I'm Charles Wyckoff retina specialist in Houston texas. Since an absolute privilege to be here with you as part of the A. D. A. This year in 2021. My disclosure listed and I'm going to break this into essentially six different sessions. Talking about the importance of screening and the importance of early diagnosis of diabetic retinopathy and then walk through the high points when related to how we manage diabetic retinopathy today and how we might be managing diabetic retinopathy tomorrow. So let's start with some basic questions I think are on most of our patients minds. For example, what are the chances of diabetes affecting my I have a new diagnosis of diabetes, my eyes are healthy, no signs of diabetic retinopathy. What are my chances? Because I really think that we have answered this question slightly inappropriately over the years. It doesn't really make sense to give people an answer that's based on cross sectional single time point data because patients in most cases are living many, many years with diabetes and therefore we need to reframe the answer to this question. And the answer I think is most appropriate for us to echo is Diabetic retinopathy is really a when not an if problem. If patients live long enough with diabetes, we know their risk of developing manifestations of diabetes inside of the eye are incredibly high, approaching 100% for type one diabetes and over 80% for type two diabetes. For patients that have lived with diabetes for more than two decades. Remember of course the diabetic retinopathy and um er the number one cause of blindness and vision loss in our country between the ages of 20 and 70. And the key message that I want to make now and again later in this presentation is available, treatments are over 90% effective at preventing severe vision loss, especially when initiated earlier in the disease states. And we know that screening works. There have been a number of great analyses, this one published out of the United Kingdom, showing that for the first time and at least 50 years, diabetic retinopathy and DME were no longer the leading cause of blindness among working-age adults in England and Wales. It became actually secondary to hereditary retinal disorders. And that is because of the effective screening approaches that have been implemented across the United Kingdom's. We've seen the same data from multiple other countries around the world also we know that screening really works. So what are the recommendations? Well, I think it's helpful to simplify them. If you're a new patient with type two diabetes, you really should be screened to diagnosis and then at least annually. Moving forward, there's some peripheral data maybe every other year screening and people with great blood sugar control with no diabetic retinopathy may be possible. I think it's helpful to keep it simple at least once a year for type one diabetes of course patient needs to be 11 years of age or older. But really there's no harm in screening before 11 years of age. So again, essentially a diagnosis for any type of diabetes I think is a reasonable principle. And then of course be careful in pregnancy which can greatly accelerate the progression of diabetic retinopathy. Unfortunately, it's not a new story for anyone paying attention here. We are not doing a great job of screening and we're not doing a great job in the U. S. Of following up patients. We need to do a better job of collaboratively caring for our patients and getting them into screening. However, that is possible whether that's directly with an eye care professional or whether that's with a screening funders, photography approach. Now there's multiple FDA cleared devices and more coming, which are really exciting to me because what matters is that patients are getting screened. So why is it the patients are not receiving the annual eye exams that they deserve and need? Unfortunately, the most common reasons that patients simply think there's no need. They don't have any symptoms, they think their visions fine and they haven't really thought of it. The second most common reason here is lack of of coverage, lack of insurance or the cost. So how do we decrease the risk of developing diabetic retinopathy? You all know most of the risk factors on this slide. Right. The bedrock is optimal blood sugar, blood pressure and cholesterol controlled decades worth of data support that optimal cardiovascular risk factor management decreases the progression and decreases the development of diabetic retinopathy. And then to flesh out those risk factors here on the bottom left other things that don't not forget about our smoking cessation, sleep apnea, pregnancy and kidney dysfunction. So again from a patient perspective, how much of a difference does it really make if I control my blood sugar and blood pressure? And the point that I like to make is that even small changes can have a very real and in fact quite large impact and this is true across the scale. So for example as we learn in the U. K. P. D. S years ago but still very applicable today. Even a 1% change in human globe and a one c. Going from a 10 to a nine We're 7-6 can decrease the risk of progression by 50%. So patients with poor blood sugar control they don't have to get to perfect control overnight. In fact, I think anybody here wants them to we want to get there a little more gradually than overnight and therefore we want to give them targets that are achievable that they can feel good about. And we know they have clinical meaning because they can dramatically decrease the risk of pathology. So for the third chapter here, how does diabetes mellitus damage the retina? What's the core pathology? And what does that look like? Well, this is an electron micrografx of a capillary. You see the perry site on the top left here, You see the red blood cell in the middle and then that little and a filial cell lining the lumen of the capillary, the core target tissue that's damaged by diabetic retinopathy. From a vascular perspective early is the parasites, we know the parasites become dysfunctional. They drop out, they formed ghost cells and you also get basement membrane thickening. This leads to then secondary micro aneurysms which are little areas of weakening of blood vessel walls where you typically get increased fluorescence on a flourishing angiogram, you can see these little white dots on this flourishing angiogram here at the bottom of the slide. These are the earliest observable lesions for diabetic retinopathy. So if you're getting funded photography um as someone seeing patients with diabetes and you want to look for the little micro aneurysms is the earliest change. The next change you'll start to see our little hemorrhages. These are places where the blood retinal barrier is breaking down because the parasite, the associate endothelial cells are no longer creating the tight junction that forms the inner blood retinal barrier and you're getting a stabilization of blood and serum as you move further down the diabetic retinopathy severity spectrum. This is what you begin to see. You see internal hemorrhages, micro aneurysms, hard exit dates. And when we quantify this, we use the DRS. S the diabetic retinopathy severity scale, which is broken up into essentially 12 to 14 different stages, with about a third of them being dedicated to non proliferated disease and about half of them being dedicated to proliferated disease critically. Through the first sort of half of this scale, patients are in most cases asymptomatic, even into the second half, many times patients can remain asymptomatic, so symptoms are not the trigger to use to begin to screen for diabetic retinopathy. You want to catch this disease process before patients are symptomatic, this is what this looks like a physiologic level. You see the normal retina here should be this sort of ground glass grey appearances I'm showing here with the mouse movement and then out in the periphery. You see these large areas of darkness. These are areas where the retina has essentially died with the vasculature has been pruned from the effect of diabetic grandma apathy. In response to that there's an ischemic drive an up regulation of multiple side of clients, including faster into the growth factor a shown here at the bottom right schematically and in response to that, you begin to see proliferated diabetic retinopathy. These Tufts of abnormal neo vascular vessels and a typical franz of vessels and become very friable. They can bleed and cause scar tissue and further tissue damage. So that's the background on screening and why we get diabetic retinopathy and what it looks like. How do we manage diabetic retinopathy today? Well, it's not a simple binary decision. You don't go from no treatment to treatment with a simple one size fits all. As you can see from this table. Were recently updated by the American Academy of Ophthalmology in 2019. This is very nuanced. The treatment and the intervention very much depends on the severity diabetic retinopathy shown over here on the Y axis, on the first column, and then it also is dependent on the presence or absence of macular oedema. Shown in the second column here. And you can see that the treatments involve either laser, two different kinds of laser and or pharma co therapy. In most cases that is going to be anti by Jeff therapy. But what are the core pathologies that were actually treating well? Traditionally they have been diabetic macular oedema shown at the top here and I'm going to leave that discussion entirely. The doctor Rishi Singh, who's going to give a fantastic talk following this and then at the bottom, the second category of diabetic retinopathy that we have traditionally thought of treating is proliferated diabetic retinopathy. There is a third category that is that is continuing to show benefit with earlier intervention. And that is shown in the middle trajectory here. Non proliferated diabetic retinopathy, these our eyes that we traditionally would have observed. But accumulating data that I'll go through in a few slides is slowly encouraging earlier intervention for these patients on an individualized basis depending on their particular um status and individual risk factor scores. But the key messages we want to avoid eyes that look like this. This is what blindness from diabetes looks like. This is a traction little attachment with various chemical retina and very thick diabetic macular oedema and we really can prevent this if we catch these patients early enough remember current therapeutics, whether they're laser on the left here. Orange injections and medications on the right are over 90% effective at preventing blindness and the key messages. Of course earlier treatment leads to better outcomes if we see and I like this in the middle of course we're going to do everything we can to save as much business as possible. But it's very hard to go back to a well sided I at that point. Okay let's talk specifics. How do we manage proliferated diabetic retinopathy. First. First of all, it's important to realize that PR is a spectrum of diseases. We talk about it like it's one thing but it's not. If you look on the left here, this is a very mild early stage PDR. E. With 2020 vision. The patients actually completely asymptomatic and on the right is a very high risk PDR. E. With a superior traction of attachment, severe schema. You can see those dark areas in the periphery but of interest. The patient is also 2020 again making the point that vision should not be the driver to decide when to screen someone. And in many cases is is limited in its ability to help us make decisions related to intervention, especially when it comes to treating specifically PDR. So the core treatment that we've been using for two or three generations at this point is panorama photo co regulation on the right is a very sort of dense PRP pattern which is not used that frequently today anymore, leaving someone with really sort of limited peripheral visual function. But of course this I is very well cited and so you can call this a raging success given the severity of disease at baseline. But on the left is sort of a more typical PRP pattern and what that looks like immediately after application of that laser sparing much more of the poster pole and therefore sparing much more of the patient's visual field. But more recently we've learned that pharma co therapy is remarkably effective at improving diabetic retinopathy. So this is the high risk P. D. R. I on the left that is transformed into a mild NPD are on the right with multiple repeated intra vitriol anti valujet objections. But the key messages, what I just said, unfortunately, this is a chronic disease. There's no cure for this disease disease. Laser is highly effective and has a durable treatment benefit. The laser is not a cure. Many patients to receive laser will continue to need additional treatments over time and especially if an anti veg fr mickel therapy monotherapy approaches being used. We've seen great data now through over five years of follow up that even after regular therapy for five years, a large majority of patients continue to need regular antivirus Jeff injections to maintain the benefits achieved. These injections are not a cure their highly effective but they do wear off and need to be given repeatedly. Secondly, we often make this on podium a debate of laser versus medicine for proliferated diabetic retinopathy when really that's overly simplistic, these approaches are not exclusionary and we need to remind ourselves, in fact, the high quality prospective data that we have from protocol esque clarity. For example, in both of these prospective trials comparing laser with anti vet Geoff mono therapy, we actually saw that many of the patients were receiving combination therapy with both laser and anti Geoff therapy to achieve the best outcomes. And therefore this is the case example from my clinic for combination therapy was used of high risk PDR. I put in some degree of peripheral laser to stabilize the I but I'm not trying to completely eliminate the need of accusation which would take substantially more laser instead. On top of that laser, I use anti VFR mesotherapy at a reduced frequency, maybe every once every three or four months to keep the eye stable. In this context, compliance is critical to discuss. We've seen now multiple data sets. This one published out of a Philadelphia. I hospital called Wills, a fantastic treatment center there where they followed over 2000 patients of PDR for over four years and found that 25% of patients were lost to follow up. Um for at least uh one year, they specifically looked at patients receiving active treatment for PDR. So, a subsection of PDR patients. I actually did the same analysis in Houston. And truly the Apollo 13 quote at the top right there applies to this. We looked at over 4000 patients with PDR. Now this was all P. D. Are not just patients receiving active treatment followed for over five years and over half of them. A huge percentage were lost to follow up for at least a full year. During that five years of follow up compliance here is a challenge and that's why laser, which has a durable effect, is still an often used interventional agent. This is what noncompliance looks like. This is a patient of mine a 40 year old patient with diabetes who had nuance that floaters. I gave them a shot of an antiviral agent. The floaters went away because the antibiotic agents are tremendously effective in the short term. The patient unfortunately thought they were cured despite extensive conversations about the fact they needed repeated treatment that eventually laser, they were lost to follow up for many months and ultimately came back when they were blind because now they had recurrence of their proliferated disease. They have additional scar tissue formation and retinal detachment formation. Of course I operated on this. I and we regained a lot of vision but it's much better if you can avoid these transitions division loss in the first place. Let's switch gears and talk about management of NPD are at this point we talked about P. D. R. So we've learned, as I showed you in a few slides before the anti veggie therapeutics have a remarkable effect that improving diabetic retinopathy. And we now have two on label agents, kind of bizarre math flipper step for the treatment of diabetic retinopathy independent of DME status. And this is what some of these images look like when you treat eyes repeatedly, you see these hemorrhages literally melt, aware. And two large prospective data sets have really guided our discussion with patients related to the management of NPR and they are panorama on the left and the DRC our network Protocol W on the right. Both of these large prospective protocols over 400 patients panorama and over 300 patients in DRC. Our Protocol W When rolling patients with what I think of as high risk NPD are more specifically, it's moderately severe severe NPR. These patients did not have DME and most of these patients were very well cited 2040 year veteran panorama in 2025 or veteran P D R C R W. And patients were randomized to either antiviral therapy with flavor Cept or sham injections and followed for two years in Panorama and two years so far in Protocol W. But ultimately Protocol W will be a four year study. And the key message from both of these programs is highlighted on this slot. This is data just from Panorama, but there was remarkably similar data at a Protocol W which was with sham treatment. If you look at far left here, a majority of patients through two years here, almost 58% of sham patients will develop one of the clinically relevant pre specified secondary endpoints of proliferated diabetic retinopathy for center involved me. And that risk is dramatically reduced down to 18 to 21% with flavor step treatment. That's a 75 to 79% relative risk reduction in the likelihood of developing these events suggesting that earlier intervention in some patients will be beneficial. So what do we have looking forward? And this is my very last slide. This is sort of a teaser because we have fantastic treatments Today patients really deserve to be screened because if we can catch them early enough when they have early DME early PDR high risk NPR those are the eyes you want to be treating before they lose a lot of vision. But what's neat is that next generation therapeutics I truly believe are going to be even better if you look at the top right there's multiple longer acting antiviral agents and development. If you look at the bottom right, there's novel delivery systems for example the court delivery system that's a surgical implant that allows drug delivery for over many months to even years without being refilled and they can be refilled in the clinic. And then on the top left we have new mechanisms of action that were investigating specifically here Angie a poet and tie to listed the top and that molecule on the top there is farris a map. This is a by specific antibody that inhibits both the veg F. A pathway but also it inhibits Angie Patin to which leads to activation of the type two receptor. This this elegant molecule has now been studied in in two very large Phase three programs in both DME and the vascular and be with quite promising results, especially on durability. And we're hoping that maybe commercially available sometime over the next year and then bottom left, really sort of the the most exciting a topic out there I think from a patient perspective are these potential one and done therapeutics and gene therapy is asking that question current. There are ongoing trials in diabetic right now but the indian me looking at gene therapies to establish an intra ocular bio factory to produce these antiviral agents which can keep these i stable for years. Gene therapy is not near ready for commercial use, It is an investigation, but quite promising at this time, regardless of which of these. Move forward to commercial use. I think it's very clear that we're going to have additional therapeutics, additional options for surgical intervention, all sorts of options coming over the near and mid term time horizons. With that, I thank you for your attention and I appreciate the opportunity to participate today. Thank you.