Dr. Joshua Dunaief
The telephone discussion features Dr. Joshua Dunaief, of the University of Pennsylvania’s Perelman School of Medicine, who specializes in the study of age-related macular degeneration.
The telephone discussion features Dr. Joshua Dunaief, of the University of Pennsylvania’s Perelman School of Medicine, who specializes in the study of age-related macular degeneration.
Update on the AMD Drug Pipeline
October 31, 2018
1:00–2:00 pm EDT
Transcript of Teleconference with Dr. Joshua Dunaief of the Scheie Eye Institute, University of Pennsylvania.
The information provided in this transcription is a public service of BrightFocus Foundation and is not intended to constitute medical advice. Please consult your physician for personalized medical, dietary, and/or exercise advice. Any medications or supplements should be taken only under medical supervision. BrightFocus Foundation does not endorse any medical products or therapies.
Please note: This Chat has been edited for clarity and brevity.
MICHAEL BUCKLEY: Hello, I’m Michael Buckley with BrightFocus Foundation. Welcome to today's BrightFocus Chat , “Update on the AMD Drug Pipeline.” If this is your first time joining us, welcome, and we’ll briefly tell you about BrightFocus and how the Chats work.
First, some background on us. BrightFocus funds some of the top researchers in the world. These are scientists trying to find cures and new treatments for macular degeneration, glaucoma, and Alzheimer’s. We take the latest and recent news from these scientists and share it with families who are impacted by these diseases. On our website, BrightFocus.org, we have a number of free publications and plenty of materials that are there to help you.
Let me tell you about today’s Chat, “Update on the AMD Drug Pipeline.” We are really fortunate to, once again, be joined by Dr. Joshua Dunaief of the Scheie Eye Institute, University of Pennsylvania. Dr. Dunaief’s name is familiar to us. He has been a guest on multiple BrightFocus Chats, and a number of times per year he writes expert articles that appear on BrightFocus.org. Through the generous support of donors, we have been able to support Dr. Dunaief and other researchers in their work to try and cure macular degeneration. Without further ado, I would like to introduce Dr. Joshua Dunaief. Dr. Dunaief, welcome!
DR. JOSHUA DUNAIEF: Hi, Michael. Thank you.
MICHAEL BUCKLEY: Dr. Dunaief, probably no surprise to you as a clinician, but the number one question we get during the Chats and other times from families impacted by AMD is, “When will I be able to stop getting injections in the eye?” We thought we would invite you back with us today to give us an update on some promising new drugs and treatment opportunities that might be down the road. I know you wrote a piece for us on BrightFocus.org on this topic that was very widely visited. We would appreciate your giving us some news from the lab.
DR. JOSHUA DUNAIEF: Yes, good question. We are fortunate now to have treatments for wet macular degeneration. Ten years ago, before these injections were developed, people would lose a lot of vision from wet macular degeneration. Fortunately, now, a lot of patients can retain pretty good vision. I understand it is difficult for patients and their families to have to keep coming back for treatments every month, or every two months.
There is a lot of research being done to try to develop drugs that will last longer. There are some that are coming along within the next year, I would say. One of them is called the RPDS—the Rigid Port Delivery System. This is developed by a company called Genentech. It is a device that is implanted just inside the eye. It can be filled with the drug Lucentis. It releases the Lucentis slowly. This looks like it is a good candidate and it is in a phase II clinical trial right now. That trial has an expected completion in the middle of next year. If this one works, it probably will be coming along within a couple of years.
Another one that should be coming along even sooner is called brolucizumab.* This is another injection of a drug that blocks the same target as Lucentis, Eylea, and Avastin. The target is called VEGF. VEGF is like a fertilizer that promotes the growth of bad blood vessels, so we want to neutralize that. Brolucizumab neutralizes it and in phase III clinical trials has shown it lasts longer than Lucentis. It was non-inferior, which is technical jargon for “just as good” essentially, as Lucentis when given every 3 months. This one should be able to space the time between injections out further. That may be available as soon as next year.
MICHAEL BUCKLEY: Great. These are all for wet AMD?
DR. JOSHUA DUNAIEF: Yes, for wet AMD. There are a couple of other drugs that also target VEGF that may last longer than the current drugs. Another one is called abicipar.
There is another class of treatments that is coming along that will target VEGF and also other proteins: It’s gene therapy. There has been a lot of excitement recently about gene therapy because it is FDA-approved for another eye disease, called Leber’s, and it affects children who are born blind. The children who get this treatment, really miraculously, are able to see after the treatment. This proves that gene therapy can work, it can be safe, and it can last for years. Now that means that there is the potential for macular degeneration to deliver a one-time gene therapy that could target VEGF or produce another protein that would be therapeutic that could last for years.
MICHAEL BUCKLEY: That is amazing that science from one disease can carry over. That is exciting. Are there any encouraging signs on the dry AMD front?
DR. JOSHUA DUNAIEF: Yes. There is a drug called APL-2 made by a company called Apellis. This is injected into the eye, and it inhibits a protein called “complement.” Complement is really more of an insult, in that it promotes inflammation in the eye and part of the immune system. There is good evidence that it attacks the eye in people with macular degeneration. This drug is designed to neutralize a complement protein called C3. In a phase II trial, people with geographic atrophy, which is the advanced form of dry macular degeneration, had a slowing of the growth of their area of atrophy. That is a really good thing. It means that their visual field would be protected. That is now advanced into phase III clinical trials.
MICHAEL BUCKLEY: That is great.
DR. JOSHUA DUNAIEF: That is the one that is really farthest along for dry macular degeneration and geographic atrophy. There are others that are in a more experimental phase. There is another complement inhibitor called Zimura that is being tested in a clinical trial. There is a drug called Oracea, which is actually the antibiotic doxycycline that has some anti-inflammatory activities that may be helpful for geographic atrophy.
Metformin is also being tested. There is a drug called lipoic acid, which is a nutraceutical that has some antioxidants and also some
iron-chelating properties, and we are very interested in that one. That is being tested at University of Pennsylvania, and the initial results motivating that study were developed in my laboratory. We have a trial that is funded by the BrightFocus Foundation, and patients with geographic atrophy are receiving this and sometime next year we will find out whether it has slowed the growth of their geographic atrophy.
MICHAEL BUCKLEY: As you outline some of these promising treatments, several times you’ve mentioned clinical trials. Could you give our listeners a peak behind the curtain? In vision science, what does a clinical trial entail? Who participates? What do you and your team, and the families involved, do?
DR. JOSHUA DUNAIEF: First, the idea for the clinical trial has to be developed—usually by researchers at academic eye hospitals around the country and around the world. They are tested in animal models first, initially mice most often. If they look protective and safe in the animal models, then they are advanced to clinical trials.
The investigators at the academic centers have to apply to the FDA in order to get permission to test the new drug. The FDA looks at all of the data, looking at the safety data and the potential for effectiveness. Once that is approved, then the institution can start recruiting patients. The patients are invited to participate in clinical trials if they meet certain criteria. Each trial is looking for a particular stage and phase of disease. There are inclusion criteria and exclusion criteria that determine who is going to be eligible for the treatment.
Once these patients are given an informed consent document that lists all of the reasons for the trial and discusses the potential risks, then they are followed over the course of the trial length—sometimes they are short, a few months, sometimes they are a couple of years—and they will come and see their doctor, who will examine them. They will get retinal imaging done. The doctors and patients usually don’t know who is getting drugs and who is getting the placebo.
At the very end of the study, all of that data gets analyzed, and it is determined whether the drug was safe and effective. There are three phases of clinical trials. The first one is for safety. That is usually small. If the drug is proven safe, then the trial advances to a phase II and then a phase III. Each of these is done with close monitoring for any adverse events so that if there are any concerns about safety, then the trial can be halted before anybody gets hurt.
MICHAEL BUCKLEY: That is really interesting. If someone were interested in participating in a vision clinical trial, what are some of the things they should ask their doctor about?
DR. JOSHUA DUNAIEF: Well, first of all, they should indicate that they are interested in participating in a clinical trial, and then their doctor can tell them whether there are any trials out there that they may be eligible for. A lot of doctors will know about the available trials, but it doesn’t hurt for patients to look at the list of clinical trials and ask their doctor if they might be eligible for a specific trial. There is a website called ClinicalTrials.gov that lists all of the actively enrolling clinical trials. Patients can look at that if they are interested.
MICHAEL BUCKLEY: For our audience, I want to take Dr. Dunaief’s last point about finding clinical trials. We have a link to that on the BrightFocus website at BrightFocus.org. You can go to our clinical trials finder and get some of those materials and learn about trials that could be a good fit for you. Secondly, we have a free publication called “Clinical Trials: All of Your Questions Answered” that outlines a lot of what Dr. Dunaief just said about how clinical trials work and what to ask your doctor. It is a great opportunity to help advance the exciting progress that we are hearing about today. Dr. Dunaief, are you okay if we move on to a few listener questions?
DR. JOSHUA DUNAIEF: Absolutely.
MICHAEL BUCKLEY: We have a woman from Canada who asked a question, “What is a membrane peel?” She heard some people talking about that and read a little bit about it. Is that something that, if she is at her doctor’s, she should ask about or know about?
DR. JOSHUA DUNAIEF: A membrane is a thin surface on the top of the retina. It is like Saran wrap. It can grow along the surface of the retina. It can cause some wrinkles in the retina and sometimes cause a little hole to form. If a patient has distortion of vision due to that wrinkling, or a hole that has formed in the center of the retina, called a macular hole, then sometimes that membrane peel can help improve the vision.
MICHAEL BUCKLEY: Thank you. Marvin from Florida is wondering about when you talked about some of the promising drugs that are being developed. Would any of those be able to reverse vision loss from AMD?
DR. JOSHUA DUNAIEF: Sometimes, yes. Patients who have wet macular degeneration have blood vessels that have leaked fluid or even red blood cells into the retina. That can cause reversible vision loss. If those blood vessels can be dried-up so that they stop leaking, and that fluid or blood that was in the retina is reabsorbed, then patients can actually notice an improvement in their vision. Some patients who are listening, who have wet macular degeneration, will notice that when their blood vessels start leaking and then they get an injection that causes the blood vessels to stop leaking, their vision can improve.
Patients who have geographic atrophy, there is nothing that we can do medically, at the present time, that improves vision. What we can do is offer low-vision aids that will magnify images or have special lights that make it easier to use the remaining vision that is intact within the eye. The one fortunate thing about geographic atrophy is that the area of atrophy almost always stops when it reaches the edges of the macula so that the patients are able to keep their peripheral or side vision and use that to get around, and to see objects as best they can. The objects need to be magnified and lights need to be brighter in order to use that vision, but it is still very useful.
MICHAEL BUCKLEY: We have a question from Lester in California, who is wondering, “How can people best deal with the anxiety that could arise from having to get an injection in their eye?”
DR. JOSHUA DUNAIEF: That’s a good question. That sounds like a pretty awful thing to have an injection in your eye. Most people have the most difficulty with it before their first one. Then they realize that it isn’t as bad as a it sounds. The doctor will numb-up the eye before the injection and the injection is done with a tiny little needle—about as thin as a hair. It only takes a few seconds. Once people have been through the first one, usually it is a lot easier and the anxiety is less severe after that first one.
MICHAEL BUCKLEY: Sounds like you have a good bedside manner as a clinician to help with that. We have a couple of questions here about exercise and lifestyle. Dr. Dunaief, you and other experts that have joined BrightFocus Chats talk about the importance of staying healthy, exercise, and good diet—as far as overall health including vision health. We have a question from a listener in Virginia wondering if it is okay to swim in swimming pools after you have wet AMD because of all of the chemicals that are in the water. Is there anything that we should be concerned about there?
DR. JOSHUA DUNAIEF: It is great to exercise and to stay healthy in general and reduce the risk of AMD. There is evidence that people who are obese have a higher risk of AMD. There is also evidence that people who eat certain foods have a decreased risk. It is really good evidence. Those foods are green leafy vegetables, fruits, and fatty fish like salmon, sardines, mackerel, and tuna—although you have to watch the tuna because it can have a lot of mercury. You don’t want to eat just tuna. Absolutely—I would encourage the swimming. Just not immediately after an injection. I would wait about one week after an injection before swimming.
MICHAEL BUCKLEY: Great. That is very helpful. Staying on the overall health and lifestyle topic, earlier you mentioned metformin and diabetes. What is the connection between diabetes and macular degeneration?
DR. JOSHUA DUNAIEF: Well, diabetes can affect the retina, but it doesn’t cause age-related macular degeneration. The causes are a distinct disease called diabetic retinopathy. These diseases can both affect the vision, but when the ophthalmologist looks into the eye, they look very different. In diabetic retinopathy, blood vessels on the surface of the retina can leak and bleed. In macular degeneration, blood vessels that are very deep in the retina can leak and bleed. In both diseases, patients can be treated with anti-VEGF drugs like Lucentis, Eylea, or Avastin, so in that way they’re similar. People with diabetes can also go a long way toward protecting their vision with lifestyle changes. So, they eat that same diet that I was talking about with the macular degeneration patients: lots of green leafy vegetables, fatty fish, not high on the carbs like potatoes or rice. The diabetics have to watch out for fruits that release their sugars very rapidly, like watermelon and bananas, but otherwise fruits are okay, as well.
MICHAEL BUCKLEY: Great. And we have a two-part question from a gentleman who asks about the injections. I guess part one is there’s different brand names that you mentioned for the injections, and the caller is wondering, how do you best talk with your doctor about different brand names? And the part two question is, is there some type of lifetime maximum number of injections someone should receive?
DR. JOSHUA DUNAIEF: Yeah, there is no lifetime maximum. I’ve had patients who have had 100 or more injections, and the eye tolerates those injections very well. The injections that are currently available, Lucentis and Eylea and Avastin, they all target the same molecules—VEGF—so they’re pretty similar to each other. There’s some evidence that Eylea can last a little bit longer than Lucentis, but ophthalmologists may find that, for any given patient, one of them might work better than the others. We can’t really predict who’s going to respond to each one the best, so a lot of times we’ll start with one, and if it’s working we’ll continue with it, and if it’s not working as well as we’d like, we’ll switch to one of the others.
MICHAEL BUCKLEY: So broadly speaking, does that tend to be the physician’s decision or the patients ask for one over the other? How does that work?
DR. JOSHUA DUNAIEF: Well, the doctor will talk about it with the patient and recommend one in particular, but if the patient is interested in hearing about the others, then certainly there will be a discussion about the pros and cons of each of the anti-VEGF drugs.
MICHAEL BUCKLEY: A question: John from New York heard about some of the promising medications you mentioned. Would any of them be available in a pill or some non-injection route? Any of the ones you mentioned.
DR. JOSHUA DUNAIEF: Most of them are injections. Certainly, it would be great to have a pill so that it wouldn’t have to be injected in the eye. The lipoic acids trial that we’re doing at U Penn is a pill for people with geographic atrophy, and there is a VEGF inhibitor. One form of that is being tested orally. It’s called the X82 or Vorolanib, that one also targets VEGF, so hopefully a pill could work at some point, but we don’t have a pill for wet macular degeneration currently.
We do have vitamins that are given to people with early macular degeneration. If patients have drusen, which are little whitish-yellow spots in the back of the eye that the eye doctor can see, then they’ll be told to take antioxidant vitamins. These are based on a study funded by the National Eye Institute called the Age-Related Eye Disease Study, or AREDS. These vitamins are available over the counter, and they follow the formula of the AREDS 2 Trial. So, if anybody is taking these vitamins, they should check to see that they follow the AREDS 2 formula. So, these vitamins were shown to decrease the risk of progression from early macular degeneration to advanced macular degeneration.
MICHAEL BUCKLEY: Great. And to our listeners, the AREDS 2 that Dr. Dunaief just mentioned, we have more information on that available free of charge at BrightFocus.org. There’s a publication called “Macular Degeneration: The Essential Facts.” If you’re interested in receiving that, it has a nice page in there that outlines exactly information about that vitamin supplement.
Dr. Dunaief, I saw a story in the news the other day that there’s signs of hope that Alzheimer’s disease may be detected a little early though an eye scan. It sounds very exciting. I was wondering what you know about that.
DR. JOSHUA DUNAIEF: Yeah, Michael. It is exciting. The retina is part of the brain, so some diseases that affect the brain, like Alzheimer’s disease, can also be seen in the retina, and there are a couple of ways that they can be seen. There’s really advanced imaging now for the retina that can be done very quickly just by shining light into the eye, and a computer detects the reflected and absorbed light and can generate a lot of information about the structure of the retina and its composition. Sometimes that will be done in combination with a dye that might be injected or eaten, and sometimes without the dye. So, there are a couple of different ways that the eye can be imaged, and that may provide information about Alzheimer’s disease risk, perhaps detecting early Alzheimer’s disease.
One of these dyes is actually a spice called curcumin, which binds to a protein found in Alzheimer’s brains but also in the retinas of people with Alzheimer’s disease. This protein is called amyloid-beta, and then this dye can be detected through imaging in the eye. The thought is that people with Alzheimer’s disease with amyloid-beta in the brain may have amyloid-beta in the retina that would be detected this way, and perhaps that could signal and detect early Alzheimer’s disease. This all needs to be proven in additional clinical trials, but it holds a lot of promise for early detection of Alzheimer’s.
MICHAEL BUCKLEY: That’s very encouraging, and as you said, it still needs more examination, but it’s really exciting. So, Dr. Dunaief, I just want to conclude with your overall thoughts. You’ve been one of the leading researchers on this disease, and I know you see patients at the University of Pennsylvania Medical Center. Is there a common message, or is there something you’d like patients and their family to know about macular degeneration that might surprise them or maybe give them a little more hope or encouragement for the future?
DR. JOSHUA DUNAIEF: It’s a good question, Michael. First of all, patients with macular degeneration—early macular degeneration—should know that a lot of times it’s possible to keep good vision for your whole life. When patients first come to me with early macular degeneration, they’re really terrified that they’re going to lose their central vision, and a lot of patients don’t. A lot of patients keep good vision for their whole life, so that’s really important for people to know.
The next takeaway I’d like people to have is that they have a lot of control over what’s going to happen. Lifestyle modification is not easy, but it’s doable and it’s really helpful. So, the diet that I was talking about—lots of fruits and vegetables, fatty fish, exercise, certainly not smoking. Smoking is a major risk factor. If you smoke, make every effort to stop. And then, there’s a lot of hope that new treatments are going to be coming down the pipeline and decreasing the frequency of those injections for people with wet macular degeneration.
I think we will find ways to slow or stop the progression of geographic atrophy. There has been a lot of interest in the use of stem cells to replace retinal cells that have died in patients with geographic atrophy, and there are some early clinical trials that suggest stem cell treatment can be safe. I’m not sure yet whether it’s going to be effective, but I think there’s hope for that as well, Michael.
MICHAEL BUCKLEY: That’s great, and I really appreciate your advice there. I think it’s a good sense of reminding people that there still are things that are in their control, even in a situation that is obviously very distressing, particularly when they first learn of it. So, Dr. Dunaief, I just want to conclude by thanking you for continuing to share your time with the BrightFocus audience, and it’s a great opportunity today to peek behind the curtain at what’s happening in your lab and research laboratories all around the world. So, I want to thank you very much for all you did for us today.
DR. JOSHUA DUNAIEF: Well, my pleasure. Thank you, Michael.
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*In October of 2019, the FDA approved Beovu® (brolucizumab). Learn more about this treatment.