fluid accumulating in the retina, and also if there’s any atrophy or expansion of geographic atrophy in the advanced dry form of the disease. So, we really have a lot more in the way of therapies than we did about 15, 20 years ago and also a lot more in the way of imaging for diagnosis.

    MICHAEL BUCKLEY: You really paint a really encouraging situation, a lot of progress, and some good hope for the future. Before we turn to some of the specific things coming down that road for those areas you mentioned, I just want to start off with a really nice question from one of our listeners that I think will help get everybody oriented, and this listener writes, “What causes AMD?”

    DR. JOSHUA DUNAIEF: Yeah, a really good question—very complicated. We’ve been working on this for decades, including in my laboratory, and what we know causes AMD is, well, first of all, age—it’s age-related macular degeneration. It’s very unusual to see this in someone younger than 55 but quite common in people as they age beyond 55. Among people 80 and older, about 25 percent of the population has AMD. So, it’s a gradual breakdown of the proteins and lipids in the retina. We think that involves oxidative stress, which is when free radicals damage molecules in the retina over time, and these are not replaced, and they aggregate—they form clumps and debris—and some of this debris is actually visible to the ophthalmologist on an eye exam and in an OCT—we call this drusen. Drusen is a German word that means pebble, and it’s as if patients had little pebbles of debris accumulating underneath the retina, and the number of drusen and the size of drusen can give us an idea of the risk for vision loss in the future. Smoking increases oxidative stress and free radicals, so for anybody who’s still smoking, it’s very helpful to try your hardest to stop to decrease the risk of macular degeneration. Oxidative stress also is influenced by diet, so people who eat a diet that’s very rich in plants—like green leafys, fruits of all different colors—can decrease their oxidative stress. Inflammation and the abnormal activity of the immune system also plays a role in the disease.

    We see evidence of immune cells going into the retina and thinking that the retina is like an invader in attacking it. So, strategies to reduce inflammation are also going to be important in preventing vision loss for macular degeneration. Drugs are being developed to inhibit inflammation, and again, we can get into that a little bit later when we talk about new treatments. But again, this diet that’s rich in plant-based whole foods and, actually, fatty fish twice a week, like salmon, can decrease inflammation. In fact, in a study that I recently did with my brother,

    who’s an internist, we found that patients who ate a plant-rich diet could decrease their levels of C-reactive protein, or CRP, which is a blood test measure of inflammation, and this could happen quite rapidly. And I think that’s going to reduce the risk … I think that’s going to reduce the risk of macular degeneration because high levels of CRP are associated with increased risk of macular degeneration. Another thing associated with risk for macular degeneration is genetics. So, my patients have often asked me, “If I have macular degeneration, are my children necessarily going to get it?” The answer is, “No,” but they are at increased risk. So, it’s a combination of genetics and environment that causes macular degeneration. You know, we’re … there’s nothing we can do about our genetics, but we can modify our environment and our lifestyle, and that can still reduce the risk if we do certain things that I started talking about to improve our healthy lifestyle. The genes that are associated with macular degeneration, again, are related to inflammation. So, that supports the idea that abnormal activation of the immune system is promoting the development of macular degeneration and the progression and calming down the immune system is going to help protect vision, Michael.

    MICHAEL BUCKLEY: Well, that’s great. And I think that the complexity of the disease, as you outlined, makes the recent and upcoming progress, I think, even more impressive. So, Dr. Dunaief, I want to start with the dry AMD—the geographic atrophy. Am I correct that there is currently no effective treatment for geographic atrophy? Is that true, and are there upcoming reasons for hope in that area?

    DR. JOSHUA DUNAIEF: Yeah, that is true. There’s no FDA-approved treatment for geographic atrophy. What we can do currently is monitor the progression and let patients know how it’s coming along and also give low vision aids. So, there are optometrists who specialize in patients with macular degeneration. They’re called low vision optometrists, and they can provide special lights and reading glasses and magnifiers that help patients with geographic atrophy use the vision that they still have.

    Now, there are some drugs that are in the pipeline that could potentially be approved as early as this year. So, there’s one from a company called Apellis called APL-2, and there’s another one called Zimura®. These drugs were shown in Phase 2 and Phase 3 advanced clinical trials to reduce the rate of expansion of geographic atrophy. So, what happens in geographic atrophy is there’s a little patch of atrophy in the center of the retina and the macula, and that will expand over time if it’s untreated. So, the patient will have a blind spot or several blind spots that will enlarge over time, and this drug, which inhibits a component of the immune system called complement, will slow the rate of progression by somewhere around 20 percent. Now, that’s not … it doesn’t sound like a huge reduction, and it’s not, but it’s a start. It’s better than the … just leaving it alone for many patients. It does require an injection in the eye of this drug every month or two, so patients and their doctors—if it is approved—are going to have to have a conversation about whether they want to have this injection to somewhat slow the rate of progression. So, the Apellis drug has been through Phase 3, and the FDA is looking at it. It may or may not be approved because in one trial, it did slow the progressing by about 20 percent; in the other trial, it was only 12 percent, and the FDA may think that’s not enough to approve it. So, we’ll see what the FDA does, I think, in a few months. The other drug that inhibits complement, called Zimura, is a little bit further behind in its clinical trials. We don’t have Phase 3 definitive clinical trial results yet, but I think we will have them by the middle of this year. So, we’ll see if

    maybe that one slows geographic atrophy progression by more than the Apellis drug did, and hopefully. that one can become FDA-approved.

    But I think even more important than the fact that these drugs are being tested and seem to be coming along is that this is going to open the door to future treatments that can be tried and improved upon just as the wet macular degeneration drugs have been over the years. And I think that in the coming 5 to 10 years we’re going to see even better and more effective drugs coming along for geographic atrophy.

    MICHAEL BUCKLEY: Are you ready to pivot to wet AMD, or is there more you want to add on the dry and geographic atrophy?

    DR. JOSHUA DUNAIEF: Yeah, so with wet AMD, there’s an exciting new drug called faricimab that was recently … finished its advanced Phase 3 clinical trials, and the results look very good. The goal of this drug is to decrease the frequency of injections for patients with wet macular degeneration. There are many patients who need an injection every month or every 2 months, but with faricimab, half of the patients in the clinical trial were able to do just as well with injections every 4 months, compared to Eylea every 2 months. So, I think for many people this is going to lead to quite an improvement in their quality of life, having less frequent injections. But the faricimab targets the same protein as Eylea and Lucentis and Avastin called VEGF, which is kind of a fertilizer for blood vessels. But in addition, faricimab targets another protein that works with VEGF called Ang-2, or angiopoietin-2. So, this double targeting is probably what makes this drug even more effective and able to be given less frequently.

    MICHAEL BUCKLEY: That’s great. In the 6- or 7-year history of the BrightFocus Chats, the number one, most asked question is, “When will there be an alternative to the injections?” So, this is certainly providing some hope in that direction. I know you as someone who’s done a top … some of the top research in this field, could you sort of give the audience just a brief overview of the journey, like when someone gets a grant from BrightFocus or the National Institutes of Health, what’s the journey from that moment to something that could be used in a doctor’s office? I was wondering if you could just give a brief overview of how it … how that happens.

    DR. JOSHUA DUNAIEF: Yeah, good question, Michael. So, the first thing that has to happen is some increased understanding of the mechanism of the disease so we know what to target. And that understanding can come from genetic studies; studies of eyes of patients that we get through imaging, like OCT, which I mentioned before; and then some patients will donate their eyes after they’ve passed away, and those can be studied to determine what happened—what went wrong in the retina. And there are a lot of methods involving analyzing the DNA and proteins and looking at the structure of the retina at a microscopic level that can give us clues about what caused the disease.

    There are also these new techniques that are referred to as ­omics, and with -omics we can look at thousands of proteins or fats or changes in genes all at once and ask in an unbiased way, “What has changed in this disease?” So, -omics can also identify some potential targets. Then once we have targets or pathways that have been identified, we can test drugs that can change those pathways, and we’ll often test those first in retinal cells grown in little plastic dishes, and then we’ll test them in mice and then eventually move to clinical trials Phase 1, 2, and 3.

    Phase 1 is mainly for testing safety; Phase 2 is safety, hoping for a little bit of proof of efficacy; and then Phase 3 is really the definitive trial that’s going to test whether it’s effective and also still safe. So, it’s quite a journey. It takes a village, as they say—a lot of researchers working together internationally, attending international meetings, these days, largely virtual meetings—and funding from the National Institutes of Health and foundations like BrightFocus is critical for making this happen. This is extensive and long-term work. And then once drugs are tested—and usually in mice—pharmaceutical companies will start to invest in them and help to develop them and test them through clinical trials. So, there’s a partnership among researchers, patients, foundations, and ultimately, pharmaceutical companies to get these drugs to patients.

    MICHAEL BUCKLEY: That’s quite an extensive journey, and I can understand why things take either some time or don’t always pan out, but I think it just gives even more reason for hope over the things that you’ve outlined for us today. And before we turn to a couple of listener questions, I was wondering over the last couple of years what you and your colleagues at the Penn Medical Center … if you have observations about how folks with low vision are coping during the pandemic. Like you and your colleagues, what are you observing, or is there advice that you think would be helpful? Particularly, we’re in the second or third pandemic winter now, and it’s a tough time, I think, particularly for folks with low vision. And so, I was wondering what do you … what are the doctors at Penn Medicine … what are they seeing in their patients?

    DR. JOSHUA DUNAIEF: Yeah, I mean, obviously it’s made … COVID has made things harder to everybody in many ways, and Penn and other hospitals have made great efforts to keep things safe for patients, requiring masking for doctors and patients and shielding and social distancing, and I’ve been very happy to see how patient care has been delivered safely. Patients, of course, are more isolated now, needing to avoid getting COVID, especially in the older group that’s more susceptible to COVID’s problems. So, it’s always important to stay connected as much as possible using Zoom, using outdoor meetings at a safe distance. AMD support groups exist and are centered at a number of hospitals and universities, and these can have some online meetings that can enable patients with macular degeneration to talk about the issues that affect them in common.

    It’s also important to keep exercising and eating well. As I mentioned before, these lifestyle … a healthy lifestyle can help to help protect vision and reduce the risk of vision loss in the future. And another issue that can affect the mental health of AMD patients is visual hallucinations. So, this is something that can affect people who’ve lost a fair amount of vision. They may see patterns, like wallpaper or even animals or people. This is pretty common, and it’s even got a name—it’s called Charles Bonnet syndrome—and it doesn’t mean that the patients are going crazy. They think that they are because they associate visual hallucinations with a psychiatric problem, but it’s not. It’s kind of like a phantom limb situation where, if somebody unfortunately loses an arm or a leg, they’ll still have the sensation that the limb is there; the brain still thinks it’s there. So, what happens when somebody loses a lot of central vision is the brain is … it’s kind of bored in a way, and it’ll make up images for the … to replace the lack of input that it’s not getting any more from the damaged retina. So, it has nothing to do with mental health, it’s just, you know, the brain substituting these images for the lack of input from the eye. So, I think once patients understand that, they feel a lot more comfortable that they’re not going crazy, and this is just a normal … phenomenon that occurs, and sometimes the patterns can even … they get used to them, you know, these visual hallucinations that they see.

    MICHAEL BUCKLEY: That’s probably new information to a lot of people. We have several questions from our audience today concerning vitamins. To sort of lump the questions together, they all center around, “What’s the role for vitamins?” And they hear that there’s different brand names when they go in the store, so could you kind of give our audience some guidance about the best role for vitamins in AMD?

    DR. JOSHUA DUNAIEF: Yeah, absolutely. So, the NIH sponsored some large clinical trials looking at whether antioxidant vitamins could reduce the risk of macular degeneration progression, and these studies were called the Age-Related Eye Disease Studies, or AREDS. There were two of them: AREDS 1 and AREDS 2. AREDS 2 modified the formula a little bit, and remarkably, it showed that in patients with early macular degeneration—patients with drusen, those little white spots that the ophthalmologist can see in the retina—taking AREDS 2 vitamins reduces the risk of progression to wet macular degeneration by about 25 percent. So, taking these vitamins is recommended for patients who have a certain number of drusen. These can be purchased in the drug store without a prescription. And you asked what brand. Look for a bottle that says AREDS 2 formula, and the brand that I recommend—I have no financial interest in this—is called PreserVision®, made by Bausch + Lomb, because that one has been actually tested by NIH to confirm that it contains what it’s supposed to contain. You have to be careful about vitamins because they’re not regulated like drugs, and sometimes they don’t actually have the ingredients that are listed on the label. So, these I have confidence in—the Bausch + Lomb PreserVision AREDS 2 formula.

    MICHAEL BUCKLEY: I know that the vitamin world can be a little overwhelming at times, so I appreciate that. We have a few questions that ask: Of the different treatments and the ones that are very promising that you mentioned, did any of them have the possibility to restore vision that’s been lost across the field of AMD?

    DR. JOSHUA DUNAIEF: Most of them are probably going to slow or ideally stop the progression of vision loss. For patients with wet AMD who have a lot of fluid that’s leaked into the retina, drying up that fluid with the drugs that we currently have actually can improve vision pretty quickly—within a couple of weeks—in some fraction of patients who start these injections, and there’s about 30 or 40 percent who will experience actual improvement in their vision once they start these injections. There are some efforts to replace retinal cells that have died. These cells won’t regenerate on their own, but using stem cell technology, there’s hope that we can replace them. And there’s some evidence from mouse experiments and also some small clinical trials that these stem cells can be safely surgically implanted in the eye, and some hint that they may be beneficial, but it’s early days with these stem cells, so these therapies are not available outside of a clinical trial. And I would warn patients not to get any kind of stem cell therapy that is not in a clinical trial registered with the government on the website, ClinicalTrials.gov, because there have been some unscrupulous practitioners who have given stem cell treatments at a high price, and patients have lost a lot of vision because these treatments were not adequately tested for their safety.

    MICHAEL BUCKLEY: We have a question that I think is pretty interesting; we’ve never really addressed this. A listener is wondering, now that more people are getting shingles viruses, and she’s heard that shingles can develop near the eye, she’s wondering: Is there anything good

    or bad about a shingles vaccine in terms of developing AMD or AMD getting worse? Is there a connection or no connection between the shingles virus and managing AMD?

    DR. JOSHUA DUNAIEF: Well, it’s an interesting question. There’s no known connection between the virus and AMD, but it certainly is true that shingles can affect the eye in a very serious way. It’s most likely to happen if the patient has a rash on their face that involves the tip of the nose; if it’s on the tip of the nose, it’s likely that it’s also going to be affecting the eye. So, for patients who have a rash on the face, they also need to see an ophthalmologist to check whether they’re developing shingles in the eye, and then they might need some treatment for the eye to address the virus infection in the eye. So, the vaccine is recommended for the elderly population. Definitely ask your primary care doctors about it because shingles in the eye, again, can be really an awful thing and could lead to some vision loss and pain. And shingles anywhere on the skin is very painful, and you really want to avoid it, so the vaccine is recommended for most older people.

    MICHAEL BUCKLEY: That’s really helpful. Dr. Dunaief, before … as we wrap up this call, I was wondering if you have … in the years you’ve been doing research and been involved in vision health, is there one big thing you’ve learned or one thing you wish that all your patients at Penn Med knew or people on the call knew? Do you have a piece of advice or a lesson or an observation that you can share with the audience to kind of close out today’s discussion?

    DR. JOSHUA DUNAIEF: Yeah, that’s a really good question, Michael. One thing I’ve noticed is when patients come in, they’re … they’ve received the diagnosis of macular degeneration and they’re terrified. And justifiably so, they think they are going to go blind and quickly, and the first think I like to do is reassure them that they’re probably not going to go blind and not quickly. So, the … macular degeneration only affects the center of the retina—the macula—and not the peripheral retina in the vast majority of patients. So, in the worst case, where patients have a lot of damage in the macula of both eyes, they keep their peripheral vision, which enables them to get around carefully, to see objects—not with … not with high clarity, but they can see objects—and they can read a little bit if letters are magnified a lot using that peripheral vision. So, they’re not going to go black blind with no light perception.

    Also, many patients with early macular degeneration are never going to lose much vision, if any, so … especially if they adhere to the healthy lifestyle issues that we were talking about—not smoking, eating a diet that’s rich in whole foods, plant-based green leafys, fruits, vegetables, and fatty fish twice a week. They’re not at high risk for losing vision, especially if they don’t have very many drusen or very large drusen. The ophthalmologist will follow the size and number of drusen over time and let patients know what their risk is based on that. But, again, many patients are going to be able to keep good vision for their whole life. And the advent of new therapies for patients who do develop advanced macular degeneration—either wet or geographic atrophy—is also protective. These drugs that we can inject into the eye every month, or now maybe as infrequently as every 4 months with this new drug faricimab, assuming it’s going to be FDA-approved this year, can help maintain pretty good vision for quite a while, if not for the patient’s entire life.

    MICHAEL BUCKLEY: I appreciate you putting this into perspective. It’s something that is in one level reassuring, but also, I think you made it clear how much the patient needs to follow

    best practices and healthy lifestyle and the recommendations from their physicians. I appreciate you putting it in that context. So, Dr. Dunaief, again, I just want to thank you so much. You know you’ve been a regular voice for us here at BrightFocus, and I think on behalf of our audiences, thank you so much for giving us hope for future research but also reminding people this is a pretty important topic to manage well every day.

    DR. JOSHUA DUNAIEF: Thanks, Michael. My pleasure and thank you for providing an opportunity to get accurate information out to patients and also for the funding that BrightFocus provides to researchers on macular degeneration to help develop that next generation of treatments.

    MICHAEL BUCKLEY: Thank you, It’s an exciting time in the field of science to save sight. So, this concludes today’s BrightFocus Chat. And on behalf of Dr. Dunaief and all of us here at BrightFocus, thank you for being with us today. Goodbye.

This program is supported in part by educational grants from NovartisGenentech, Delta Gamma Foundation, Apellis, and Alexion.

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