 Alright, so we're going to be talking today about age-related macular generation one of the one of the most common retina problems you're going to see here in your at the VA and here in the retina in the retina service and This is going to be more or less an overview. I want this to be fairly informal And discuss what we're doing today So as always and this is true on every grant that I that I read and every paper that I read review article I was talking about age-related macular generation's leading cause of blindness in the Develop world and it it truly is but you know the it's It's really really Common and it was you know thinking back 25 years ago when I was starting in this it was a it was a neglected problem Now it's it's the focus of a lot of Clinical practice focus of drug companies. It's really It's really changed dramatically and with that change we see We see a lot of interest. There's a lot of in terms of research Funding Richard research interest foundations, etc there's a lot of interest in trying to get at this disease and It's it's changed from a disease that I would see when I would see patients with age-related macular generation coming into my practice Starting there really wasn't much that I had to offer them in the 1990s when I was starting in practice here. It would arrange from Just telling them well you have age-related macular generation if you have the weft form the exudative form your There's there's not much we have to there's not much we're going to do for you beyond laser That's going to make your vision worse initially, but in the long term you're going to thank me, but they never did in the end and You know and dry age related macular generation was even worse We didn't have anything to offer and we've we've made a lot of progress on wet macular generation We've not we it will go over that today. We haven't made as much progress as we'd like in Dry age related macular generation But there's been a dramatic change in the way the patient attitudes and just in clinical practice We see patients now routinely patients that we see Monthly coming in so I get to know them very well as opposed to just seeing patients every six to twelve months and kind of moving them on When I was starting in practice The AMD I'd like taking on diseases that were not the common things that you know We already had when I was a resident diabetes was Understood in a lot of ways. We had at least laser that would work reasonably well We knew other we knew how to fix retina detachments of course not as well as we do now but AMD was a was a frontier and that caught my interest from the start and It was a disease that was relentless. So there was a lot of I certainly had a lot of interest in prevention trying to figure out how some of my background in nutritional biochemistry could be of use and we'll cover kind of a little more detail on some of the things that I know about in nutrition and in a read study which I was involved with so just kind of going over the statistics Depending on how there's still just a lot of controversy on how you define AMD. Is it a few little drusen? Is it? is it Large soft drusen. Is it the advanced disease? What is really AMD and That has led the National Alliance to a lot of other a lot of other And that has led a Lot of other private foundation groups etc to try to define what AMD is And we won't have time to go into the the controversies involved in that and what but basically You know, we've learned that the very earliest stages of AMD may even be part of just normal aging very small Small soft drusen are not considered high-risk. It's the it's very large very small hard drusen Are not considered high-risk large soft drusen? Yeah, there's a lot of good epidemiology that has shown that that's important and certainly the advanced disease So depending on how you define it, you know There are tens of millions of people in the US that have at least the earliest stages of AMD Intermediate AMD is is seven point three million at least on this chart here advanced AMD is You know somewhere in the in the couple million range and there's a couple hundred thousand new new cases of advanced AMD That are happening every year and it goes up with age. That's certainly one of the major risk factors for AMD So that in the 50 to 60 year old range You're going to be making the diagnosis of AMD and only about one or two percent of patients coming in But as it goes as as the population ages and we have lots lots of people that are in their 70s 80s 90s and beyond about 30% of individuals have at least some form of age related macular degeneration and The numbers are roughly 10 or 15 percent are going to be in the exudative category of AMD But 90 especially before we got anti-veg F compounds about 90 percent of blindness was occurring in is was caused by the wet forms of macular degeneration and In this National Eye Institute figure this kind of just shows the exponential rise both in men and women as you as you age Here and that it also emphasizes that this is a disease. That's primarily of the Caucasian population. It's not while African-Americans and other more darkly pigmented people have less of the have a lower prevalence consistently throughout throughout aging and I Don't need to emphasize. This is a disease of the central loss of central vision My patients coming in with advanced age related macular degeneration have are complaining about reading driving Recognizing faces. They don't come in They don't come in with mobility problems except for the fact. They can't drive. They're not running into things they don't typically need other assistive devices and We'll just kind of skip through some of these but You know they and AMD comes in all sorts of all sorts of different flavors Whether in the dry form down below with drusen and eventually going to geographic atrophy Which looks at least pretty faded out on this picture Or the exudative form where you can have just small Hemorrhages, which is when you want to catch things early and there's an early chorotomyovascularization Versus these large submacular hemorrhages, which we can which Cause much more vision loss and are a little more difficult to manage and eventually advancing to Discoform type scars that you see here the And chorotomyovascularization is a very complex problem and as you can see there's a blood the The blood vessels grow underneath the retina and whether you're getting type 1 or type 2 chorotomyovascularization where you have either Neovascularization underneath the retina Underneath the retinal pigment epithelium or between the RPE and the retina this growth of blood vessels Which I would say we still don't adequately understand what the stimuli are this leads to a vision loss either from bleeding or Were exudation and scarring that eventually can occur and we don't want it to advance very Very quickly we know that this by the time you get this sort of chorotomyovascularization you want to suppress it so through the years we've had a lot of a lot of diagnostic studies and so just kind of it's listed here But I want to open it up to you so when a patient comes in they have AMD what are they what are they complain of? What do you do? And I'll start with Becca just right here. So it's pretty easy Yeah, so, you know you want to kind of assess the degree of visual impairment check vision and see what kind of Scatoma or you know visual distortion they have using so an absolute grid and so Hopefully at the VA when you're when you're doing this you actually get an absolute grid I would say that well the techs here are pretty are pretty remiss in doing that I almost never get an absolute grid coming in with them Despite my request that they do it. They it's a low-tech thing It's almost too low-tech for them to do but you want to see quantified do they have distortion? If the patients do have distortion or what can they do at home you tell them we'll look at look at door door Ways look at blind something like that to see that Are you familiar with the 4c device? Which we sometimes have for our patients. Do you know about it? Anyone here so there's there is a way of doing of quantifying the answer grid and you can do a computerized Version that the patients have and this is paid for by medicare at about 20 dollar and they have with a copay about $20 a month, but they get a device that they have at home. They look into it It projects on a computer screen a small computer screen Straight lines which will look distorted to them, but it also will project distorted lines Which may look straight to them instead and the machine projects all these different things and The patients just click there what they see is straight and which which is the more straight one And then this is all communicated to a central reading center that computerized reading center that will then establish what is their baseline of distortion because they they may have some baseline distort they may have some just Distortion that they always have but if there's a change in distortion it then Sends a notice to them and to us and to me to come in sooner This has been Statistically proven and in prospective trials to pick up exudate of macular generation often before they even have it So it's an option. It's an option for patients who are very motivated Computer somewhat computer savvy, so it's not for every patient How long does it take to do that takes five minutes probably and we encourage them to do it If they're doing it right they do it if they're motivated, they'll do it every day They don't have to do it every hour or anything like that, but some of them do it once a week I definitely have some patients coming in with With earlier than they normally would on the other hand it does generate false alarms as you would expect So you have to kind of kind of balance that So after after you've noticed this distortion, what else are you going to do? Well, you're going to do a dilated eye examination After you've taken a visual acuity and just and a history of their patients to you and even before they have a dilated eye examination they will already have an OCT so you get everyone gets an OCT these days and You're going to be looking for changes there's As you can see here. Let's see. I guess I can't show that but you'll see doesn't you'll see either Subretinal fluid intra retinal fluid you may see these subretinal hyper hyper fluorescent material Fibrotic scars all sorts of things, but you're you're all familiar with looking at OCTs and seeing that there's something different going on and We so you're going to get that and As you can see actually the 4c device has shown up on the top here upper right so that's kind of what it looks like through in this picture and then Then we get fluorescent angiography. How often when do you want based on my practice and others practices in your practice at the VA? How often do you get fluorescent angiography? Is it important to get now? That's a lot of people would argue that I still Although it's less and less I do I do still get it and a lot at least in the first presentation but it's it's Even though all of these studies, you know the original anchor marina And even previous studies those were all based on fluorescent angiography Once OCT came in and clearly is is a way to is the best way to follow at least Inexpensively and to be getting to be getting serial Examinations but fluorescent angiography can help you distinguish between things that are going to be higher risk lesions like rap lesions and other ones that are not going to respond as well and Sometimes you pick up things that are occult lesions that you really don't see in on angiography So I still will get them often But not not always and then I see gee angiography is good for looking at again even more unusual lesions So don't forget to do it is basically the thing to do so with past treatments of AMD Originally as I said in the 1990s there was the macular photocoagulation study the NPS study Which is a historical interest only and that was that's where at least we were trying to the first steps were being made to try to shut down these these vessels and We would do argon laser typically right to the fovea is what it was recommended to do that was proven through large Research studies that you would say even though they had 20 30 or 20 40 vision You're better off ablating a very small vessel right in the center and then following them and And if they don't have a recurrence which unfortunately many of them did They would be better in the long term than if you let them just grow and grow and have huge scars Now I do have one patient I see monthly now getting treatment I can remember her from 25 years ago where I did where I ablated her fovea and that eye is still stable to this day and she's 2070 in that eye and his has come and While the other eye was for came out came out in that anti-vegetary, and I'm injecting that I to keep it stable So it did sort of work. It wasn't great, but that was what we had back then Then as other things were starting Mano Swartz was on the faculty here did was starting to do plasma Phoresis, you know, he was kind of ahead of his time realizing that Complement factors might be important and if you can if you can wash out all of these by doing plasma Phoresis you might be able to slow down the stuff the progression of the disease it worked a little bit It was not a very good Good Good treatment. It was very expensive. It had risks to doing that but Statistically there was a small a small effect, but it wasn't statistically significant to do Then there was a period Around 2000 that surgical approaches got really popular vitro vitro retinal surgery surgery was getting to be very good We it was getting to be lower risk and people said well Why not reach underneath the retina make a small retinotomy? Pull out the Coridoneovascular membrane So, okay. What do you think red on that? What was that good or bad to do? Yeah, so What it did is why why would it be bad? What was what was gonna happen? I mean, I think that there are many things I mean you're first of all you're making a retinotomy so that in itself could lead to complications Detachment and then I mean you're pulling out the Coridoneovascular membranes You're still going to have that defect in Brooks that doesn't get rid of that. So I mean I think it Kind of puts a bandaid maybe on the problem, but then you're probably going to have so much submacular fluid after surgery That arises just from the trauma of just pulling out, right? So what comes out with it if you think when you're pulling on these coridoneovascular membranes? Some of the coroid right the RPE all sorts of things so you were left with not much there So it was you might as well just ablated with laser same thing so and you would also be putting patients at risk of Surgical complications taking an eye that was not gonna that was going to have a central scatoma and giving them a retina Detachment or a massive subrat retinal hemorrhage. So that was one approach The other surgical approach was to actually do macular translocation to either detach the retina with a large 360-degree Giant tear and move it to another area or to do scleral Implication but try to move it out move it elsewhere and what happened is not only did that have horrible surgical complications potentially But also the coronal neovascularization would just move over there. So there was something about the fovea that was actually that was Encouraging it to be to form coronal neovascularization. So that that didn't work very well other other things that were tried were external radiation using various ways and that is an anti angiogenic Means of doing it it had significant complications because eventually you would get radiation retinopathy and other problems like that They were it's been tried in various ways but it never really caught on and then the first the first treatment that finally kind of At least was changing the natural history of the disease not not dramatically But was better was photodynamic therapy and you'll still see us occasionally doing that So photodynamic therapy is involves giving a photosensitizing dye intravenously and then And then treating it with a with a low-power Infrared laser red or infrared laser that would help close down the blood vessels this Worked well in animal models it worked Reasonably well in humans, but attended to generate kind of a fibrotic a slow fibrotic Needed retreatments, but when it first came out it was common basically I would if right now if you ever see me doing PDT which what do we do it? What do we use it for now anyone know? CSCR it's very good for if you had a chorotal hemangioma, which is really rare That would be the other other reasons occasionally for Recalcitrant AMD we will do we will use it, but the problems with this is also the photosensitization When we were doing the original trials this was one of the first trials I was ever involved with was it was with the Miravot drug and that one Required that the patient stay out of the Sun for 30 days afterwards, otherwise they would get a sunburn so that that The newest the one that we use now vertiporphin Uses just they have to stay out of the Sun for three days for sunset cessation, so it works Reasonably well, but it's not great, and it wasn't and then and that lasted that you're a photodynamic therapy Where I would do six or seven of these on a surgery day in between cases has gone away We do one a month, but you should see when we do them you should see how it's done But the main thing that the big thing that changed was The anti-vegeph era and you've had a lot of drug I'm not going to go into the basic biochemistry of this, but we learned that vascular endothelial growth factor, which is involved in diabetic Neovascularization and is also involved in carotoneovascularization and that Veg-ef so very surprisingly to me turned out to be the choke point that you could really attack one Even though carotoneovascularization has a lot of different causes you could go after a single a single point in the neovascularization Biochemical pathway and knock things down very well and the original the original anti-vegeph drug was macogen and Does anyone know about macogen at all or what what was different about it? So Mac macogen was an aptimer, so it was not an antibody and They they targeted VEGF. They really targeted just the VEGF a isoform Just one one isoform and they marketed it as being the best way you're going to really target things But they got a little too narrow in what they were going after and it Changed the natural history, but it didn't it didn't cause vision improvement So it wasn't as good as the next generation compounds Which were a vast in Lucentus and all the other ones that are that are antibody-based and have a little broader Attack on the various forms of VEGF and so macogen originally was given every six weeks It had it had its its time of about 18 months on the market and that was it before it was realized that The other compounds were better Lucentus is the one that Genentech put its big money on into and May they made it specifically targeted for the eye went through the process and Phil Rosenfeldt was one of my residents when I was a fellow realized that he That you could just use a vast and they're the the intravenous form that did the same thing and that kind of messed up everything for Genentech in terms of their Marketing etc. And as you know a vast and still works pretty good It's gone through the trials like the cat trial that's shown in general that it is just as effective as the more expensive compound And so that's still controversy to this day in terms of which which should be the first line treatment We're not even consistent here at the Moran. What's the first line treatment? Is it is it a vast and or is it is it idea or the newer ones? Like I lia and then we're going to be a view is going to be coming out within months And so we it lot depends on insurers it depends on physician preference what you do But they all they all are fairly close. I personally Generally don't use a vast I tend to either I tend to use I lia right now as my first line treatment as long as it's allowed But a vast and if there's payment issues if there's something very typical if I'm using it more off label is what I use But you'll see you'll see differences. There is no right answer in private practice for a long time A vast and was the cheaper way to go I think it's actually getting more difficult to use new so many and Availability is getting more difficult Some of the more unlabeled ones are the ones that are being used now With be of you the one that will be coming out within the next months It's basically being marketed as something that that has longer acting That's a higher affinity. So that's the one that we may be using and they're all priced to be very expensive So we need to make things better as you see in our practices The end of the VA these patients keep coming back month after month With recurrences with me you know being meeting me and so we need to improve a sub-sort of drug delivery and durability And that's what you'll see in some of the clinical trials that are being presented and that we're involved with Through the years people have tried topical trying to do topical anti angiogenic compounds the problem is you can get it to work Maybe in a mouse with a little tiny eye or a rat But a human eye is pretty big and what you put on the surface is just not enough of that is going to get back To the back of the eye We've people have been working on a rotable implants They've been working on refillable reservoirs. That's that's the hot new thing from Genentech is their Their reservoirs the problem is what with any sort of reservoir you have to you have to refill it it's a potential site site for for endoplamitis for infection coming in you may also get You may also get You get vitreous hemorrhage when you're doing a surgical surgical implant and it it's probably going to be ridiculously Expensive once it comes out. So it will be that's but that's the future of what's coming next and then people have tried systemic but that generally hasn't worked very well because Angiogenesis is very important a lot of other parts of your body. So how are you going to target it directly to the eye? Obviously if we can just inject it in the eye or keep or focus it specifically there so Just kind of summarize in terms of other things that have come and gone really the next generation treatments people have tried You know it as with chemo cancer chemotherapy You think well, let's work on multiple pathways and shut this down and so that seemed like a good idea and there were There were there we were involved in the trial with fovista, which is an anti-PDGF compound, which is another Another part of the pathways of angiogenesis and they would made a big deal that this is going to work by putting this all together the By by attacking multiple pathways in the end it didn't it didn't make any difference So though they had a big trial that didn't go very far There've been darpins, which is another form of anti-veg F made by Allergan and we've been part of that trial And it's been shown to At least the results that I've seen it's been shown that it works as well The problem is about 20% of people get significant uveitis from the compound from the compound We all we enrolled exactly one patient and he got uveitis within within three months, and so he's So I don't think it's going to get approved I don't think it'll get to market it just there too many other good compounds out there in the The side effects the side effect profile is really pretty bad Other compounds that have come and gone include squalamine, which is a topical anti-angiogenic That one is that one never worked very well and focal irradiation has talked about that They even developed this whole kind of almost stereotactic way of General of delivering radiation that's shown down below with that chair there other another trial that we weren't involved with involved taking a little strontium 90 source at the end of a probe that you Would that you would do have a track to me and hold over the macula for about two minutes To irradiate the macula again that that didn't go very far So just this is fovista which they spent a lot of money in it Now we'll talk about dry macular degeneration so The that's kind of the new frontier and there's a lot of the different things that have been tried through the years and They range from growth factor implants including the Neurotech implant where they had a Transformed RPE cells that secrete CNTF we tried that for we tried that for AMD RP failed What's the one kind of what's the one positive that they've had anyone know? What what condition? Mac tell that's the one that it did Actually in phase two show that it did slow down the disease We're part of the phase three trial you so you will see these implants We're up to about 10 We're the leading center for Enrollment certainly in the in the in the west of the western United States And I think we'll soon be for the world soon because we have a lot of patients And so this will this trial will close enrollment Within the next month or two it's going to close at the end of at the end of December And we'll have the readout within a year or two Why it works for Mac tell I don't know and we will find out if it does work Other things that we've been involved with through the years include anti amyloid beta Compliment inhibitors visual cycle modulators neuro protective factors antioxidants. We're trying to slip, but Why is dry AMD so much why did it turn out to be so much more difficult than what AMD? Any thoughts Theresa? Well, it just really you think about what AMD Patients are coming in early or coming in they've had a two-week vision loss and You're injecting a compound and you can actually you can see the difference, right? You can see it and I can tell it in the clinical trials when we finally got When I first started using Lucentus in clinical trials I didn't know who was between treated or not, but I could tell the difference I could see I knew something was happening and changing the natural history What's going to change the natural history of dry AMD geographic atrophy that you're going to notice? It's going to be hard because we're looking at growth slow relentless growth of a Central area you can see it maybe over two years, but you're not going to see it over a period of a couple of weeks So that's that's one of the big challenges that we'll talk about probably the most promising Dry AMD approaches right now at least Seem to be the ones involved in the compliment cascade So we've known that and that compliment is involved in AMD It's known from genetic studies But and it's a very complicated pathway and so from the start when Greg Hageman and others identified the compliment was going to be a good target The the drug companies went started looking into this and they had lots of inhibitors both from the eye I standpoint and from and from immunology and A lot of them failed initially and especially lampalizumab the one that from Genentech shown up on the right That one has done that one. They spent I think it was 300 million dollars is what I've heard They got a completely negative study in the end they had some promising they were very they were unusually optimistic with their kind of Not very good phase two results that they but that were positive after they did Post-hoc analysis they put huge amounts of money into it and it failed completely once they had to do the full phase three trial but interestingly both APL one which is made by Appellas and Echo echo Lizzy Muro, which has made they can change the name of the company again, but that was originally off the tech I can't remember the name again the new one both of them have announced both in the in the last year or two positive phase two trials For Sloan the growth of geographic atrophy in AMD So they're both gonna put the big money in hundreds of millions of dollars to do phase three trials We're part of the phase three trial for APL two and Yeah Time you need in a these trials to show slowing and dry AMD like how many minimum 12 months Generally 18 months occasionally 24 months. So it's in that range one to two years is what you're what you're looking at And you're trying to get they they seem to be looking for about a 20 or 25 percent reduction in the growth rate So that's that's what they see right now now Do you happen? Does anyone know what is the side effect that I think that I've seen in both of these trials? Well, the main thing is they seem to be in They seem to be stimulating coronal neovascularization So they're doing something not necessarily good not necessarily good in the long term is that Yes, these injectables both of them There's an increased rate of coronal neovascularization. I just saw this they don't play it up on the Zimura stuff But is it it's there it takes it from about two or three percent rate of coronal neovascularization To eight to ten so it it's a significant change The the good news and when I see that is it tells you that this really is changing a biochemical pathway something is happening and they kind of They say well, you just do injections for the wet AMD. So now you're giving Zimura it requires two injections in within 30 minutes to do this of a hundred microliters. It's huge and It so it's so now you're talking about multiple injections into the eye I have one patient who's when she gets it needs a paracetesis after each one. So you're sticking the needle in her eye She's getting it for for start right now in the trial. So it's it's a big problem so That Right now. I think that's got the most potential. We'll see how it how it plays out But this is just a slide I made a year or two ago that just shows how many different drugs have been tried how many different pathways have been have been looked at and most of these are failures, so it's But they're looking for the big payoff Why is it a challenging target? Well, because we don't know exactly what we're treating. We don't completely understand the genetics We don't understand inflammation and oxidative stress the roles of inflammation oxidative stress amyloid lipofusin We discussed it's a slow disease and you don't have any good animal models to show this and then finally in this We can discuss this here. What are what are you going to use as your endpoint is? Right now everyone uses almost every trial uses growth of geographic atrophy. Is that really a good thing? What what's wrong with that? It doesn't show you the impact on the patient and you know, kind of what did they notice? Yep, that's definitely a problem. Another thing is Geographic atrophy is really late in the disease and some people will argue What by the time you've got a significant area of geographic atrophy enough to follow in a clinical trial You know, it's you should have been treated five ten years ago You know, it's just those cells are destined to die already on the edges It's going to just keep growing. Can you really modify modify the natural history at that point? So that that I think is a big problem, but that's the best way that we look at I think OCT is going to be another way that people are looking at it Maybe we'll be able to look at things earlier as OCT gets more and more high resolution We get better ways of analyzing it. That's coming into a lot of clinical trials Visual acuity is terrible. That's not going to be the way to go. FDA has finally realized that that's not going to be part of the way we do trials and Color photographs are probably not going to be as good as some of the others But it's going to be still I think structural OCT and auto fluorescence So that's what we have now in terms of the new frontiers We know that AMD has major genetic component about 50% of it ABCA4 was the original one where we at least thought we might have a genetic basis of AMD It turned out that complement factor HHTRA one HTRA one arms two are really the major two genetic risk factors And and Greg Hageman here is trying to develop trials and targeted to actually look to identify People who have the highest risk of genotypes target those target that for particular form chromosome 10 Versus chromosome 1 AMD should be treated differently, and I think there's probably something to that There've been a lot of genome-wide association studies that have shown that they're beyond the couple that I've shown here That there are probably 15 or 20 risk factors, but they all are 10% risk, you know increase your risk by 1.1 Relative risk, and it's very very small changes that you're going to be seeing And then there still is the question should you be genetically testing patients in the first place? When they're young and healthy to try to identify whether they would be Whether they should be doing any any interventions early on and then the other thing that's happening soon our gene therapies Are coming not only to try to alter the complement pathways, but also people are trying to deliver the anti angiogenics You know deliver various anti angiogenics by gene therapy the problem The good news is that would be a one-time, and you're done the problem Is you can't control anything once you've treated them There's no turning back as there is if you just stop the injections or take out your reservoir But people why do people like gene therapy? Well, we know the price of gene therapy is a half million dollars an eye for for our pee and so they can price it very high through this so We There's She currently we don't recommend pre symptomatic testing for for AMD I'm going to be writing a clinical trial of trying to look at whether that really is important If people do make lifestyle changes, so there's still I think a future in this as especially as gene there as Genetic testing comes down in price. It's only a couple hundred dollars People who are getting 23 and me and various other gene therapists are already starting to see that they come back with That they are at quotes elevated risk of developing AMD and that That and then you're there you're going to see more and more of those patients coming in VA and in the clinics But we need to prove that they actually are useful And then restorative treatments like stem cells are coming down the line. The patients are are well aware of them But as we all know stem cells are higher risk than any benefit that we have right now but that can change over the next five to ten years and Artificial vision is important Or has at least an important option. We tried the intraocular telescope I don't know if any of you ever seen any patients with that. You have I think it was your patient Don't you have one with it? I have one or two and you know what? I've never seen him since it was there So maybe you may have seen him in Florida clinic, but that's what I found very disappointing I found it was a device that was essentially magna was an implant that was put in During cataract surgery it magnified there was a The image on the retina I'd send them off to cornea clinic to the cornea people who did it And I never saw the patients back again I literally have never seen a patient with this implanted in and so I stopped referring them because it doesn't really get Positive results. They cost about five or ten thousand dollars for that implant the artificial the Chip implant that we use for RP The Argus 2 people they were looking at it for AMD And it's been totally pulled off the market now because they couldn't they could not justify the hundred thousand dollars that That it went in that required to be put in they're looking at cortical implants But cortical implants are never going to be good for AMD the patients. I would never recommend that So what why? For AMD because the resolution is so poor Yeah Yeah, and then of course we have to look at low vision services. Just remember we have a lot of We have a lot of options for patients here and it is important to use our our low vision services and Then of course my patients especially come in with all sorts of other Complementary and traditional medicine they they asked about electrostimulation. There were people up in In this town who were doing acupuncture for dry AMD that are taking base basically the patients monies money for that So in the last 10 minutes, I'll talk a little bit about the ARID study So we've got all these treatments for AMD some work. Some don't how do we prevent AMD? Well, it's important to identify risk factors and modify those that you can as you know age heredity gender pigment There's not much we're going to do about changing that for for patients, but through the years through epidemiology We've identified we know that smoking is a huge risk factor for AMD Always recommend that they don't smoke. We don't have here in Utah the smoking rate is not high The VA it's higher and you do need to counsel the patients and get them to stop smoking changing the trying to alter various risk factors for cardiovascular disease always good for the patient and for AMD and Alcohol consumption has been variable in terms of whether it's a risk factor certainly alcohol In excess is not good. It may be in low amounts. There's at least some epidemiology that alcohol Consumption may be mildly protective. We know that light exposure is a risk factor, but in only extreme cases So you're talking about farmers You're talking about fishermen people who are out all day every day in bright sunlight It's been shown in epidemiology studies. They have a higher rate of AMD if they don't use sun protection for those of us that live in Florescent lights look at blue screens. It's not really clear whether that's a risk factor or not and Through the years, I've been working a lot on nutrition and AMD We know that the retina and the RPE are region of highly unsaturated lipids that are susceptible to oxidative stress and The end with and antioxidant nutrition is the main way that we get antioxidants but these are going to be difficult studies to perform because You know, you're living with free living humans. They have they eat they eat a lot of nutrients How do you know that a nutrient is going to be protective against AMD? Patients want to know here in Utah. They want to take supplements, but how do we give them good guidance? so in terms of identifying Nutritional factors for AMD the first step is in the past has always been epidemiology just looking at associations Doing large studies that are going to involve hundreds or thousands of patients Looking at who gets AMD and who doesn't essentially case-control studies doing nutritional surveys doing Blood levels of various nutrients and trying to figure out trying to tease out which ones would be important And we'll talk a little bit about those in a second Animal studies are important, but we don't have good animal models for AMD And then of course you want to do physiology if you're going to talk about nutrients you have to You know the nutrients need to be getting into the eye. They need to be actually doing something there So that's what I do in my basic science laboratory is trying to figure out what nutrients help and then of course They're going to be prospective trials in the end So through epidemiology, this is the list of the ones that have come up most commonly zinc came up actually Early in epidemiology the original prospective zinc studies where we're done here at the University of Utah by Mano Swartz But and and this was eventually tested in the A-Reds to study and came out positive as we'll see in the A-Reds one study Antoxid vitamins like vitamin C, E, and A are commonly used DHA is thought to be very important because it's specifically concentrated in the eye and it's important for structure of the retina and keeping it Keeping it healthy So we'll talk a little bit about that and then the carotenoids lutein and zeaxanthin which I've been studying for decades are specifically concentrated as the macular pigment of the eye and Then then my patients are always bringing in new things like bilberry and polyphenols that are not adequately studied so right now the The mainstay of our nutritional recommendations are still based on Large clinical studies like the A-Reds one study. This was going on when I was a fellow in the early 1990s Masinir was one of the sites I would see a number of the patients coming through but this was based on the nutritional knowledge of the 1980s basically and They chose the bet what they thought would be the best antioxidant combination. It was a large study This is to shows what you really need to do to get clinical recommendations You have to have nearly 5,000 subjects you need to pick them in the right age And you need to follow them for five years AMD especially early AMD is a slow disease and they were randomized to antioxidants and supplements and they looked at the incidence of cataracts and severe vision loss They had to devise a grading scale This was one of the early grading scales for AMD and they they ranged from one and two Which are well especially one which was just a few small brews in which they effectively established through their natural history study is Essentially not AMD. That's normal aging Then they found early AMD at age two or At grade two which are non extensive small and intermediate Druzen good acuity then But they really needed they learned that they need to focus on high-risk patients the ones who have True intermediate AMD with soft Druzen early atrophy pigment area changes or to look at patients who were really high risk and that they'd already lost one eye to Advanced AMD and you wanted to slow that down for those patients. So Their original formulation was zinc oxide at pretty high levels. This came from Mano Swartz Swartz and Newsom study here The they had to put copper in there because that dose of zinc would cause anemia So they had to put in a little bit of copper They did reasonable doses of vitamin C and vitamin E and they did 15 milligrams of beta carotene Basically because it was a precursor for vitamin A and that's what they had that was the carotenoid that they had What was the problem what does anyone know what the problem was having beta carotene in there? Lung cancer yeah lung cancer and that came out in the middle of the study that Not in not so much for that study But there were some other studies that came out at the same time that that giving so much of a single antioxidant Might be a problem. Anyway, they found that This was a very important study and that they did find that there was a positive Result of taking these combinations, especially the the full combination of zinc and Antioxidants and that it reduced the risk of progression to advanced to severe vision loss and advanced AMD by about 25% Not a huge effect takes a long term But when you're talking about millions of people at risk this is and we had at least some good That good relatively low-cost low risk intervention except for the beta carotene. This was This seemed to be this was a major advance They thought it might work for cataracts that didn't work at all in this study It's at least in the US population and it really had to do with progression to advanced AMD Primarily to exit of AMD rather than geographic atrophy. So they This was published in 2001 and the a reds one formulation was Rapidly became a standard of care. That's what we did and it's still a reds one If you unless you've told me any differently is still what the VA does. Is that correct? They're like the only people that never moved a reds to I Just claim everyone's a smoker But it's still strange In the last couple minutes, I'll talk about lutein and zeaxanthin no more than the macular pigment I've been fascinated why they are concentrated in the retina and we get them from dark green leafy vegetables And they act as antioxidants and light screening compounds. This is as opposed to beta carotene These are naturally found in the eye. It's as the actual molecules. So the once we had a reds one the data for a for lutein and zeaxanthin was much better known and also in 1990s when I was doing some my fellowship with Joanna Sutton This work was just coming out that epidemiology that truly that dietary consumption of lutein and zeaxanthin Especially at the high ranges of six milligrams per day that a that a vegetarian might be consuming That was a that could reduce the risk of advanced AMD by about By about 50% so it was really a pretty interesting finding and based on that The a reds two study was formulated to try to get the beta carotene out and to see if lutein and zeaxanthin would be a good Edition and they chose 10 milligrams of lutein a day and two and two milligrams of zeaxanthin, which is What a very high dose what a vegetarian might be consuming and it turned out that's a pretty reasonable dose To be given and there's not many they're not many known side effects. I've only I've published actually the only Morbidity of taking very high doses of lutein and zeaxanthin, which is crystallization in the retina those patients were typically taking double this dose and having a huge amount in their diet and not having AMD or something else and then Rarely rarely will you see crystals forming in the retina the other thing? They wanted to study were omega 3 fatty acids and at a dose of 1 gram per day That was thought to be a reasonable dose to be taken equivalent to a couple servings of fish a week and they evaluated AMD progression cognitive function Etc. And we enrolled about 60 subjects of the 5000 subjects or 4,000 and we announced the results in 2013 you can see this was a nationwide study and And they picked patients with large drusen GA and neovascular is that and GA or neovascularization in the other in the fellow eye and Unfortunately, they had they started with a very simple design of looking at The top row here lutein and zeaxanthin DPA and EGA and then together But then they started subdividing everything into various different formulations of of the arids with or without With with or without beta carotene or with or with or without high lows high and low zinc and made it ridiculously Complicated so that no one quite understood exactly what we were doing But in the end the results were not overwhelming We did see that adding lutein and zeaxanthin Decreased some of the progression to to advanced AMD that was statistically significant But it did not reach the primary endpoint So when we published the the article on this we had to publish it as a completely negative study in JAMA that it did not reach its end point the and even worse is that EPA DHA actually did nothing in this study probably because the patients were So nutritionally aware coming in and ate too much fish even coming into the study But so I said we had to report it as a negative study But we then came out within a year of a secondary analysis that showed that if you take out the beta carotene and and replace with lutein and zeaxanthin that you could slow down the disease statistically significant and this Became the standard of care very quickly because we really wanted to get the beta carotene out because even in this study We didn't allow the smokers to take beta carotene But the past smokers could and even the past smokers had higher rates of lung cancer Statistically in this study, so yeah primary endpoint was the way it was Whether lutein it was whether the lutein and zeaxanth whether any of the active groups were better than controlled by 25% so you already had an effective an effective treatment But you had to get it we had to have a very a strong increment over an already effective treatment and there could have been other ways that they set up the The the groups and I can get into the subtleties of that sometime with you, but it just in the end You have whenever you set up a study initially you have to the FDA requires you to say this is the primary endpoint And I'm not going to change anything beyond that and they picked the wrong one basically that close but We still changed it and put in and we found that lutein and zeaxanthin did not increase risk of lung cancer so it became very it it became that the That lutein and zeaxanthin was considered a good way to improve the safety by removing the beta carotene and Putting in lutein and zeaxanthin that's shown here These are some of the original arid slides that we were presenting and so in the end the arids to formulation Which is generally the standard of care is take out the beta carotene add lutein and zeaxanthin and don't And don't put in omega omega 3 fatty acids although I strongly encourage my patients to consume fish several times a week and if they don't Then then they could take the supplements, so I still at least do that kind of off label and so in the end What do I tell my patients still? Especially if they're the worried well the patients who are coming in the children of the patients coming in We ask well should I be taking the same supplements that you're giving my my parents here The bottom line if they're still in their 40s and have a totally normal High-examination I still say work on your diet at least initially don't take high-dose supplements so eat a healthy diet lots of fruits and vegetables and fish and Arids to is really for the patient patients who fit into the high-risk categories. At least that's what I say in my practice Other supplements are still coming down the line. There's mesozeaxanthin There's all sorts of subtle things that I can talk and people are looking at Coenzyme Q and everything else, but right now. We just don't have enough data to go forward To make any recommendations Clearly alcohol should be if it's being used should be used moderation Don't smoke avoid excessive light exposure, and I always just thank my patients to to participate in clinical trials We have right now there will even will there be an arids 3? probably not I think a reds to What works pretty well at these were very very expensive studies? We're talking about tens of millions of dollars minimum for the to do each of these studies And it's going to come down to the drug company to the supplement companies and because supplements don't require Going through full FDA trials or anything else. They just don't bother. They they approach me They want to do kind of poorly designed studies and say can you can I try this supplement and you know Can you to give me the results and in six months on 40 patients to prove it works? And it's just like it's not going to happen that way So in terms of what I'm doing nutritionally right now is I'm looking at more subtle more focused questions and actually As you'll see in my clinic news here. I've actually switched to early in the lifespan now I'm we're doing studies on pregnant women Looking at supplementation of lutein and zeaxanthin whether that Prevents some of the depletion that occurs probably during pregnancy and whether that can improve Macular pigment and visual function eventually in their children. So I've got I got significant funding from the National National Institute of Health and we're we've recruited In our first month that we've been open. We recruited seven pregnant women. We only need 60 so we're we're on track for all this Anyway, that's I think everything here and just of those you can see That's the original Moran the way it looked when I first came here when it before it was surrounded by all the buildings before the Huntsman cancer Institute Look kind of idyllic sitting there against the mountains and then they built all the buildings around it We had to move so all right any questions