00:00 All right, let's get started.

00:01 Thank you for coming.

00:03 This is the Medical Retina and Uveitis, session.

00:05 It's a case-based approach, so we're gonna have lots of cases for discussion.

00:09 My name is Rishi Singh.

00:10 It's a, a pleasure to be here back on the Big Island again, to this, part of the program, and we're gonna cover almost everything in the retina, hopefully you'll see this week in a very bite-sized package.

00:22 Here are the first sort of, audience response questions: How confident are you treating geographic atrophy secondary AMD with approved therapies?

00:29 All right, so lots of non-confident, not confident at all, somewhat confidence.

00:34 We've got some work to do here.

00:35 Next slide.

00:37 How often do you currently use new options to treat GA secondary to AMD?

00:40 Okay, many nevers, so let me see if I can help you with that.

00:45 I'm gonna give that talk on GA.

00:47 Next slide, please.

00:49 How confident are you using the extended duration anti-VEGF agents?

00:52 All right, so this looks like you're much more frequently using these drugs.

00:57 Next slide.

00:59 And how often do you currently use extended duration anti-VEGF in practice right now?

01:03 All right, and the answer looks like many of you are using frequently or sometimes, very few, rarely and never.

01:09 Next slide.

01:10 Okay, so first and foremost, I want to thank my co-panelists today, Sharon Fetkraut from Duke University and Steven Ye from the University of, Omaha, Nebraska.

01:19 Thank you for being here, at Drusen Eye Institute.

01:23 Really great to have you all here for this program.

01:25 I'm gonna cover geographic atrophy, and let's start off with, here are my financial disclosures for the presentation.

01:30 Let's start with some facts.

01:31 I think they're important to kind of level set what we know about GA right now.

01:34 About one point five million patients are, living with GA, which is really un- underdiagnosed, I think, in this population.

01:42 And despite the availability of therapies, only about fifteen percent of our total population is being treated actively with complement inhibitors.

01:50 I think the one misnomer in this disease state, which I hope to alleviate and give you some information on, is that GA is a progressive disease.

01:57 About one point six years after diagnosis, sixty-seven percent of patients lose their ability to drive, and that is a good, I think, functional endpoint for us to understand that.

02:05 In two years of diagnosis, fifty percent lose two lines of vision.

02:08 So these patients do lose a significant amount of their life activity of living through these, these sort of drugs and the- these sort of processes, processes over time, I should say.

02:17 And about seventy-seven percent of patients, report that GA impacted their vision faster than expected. And if we look a little bit at how we measure this, we have all these different measurement techniques, visual acuity, near-infrared imaging, color fundus photography, fundus autofluorescence, OCT.

02:32 And I'll talk about artificial intelligence, how it's enabling a lot of these technologies.

02:37 First and foremost, I'll say that vision is not a really good surrogate biomarker for GA.

02:42 And you can see this patient, who essentially was followed over many, many years within the, this, evaluation.

02:48 And you can see initially their vision dropped and then improved, and they're refixating their fovea, but essentially, this patient gives you a great example of why vision is probably not the biomarker.

02:57 We're following a lot of our GA patients because it is just, highly independ- dependent on the patient's responses and obviously can change over time.

03:05 We have great classification schemes that have been kind of popularized the past couple of years. There was initially the ARADs classification scheme, which kind of was, really basic in nature, but helped us first, first and foremost, determine who were at the highest risk of progressing, from intermediate AMD to advanced forms.

03:23 Now, we have the Beckman classification, which is on the right side.

03:26 In that case, we've now learned that things like druplets, which are very small drusen, about sixty-three microns in size, are actually considered pretty much normal without any pigmentary change.

03:35 And on the left side of the le- screen there, you see some of the common kind of definitions we all use, things like Irora and Ciorra.

03:43 Those are important, more used in clinical trial endpoints than in real clinical practice, but understanding where the atrophy is and how significant the atrophy is, is what these classifications try to do.

03:54 I mentioned Beckmans. Beckmans is a very important classification scheme because it first establishes that AMD is not always universally just with drusen.

04:02 There can be obviously the, the need of drusen and pigmentary changes in patients to call it AMD, and when you go on to developing those advanced forms, it's really the same kind of classification scheme as we saw for ARADs over time.

04:16 This CAM definition or consensus, of, of, macular definition, is what we, we were talking about just a moment ago with how we define geographic atrophy.

04:25 So from a, an endpoint of clinical studies, we look at GA as being a hypertransmission of two hundred and fifty microns or more, a zone of attenuation or disruption of the RPE associated with this. So you can see in this patient's picture here, if this pointer works, if it works-- Oh, yes, here.

04:43 You can see the total transmission of the OCT image through the patient's macula.

04:48 The zone of attenuation or disruption of the RPE is about two hundred and fifty microns, and there's ev- evidence of overlying photoreceptor dysfunction.

04:55 So you're losing both this RPE layer as well as the ellipsoid zone on top of that together.

05:00 So that really is Ciorra or, or what we call essentially geographic atrophy.

05:05 But y- the, the, the thing I would say is that we see so many patients, and this is just some of those patterns in what we see them come in, either multifocal, unifocal, large lesions, small lesions.

05:17 They can be subfoveal in nature, they can be extrafoveal in nature.

05:21 It's really a kind of a plethora of, of interesting findings for these patients that we see. And so it's important to understand kind of where this might help us in prognostication.

05:30 Not every patient progresses the same way, so maybe this can be a fingerprint at determining how we can do that, and I'll talk about that in a moment.

05:39 Here's another example of what we really learned in the past couple of years, things like drusen. Drusen are kind of universally thought of to be singular in nature or a part of AMD, but really there's a va- a whole host of different drusen types.

05:52 There's even a, a type called reticular pseudodrusen, which are irregularities above the RPE, but usually they're so-- they're, they're, parafoveola in nature, as you can see in this, this, patient on the left.

06:03 On the right side, you see the classic drusen, which are irregularities below the RPE.

06:08 Why is there a difference here?

06:09 Well, we know that reticular pseudodrusen, in particular, are mel-- most associated with geographic atrophy progression.

06:16 So if you can find these and see that these lesions are above the RPE, these will indicate this patient has a high risk of progressing to GA in comparison to the patient on the right, who's more likely to progress to neovascular AMD, so kind of differences there.

06:30 Probably, as I mentioned to you, I showed you a lot of different imaging techniques.

06:33 We use all of them together.

06:35 I think when we're really trying to make the diagnosis and decision of patients in our populations, we have fundus autofluorescence, we have color imaging, we use en face imaging for looking at, things like neovascularization with OCTA.

06:48 We obviously use the OCT to look for exudation as well, because that's the biggest risk of conversion of patients in these, both in the, treatment phase as well as the observation phase of these patients. So we use a lot of these together to help us determine what to do with these patients over time.

07:03 So what has been kind of the assessment of all of these sort of biomarkers we have, and how do we know a patient's gonna progress?

07:11 Because if you think about it from the standpoint of, of practice, you really want to treat those patients who are high progressors.

07:18 Many patients, or a few patients may be not progressing at all.

07:21 So how do we separate those kind of fast progressors from slow progressors?

07:25 Well, there's a larger baseline lesion, in some patients we can predict progression.

07:29 Multifocal lesions grow faster than unifocal lesions.

07:32 Perilesional hyperfluorescent patterns, banded or diffuse patterns, are, are considered high progressors.

07:40 Non-foveal locations grow faster than foveal locations.

07:43 This can be really helpful at looking at this, and then you can look at the fellow eye as well for their progre-- for presence of geographic atrophy, and again, some moderate evidence if they have neovascularization in one eye, that they'll have it in the fellow eye. But we're learning more about all of these sort of things and what they can do together to help us better risk stratify these patients over time.

08:02 This is where AI becomes, again, very helpful.

08:07 And what we've learned essentially through many different studies is that if you can quantify photoreceptors and RPE, that you can develop ratios.

08:15 And this is where AI really becomes helpful because this is truly not something we can do clinically, by our own measurement techniques.

08:21 But this is an example of one of those reports, that shows you that map of both the, photoreceptors in the green section, and in the blue section shows you the RPE.

08:32 You see that they don't exactly match, right?

08:34 So there is some advancement of photoreceptor loss ahead of the RPE loss.

08:39 This then produces a ratio which you can then see over time.

08:44 And here, what we can determine from that is when we look at those changes over time, there's various levels of changes in regards to what might those progress in patients.

08:54 One of the things we see in patients with drusen, for example, we see photoreceptors go get thinner, and hence they become geo-- they, they eventually form geographic atrophy.

09:03 We also know that drusen height actually goes down before you develop geographic atrophy as well. So we always thought that bigger drusen caused greater problems. What we actually realized through some of the studies was that as drusen are actually growing, they're also gonna collapse eventually, and once they start collapsing, that's when you have impending GA gonna come-- that's gonna come out in your patient population.

09:25 And from this, we also can determine these photoreceptor-to-RPE ratios, which are very valuable. So the highest quartile on the right versus the lowest quartile on the left, have very differential responses to some of our GA agents. So this is showing you that for every month and every other month patients, the progression-- the decreased progression of patients with these high ratios of photoreceptor to RPE have a greater response to the complement inhibitors.

09:53 So we can use this to tailor our therapy in patients, to determine who will need therapy and who will better respond to therapy.

10:00 You can see all patients pretty much respond, but those in the far right with this ratio respond fa- better than the other ones do.

10:09 So let's talk a little bit about the, approved inhibitors for complement, and where do we get the information from?

10:14 They come from both the drusen analyses we've done on post-mortem eyes, as well as from GWAS or gene as- w- associated wide studies on these patient populations.

10:25 And what have we found together with these patients together is that, if you look at oxidation in these patients, which can occur because of lifestyle issues, their genetic predisposition and environmental factors together, that they essentially form this chronic, low-grade complement deposition within the Bruch's membrane, the RPE, and eventually, these patients go on to developing either geographic atrophy or neovascularization. Since twenty twenty-three, we've had two approved agents for both C5 and C3 inhibition, so they've been out for a long time, and we have data on them now.

10:56 Let's focus first on pegcetacoplan, which is the first FDA-approved geographic atrophy treatment to market. This was an inhibitor of both C3 and C3b, a little bit higher up on that, complement, pathway, but prevented the downstream inflammation and, o-opsonization and cell lysis, which occurs from cells.

11:18 Excuse me. The Phase III OAKS and DERBY study had some pre-specified endpoints, thank you, that, w- were looked at.

11:28 This is a study that randomized patients to getting pegcetacoplan monthly, every other month or sham treated.

11:34 They had a primary endpoint at month twelve, with pre-specified endpoints at twenty-four months.

11:46 There was a, a three-year Gale open label study that was done for a five-year total span of these patients, which was really the largest- a population of patients with GA studied, over twelve hundred patients, in fact, were looked at over in the course of this trial.

12:03 So this is what they found essentially at twenty-four months, was that both in OAKS and DERBY, with every month and every other month pegcetacoplan treatment, there was a decrease in GA progression in these patients.

12:14 Again, preserving more retinal tissue, preventing the foveal involvement, all those things were involved in looking at this, these patient populations.

12:21 And in fact, that reduction in GA lesion growth by six-month periods, again, shows you quite a significant reduction over time, which increases over time over that twenty-four-month period.

12:33 Now, we talked about the location of these lesions, whether it be the subfoveal or non-subfoveal. Again, non-subfoveal tend to grow quicker than the subfoveal.

12:43 So in this population, was there a differential response in these patients?

12:46 And the answer was yes.

12:48 The non-subfoveal lesions were affected and, and, and actually reduced more with pegcetacoplan treatment versus-- thank you, versus subfoveal lesions.

12:58 So that was a really huge benefit in these patient populations, to see that there was truly a better o-outcome in regards to, the non-subfoveal groups, which gr-go quicker.

13:08 What about photoreceptor loss?

13:10 Again, we talked about how RPE cells are important and photoreceptors are important.

13:14 This, again, showing you both in DERBY and OAKS, huge reductions in both photoreceptor loss in the patient population.

13:20 So there is that anatomical preservation of tissue, which is wonderful to see in these patient populations.

13:26 One of the more important things, I think, this is a, one that I think has led to a little bit of controversy, is that, you know, we always think that these patients may not necessarily gain vision or at least have a, a better functional outcome.

13:38 And the answer actually was shown, is that if you can actually preserve their foveal center, that they actually have a better outcome in regards to their visual acuity.

13:47 And those patients who were in the PEG group versus the sham-treated group, the difference in visual acuity was about five letters by the end of twenty-four months.

13:56 Now, that again, is looking at those patients who had foveal and non-foveal involved lesions and seeing that there was foveal preservation of these lesions over time.

14:05 There was also some really great OCT-based sensitivity analyses, again, looking at, the preservation of the, of foveal tissue, and again, showing you very similar dose-dependent sensitivity pre-pr, preservation by microperimetry, which is a way we measure the center, points within the retina to see what the benefits are over time.

14:24 The safety data has been well known in this population.

14:26 We've seen patients with intraocular inflammation at a, a low rate, one in four thousand patients develop these IOI rates.

14:33 Lesser over successive injections, which is good to see.

14:36 It's usually the first or second exposure, which may lead to this, but again, the signal still exists in our population of patients.

14:43 Now, we have learned a lot about how we can manage these patients over time, and the extension trials have really shown, again, incredible, significant, persistent reductions in GA lesion growth over forty-eight months in these patient populations and preservation of tissue. So I think this is one where I always talk about with my patients when I'm ever discussing GA treatments, we can talk about this with our panelists, too.

15:06 How do you get a person to be convinced that complement therapy is actually going to benefit them? Well, you talk about tissue preservation.

15:12 How closely do we get to the fovea, and how much tissue can we preserve?

15:16 The answer in the study was about three point one six millimeters squared, which you can see right, located here.

15:22 For reference, a disc area is about two point five millimeters squared, and the foveal area is about one point seven seven millimeters squared.

15:29 So quite a large swath of tissue is preserved with these drugs over time.

15:34 Again, the con- the consistent concern with any complement therapy is exudation.

15:40 We see some patients develop, near occult or occult-like, like lesions in those patient populations, but overall, the IOI rates are point two three percent per injection.

15:50 Other rates are really quite low, and again, looking at some of the study results, they've been very encouraging to see low rates of these inflammate- inflammatory events.

15:58 Let's switch gears and talk about avacincaptad pegol.

16:01 This is a C5 inhibitor, a little bit farther downstream than C3, but has the same sort of, complement, alternative complement pathway inhibition.

16:11 This was studied in a very large, sorry, small GATHER1 study and a larger GATHER2 study, again, showing you randomization of patients to ACP, monthly versus sham and two different doses with a primary endpoint analysis, which was still the mean change in GA area from baseline at month twelve. This was GATHER2, a larger population of almost four hundred and forty-eight patients, just looking at that.

16:33 But both the studies showed the same thing, reductions in GA lesion growth, probably by numerically the same values that we saw with pegcetacoplan, and both studies very, not, not, easy to differentiate these two, over time.

16:47 But looking at month twenty-four, you saw continued benefit in these patient populations with ACP monthly and every other month compared to sham treatments over time.

16:56 In over twenty-four months, you saw a greater, mean GA lesion growth from baseline.

17:01 That was, again, showing you better tissue preservation in these patient populations over time. And looking again at those post-hoc analyses of the vision, here you see a reduced rate of severe vision loss of up to three lines, which is good to see, and again, showing you that those patients, had less of a chance of developing both ten letter losses, twenty letter losses, and even fifteen letter losses in these patient populations over time.

17:26 There's been a lot of good, data on the safety of GATHER, two, over twenty-four months, the IOI and CNV rates.

17:33 CNV rates are similar to what we saw with pegcetacoplan, around ten or so percent after two years, but the IOI rates were, actually slightly better, than we saw in any other population, only one patient developing an IOI rate in, GATHER2, in, in that population.

17:49 And there's recently been this open label extension, which showed again, a twenty-eight percent reduction over a forty-two-month period.

17:56 Again, I'll say this much, that the number of patients in this population goes down precipitously.

18:01 It-- the retention rate is difficult in these patient populations, as you can imagine, but yet still showing a benefit in these patient populations over time.

18:09 And again, just showing you the reduction in, in these patients, in regards to their, progression at that rate....

18:16 Let me just fast forward to kind of the ASRS and the REST Committee and what they've been able to show, and essentially that they've been monitoring both drugs at this given stage.

18:25 No real change as far as what they've been able to report in the REST studies overall.

18:29 They do look at the real world experience i- in a lot of different studies.

18:33 Recently, it's been showing us that there's still that same rate of IOI, in, those patient populations. This is from RCA, Retina Consultants of America, which showed very, very so- good safety results for pegcetacoplan and more impressive results, again, for avastin captategol, with zero cases of IOI in these patient populations over time.

18:53 So just to summarize, this is a relentless progressive disease.

18:57 I, I want you to leave with that information, I think, first and foremost.

19:01 We have drugs that are available for us to use now.

19:04 They've been around since twenty twenty-three.

19:06 We have good five-year data with pegcetacoplan.

19:09 We have, we have good data from ACP as well, of up to forty months now.

19:14 We see that there's benefit in treating these patients in regards to t- tissue preservation and functional endpoints.

19:20 I think that that's, again, another misnomer in our patient population.

19:24 And the real world data on safety efficacy is really growing, and we're learning a lot about what we can do with these drugs in our population.

19:30 This is some of, you know, the-- just the limitations, I'll just say, and the-- I've mentioned to you before, only a subset of our patients are currently on these drugs, and that's because there's just a lot going on in regards to treating these patients monthly or every other month. And again, because there's no vision bump and only preservation of tissue, some patients are less motivated than others to continue.

19:51 But we have some really great future targets, which I'm not gonna go into for time.

19:55 They'll be covered, I'm sure, during the Retina Abstract Sessions, as well as our Retina Sections, during the week, but lots of different ones to do.

20:02 And but just to show you kind of a timeline of these drugs, they're really a couple of years away. So I think a- the call to arms right now is those drugs are not gonna come out till potentially twenty twenty-eight or beyond.

20:14 And so we have drugs right now in our practice, so I would not recommend waiting two years before instituting these therapies in your own clinical practice, in your own hands.

20:23 So we talked about this again, and I will pause there, and happy to take questions.

20:28 So, Steve, just love to listen to you and hear about how you incorporate GA in, treatments into your patient populations.

20:34 We'll ask the same of Sharon.

20:36 Yeah, no, I think that's a really, really fascinating talk.

20:38 I think that just as you mentioned, just the importance of, of having these metrics, both fundus autofluorescence, also spectral domain OCT.

20:45 And the other thing that we're learning about, other things we've talked about before, like low luminance visual acuity, which we don't ordinarily- Yeah ... test.

20:50 I think that, I think a lot of it is like patients are realizing the, the, the importance of, I mean, these, obviously, these medications from a lifestyle perspective, as you nicely showed.

20:59 But I think that if, especially if patients have af- one affected eye, they're more inclined to move forward with, GA therapy. Yeah.

21:06 But that being said, just again, knowing the be- the, the risk-benefit ratio and the potential for vision preservation, I think is extremely- Yeah ... important.

21:13 Sharon, I remember the one of the first patients I treated with pegcetacoplan came back and said, "My vision is better." well, how do you kind of manage that expectation from patients? 'Cause that's something they're always looking for, right, is to say that vision is better after these treatments. Right.

21:27 Well, I have a patient, too.

21:28 He swears his vision is so much better after he first got his first, pegcetacoplan injection. So I try to emphasize to patients prior to treatment and during treatment when they say, "Hey, doc, is it working?" Yeah.

21:40 Cause currently, it's very difficult for us to determine if these complement inhibitors are actually working because it just slows down the geographic atrophy.

21:50 It doesn't stop or reverse it.

21:52 But I do remind them that our goal is to slow down the process to allow them to, you know, maintain or preserve some visual acuity for as long as possible.

22:02 Yeah, that's great.

22:03 I just have one, one- Yeah ... Just comment related to that.

22:05 I just think that as we think about our patients, and the conversation that we have prior to GA therapies, it's always like, even if we, we saw for, like, say, we follow up in six months and we don't necessarily did-- see the difference, they know that their visual acuity has gotten worse.

22:18 It's always like, "Doc, I've gotten worse." Yeah.

22:19 Now that we have therapies, we have a chance to slow or, yeah, slow down the process.

22:23 Yeah, and I know the companies are working on a way for us to potentially monitor these patients or give them a report.

22:28 That would be, I think- Yeah ... Very helpful and encouraging to kind of continue that therapeutic option, 'cause I think many of them are sometimes difficult to keep, you know, going on therapies if they don't see benefit. Yeah.

22:38 Right, and I'll also add, it's really important to, at the very least, mention the complement inhibitors to your patients.

22:45 I know there's a case or two out there where the patient is filed litigation against their physician, who didn't necessarily believe in complement inhibition, after they lost their visual acuity from geographic atrophy and th- claiming they didn't know- Yeah, ...

22:59 That that was an option. Yeah.

23:01 All right. Well, thank you.

23:02 I'm gonna have-- turn this over to Sharon Fetkrath.

23:04 She's gonna c- talk about current management in diabetic retinopathy and diabetic macular edema. Thanks, Sharon. Wonderful.

23:10 Thank you. So many of our patients have diabetes, so it's really important to, understand what the current management is.

23:17 So let's roll.

23:19 These are my disclosures.

23:22 So we're gonna start out with a case.

23:24 This is a sixty-eight-year-old pseudophakic female with non-proliferative diabetic retinopathy and center involving diabetic macular edema.

23:32 The visual acuity was twenty/eighty.

23:34 We didn't obtain fluorescein angiography.

23:37 We did not consider focal or grid laser, as first line, and we were thinking about the Diabetic Retinopathy Clinical Research Network Protocol T results, whether we should start with aflibercept or bevacizumab.

23:51 And so for this patient, step therapy was required.

23:55 And so the American Society of Retina Specialists Preferences and Trends survey, said: "What is your preferred first-line anti-VEGF agent for diabetic macular edema and visual acuity worse than twenty/forty, with no payer access restrictions?" So this is for patients who did not have step therapy required but otherwise fit the bill of our patient. And you can see here, about forty percent of, retina specialists who responded in the United States, wanted Eylea or aflibercept two milligrams, and the about thirty percent were interested in fair, faricimab or vabysmo....And so then, what percentage of your patients require step therapy for anti-VEGF, ah, VEGF agents?

24:41 And that was asked to both US and international retinal specialists.

24:46 And about sixty percent of US retina specialists answered that less than half of their patients require step therapy, whereas eighty percent of international retinal specialists answered that less than half of their patients require step therapy.

25:00 So step therapy is more common in the United States, as in our patients.

25:05 So we started with step therapy, which mandated bevacizumab, and that's not what the DRCR Protocol T recommends.

25:13 So we started with bevacizumab, since this patient's vis- vision was, twenty/eighty, and she got three monthly injections, and there was some improvement of the DME, as you can see, but there was still some that remained.

25:30 So now what? Well, we decided then to finally switch to aflibercept two milligrams monthly for three injections, and there was still some DME improvement.

25:39 But how can we drive further and also improve durability?

25:45 Well, according to the ASRS PAT Survey, you know, how would you treat a DME patient with an inadequate or suboptimal response to three or four monthly anti-VEGF injections?

25:55 And you can see that about seventy-five percent said, "Well, I'll just switch to another V- anti-VEGF agent." So that's what we did.

26:04 So we tried faricimab, gave the patient four monthly loading doses of faricimab per the Yosemite and Rhine studies, and this is a previously treated eye with DME.

26:16 And so now that we got this great response, you can see the drying effect, after the four monthly loading injections.

26:23 Now we're aiming to treat and extend and aim for the twelve to sixteen-week intervals.

26:30 So, as we all know, diabetic retinopathy is very prevalent.

26:34 There are about ten million, individuals in the United States that have diabetic retinopathy, and the incidence and prevalence are doubling.

26:44 Diabetic retinopathy is still categorized as either no visible diabetic retinopathy, non-proliferative diabetic retinopathy, and I think in the clinical setting, we don't really try to subdivide it into mild, moderate, or severe, and then proliferative diabetic retinopathy, as shown here.

27:03 Now, diabetic macular edema can occur at any stage of diabetic retinopathy, and it's more likely to occur as the diabetic retinopathy progresses.

27:12 We now are basically dividing, diabetic macular ed- edema into center involving and non-center involving, based on the OCT, so it's becoming an OCT diagnosis.

27:24 And you can see here, it's either non-central involving here at the top or center involving on the OCT. So let's just mention laser pho- photocoagulation, which has been around for a very long time, and it was the gold standard until two thousand and five when anti-VEGF became available.

27:44 And so on the, left, you can see, a patient prior to focal or grid laser treatment with a lipid ring, and then four months after the focal laser was delivered, there's some improvement. And so laser is rarely used now.

27:58 Sometimes it's used in conjunction with intravitreal pharmacotherapy in just some eyes.

28:04 You know, there are a lot of challenges with focal grid laser.

28:07 It destroys retinal tissue, creating, blind spots.

28:11 It's slit lamp delivery, which takes more time, and there's often no view of the guiding fluorescein angiogram right next to you, and it's just awkward positioning.

28:20 You have to focus manually, and it really is dependent on the physician and the patient.

28:26 Now, we all know that retinal hypoxia in diabetic eyes leads to increased vascular endothelial growth factor, and that contributes to the retinal capillary leakage, leading to diabetic macular edema and ischemia that leads to, neovascularization.

28:44 And it's been shown multiple times that VEGF levels are indeed increased in the vitreous of eyes with diabetic macular edema.

28:54 And so the current landscape has a lot of intravitreal, treatment options for diabetic macular edema.

29:00 There are the first-generation anti-VEGFs, and you'll see, we think about these agents, as with other things, in the order they come to market.

29:08 So there's bevacizumab, which remains off-label, ranibizumab, that now has a port delivery option, which I'll talk about, like a little gas tank implanted into the eyeball, and then aflibercept two milligrams.

29:20 There are so many biosimilars, we can't really keep track of them at this point.

29:24 And then there are the second-generation anti-VEGF agents, brolucizumab, which is rarely used because of safety concerns, and then faricimab and aflibercept eight milligrams. And then, of course, our plan B, and for some, plan A and combination therapy are the steroid options listed here, including the dexamethasone implant and the fluocinolone implant.

29:48 So talking about intravitreal anti-VEGF, we know it does improve retinal anatomy, it reduces progression of DME, it leads to significant visual improvement in many individuals without underlying, macular ischemia, and does, decrease the diabetic retinopathy severity scale score, by really getting rid of visible diabetic retinopathy in some eyes. So the first-generation, agents are bevacizumab, if I men- as I mentioned, which became available in two thousand and five for intravitreal use after some of the pioneering work by Phil Rosenfeld at Bascom Palmer.

30:28 It's a full-length, monoclonal antibody against VEGF.

30:32 And then ranibizumab is an antibody fragment....

30:36 To VEGF from the same parent mouse antibody as, bevacizumab, and the Rise and Ride studies led to FDA approval in, two thousand and six.

30:46 And then aflibercept, the Vivid and Vista Phase III trials, led to FDA approval in two thousand and eleven.

30:55 A- aflibercept is a decoy VEGF receptor.

30:59 So we're gonna focus, for the purposes of this talk, on the second-generation anti-VEGF, F agents, including aflibercept eight milligram, that was FDA approved in twenty twenty-three, from the Photon trial data, and then faricimab, that was FDA approved in twenty twenty-two from the Yosemite and Rhine studies.

31:21 And so aflibercept, we'll start with that, which is the eight milligram, and remember, the standard non-high-dose aflibercept is two milligrams.

31:29 So it's a fully human recombinant fusion protein, and it binds to VEGF-A and B and placental growth factor.

31:37 It delivers a fourfold higher molar dose and a slightly higher volume of point zero seven cc's, compared to the aflibercept two milligrams.

31:48 And it's led to improved functional and anatomic outcomes at intervals, often, twelve weeks or longer.

31:57 And so I'm not gonna get into the weeds on, of this, but I'm gonna give you the high-level overview so you can actually remember a thing or two from the talk.

32:05 So the Photon Phase III trial for the aflibercept eight milligram for DME, it was treatment-naive patients that were enrolled and also previously treated patients.

32:18 There were three, arms.

32:20 It was the aflibercept eight milligrams given every sixteen weeks after three loading doses every month, aflibercept eight milligrams every twelve weeks after three monthly loading doses, and compared to aflibercept two milligrams given every eight weeks after five monthly loading doses.

32:40 The primary endpoint was forty-eight weeks, and the study ended at ninety-six weeks.

32:47 And so both aflibercept at, eight milligram groups achieved similar visual acuity gains to the aflibercept two milligrams at ninety-six weeks.

32:59 You can see here that on the left of those patients randomized to the aflibercept eight milligram every twelve-week group at baseline, eighty-eight percent were able to maintain the twelve-week or longer, dosing interval.

33:15 Of those randomized to the aflibercept eight milligram, sixteen-week, group at baseline, eighty-four percent were able to maintain the dosing interval of sixteen weeks or longer.

33:28 And for the entire eight, milligram aflibercept group, eighty-nine percent maintained a dosing interval of twelve weeks or longer through week ninety-six. The outcomes were comparable across the treatment groups within the subgroups of patients with or without prior diabetic macular edema treatment.

33:51 The visual acuity gains trended, as you would expect, a little bit higher across all treatment groups in patients without prior, DME treatment, so the treatment naives did a little bit better.

34:06 And there were also similar proportions of aflibercept eight milligram given every twelve weeks, and eight milligram every sixteen week patients, maintaining the twelve-week or longer dosing through week forty-eight, irrespective of whether they had prior DME treatment.

34:27 Now, the improvements in visual acuity and the central retinal thickness, so the functional and structural, structural improvement through week forty-eight were comparable across all three treatment groups.

34:40 The majority of the aflibercept eight milligram-treated patients maintained their dosing intervals, as I had shown earlier, through week forty-eight.

34:51 Now, we'll go ahead and talk about the faricimab from the Yosemite and Rhine studies.

34:59 So faricimab is a little bit different.

35:01 So it's a bispecific antibiotic-- antibody targeting Ang2 and VEGF-A, as you can see here. So it's one molecule with two signaling pathway targets for vascular stability and efficacy that is durable.

35:18 So the Yosemite and Rhine trials were for faricimab six milligrams for diabetic macular edema, and this also had treatment-naive patients and previously treated patients.

35:30 The three arms of the study were the faricimab six milligrams given every eight weeks, the faricimab six milligrams given in a treat and extend, and these are the, loading doses, so there were six loading doses monthly, then four loading doses monthly.

35:47 And then for the third group in arm in the study was the aflibercept two milligrams given every eight weeks, with five monthly loading doses.

35:57 The primary endpoint was fifty-two weeks, and the study ended at ninety-six weeks.

36:05 So the vision gains through year two were similar among the three groups in Yosemite and Rhine, comparing the faricimab every eight weeks, faricimab treat and extend, and aflibercept, two milligrams every eight weeks.

36:21 There were also reductions in the central su- subfield thickness, and it was similar among the three groups in Yosemite and Rhine through year two.

36:32 And about eighty percent in the pooled faricimab arms achieved, a dosing interval of twelve weeks or longer, and sixty-two percent, as you can see there in the year two on the right, achieved a dosing interval of sixteen weeks or longer through year two.... Now, some interesting post-hoc analyses of Yosemite and Rhine showed some interesting findings.

36:58 There was a greater reduction in hard exudate volume and count in the three-millimeter central subfield, with faricimab given either every eight weeks or treat and extend, compared to aflibercept through year two.

37:13 Also, there was about a fifty-two percent risk reduction of epiretinal membrane formation in eyes receiving faricimab, compared to aflibercept through year two in this post-hoc analyses. And there was greater reduction in the hyperreflective foci volume with faricimab, compared to aflibercept through forty-eight weeks, and you can see some nice, images there on the right.

37:39 And there was also a greater reduction in macular leakage area with faricimab, compared to aflibercept at week sixteen.

37:48 Now, there's also the Rhone X extension trial, which was the long-term safety and efficacy of faricimab treat and extend in DME through year four.

37:59 So it added two additional years to the, Yosemite and Rhine studies.

38:06 And so the vision gains and central subfield thickness improvement in Yosemite and Rhine were maintained in the Rhone X study at four years.

38:16 Over ninety percent had no diabetic macular edema at the end of Rhone X at four years, regardless of prior treatment arm.

38:27 And also, seventy-eight percent in the prior Q eight-week faricimab treat and extend, and the faricimab treat and extend made it to every twelve or sixteen-week interval.

38:40 And a very similar, finding for the prior aflibercept, now faricimab, treat and extend group. so what else is there?

38:51 Anti-VEGF injection now in some eyes can be given every thr-- every three or four months with these second-generation anti-VEGF agents, and it's not too bad.

39:00 But what else is there to try to improve durability?

39:04 So the Pagoda for DME and the Pavilion, NPDR trials looked at the ranibizumab port delivery system, which I mentioned earlier, as the little gas tank.

39:16 And that's the continuous delivery of ranibiz- ranibizumab, that you refill the gas tank, every six months, so twice a year, w-- and that was found to be non-inferior to monthly intravitreal ranibizumab.

39:29 That was recently approved by the FDA for both DME and diabetic retinopathy.

39:36 But as we all know, there remains a small, real-world risk of endophthalmitis or retinal detachment any time we enter the vitreous cavity.

39:46 Also, the Altitude study is a Phase II trial for the supracochleal drug delivery of gene therapy for non-proliferative diabetic retinopathy with or without DME, and this is ongoing. There's also the Phase II Elevate, ongoing for subretinal delivery, for DME, and then there are several others ongoing.

40:10 So what about anti-VEGF for diabetic retinopathy?

40:13 Because we've been talking a lot, a lot about diabetic macular edema.

40:18 And so there's a lot out there, and I'm gonna give you the take-home points from the, DRCR protocol W that looked at aflibercept for NPDR.

40:27 And there was no significant difference in visual acuity outcomes between early aflibercept compared to observation with treatment once PDR developed.

40:39 There's also the Panorama study, and had-- it had a significantly lower proportion of patients in the aflibercept arms that developed vision-threatening diabetic, retina complications or center involving, DME.

40:56 And we have to mention corticosteroids.

40:59 So we know, steroids reduce many inflammatory cytokines, including VEGF in some cases, and Ang II. there are numerous inflammatory mediators in eyes with diabetic macular edema, and many are not specifically target- targeted by the anti-VEGF agents that we have available to us.

41:20 Intravitreal triamcinolone with preservatives is not indicated for intraocular use, although it can be used for sub-Tenon's delivery.

41:29 And triamcinolone without preservatives is also not specifically FDA-approved, for DME. the dexamethasone biodegradable intravitreal implant, for the MEED study is FDA-approved and available, and there has been shown to have significant improvement in eyes with, DME using this dexamethasone intravitreal implant.

41:53 But of course, the steroids have an increased risk of cataract development and progression, as well as increased intraocular pressure.

42:01 But studies have shown for, dexamethasone that there's a very low frequency of incisional surgery. Following the fame Phase III study, we also have the point nine milligrams fluocinolone injectable implant, which is not biodegradable.

42:19 It is thought to last thirty-six months once you inject a single one into the eye.

42:24 But in the real world, we know that it may require boosts of anti-VEGF or dexamethasone along the way. So this is FDA-approved for the treatment of DME in eyes that have been previously treated with corticosteroids, without a significant rise clinically in intraocular pressure.

42:44 And then we also have the New Day clinical trial that was assessing the efficacy of the fluocinolone implant as baseline therapy in treatment-naive eyes with early DME....

42:56 And it did extend the time to the first supplemental boost injection, and in post-hoc analysis, reduced the overall injection burden.

43:07 And then, of course, there's the very much sought after topical dexamethasone, and the Phase 3 study called DIAMOND, has been completed, and we're waiting to see, what it shows. So what is the greatest challenge we face in treating our patients with DME?

43:24 Well, you can see here, forty-one percent of retina specialists in the US said it's the prior authorization- -that is really getting in our way, and patients that get lost to follow-up. So just some take-home points is early intervention in vision-threatening DME can prevent long-term visual acuity loss.

43:44 This is your doggy bag.

43:46 Good visual acuity DME can be safely observed.

43:50 Laser is no longer first line for DME, but it often remains that way for proliferative diabetic retinopathy.

43:58 All anti-VEGF agents can improve visual acuity.

44:02 Keep treating persistent DME because the vision can still improve, and eventually seems to. Adding steroid to anti-VEGF does not always translate into improved visual acuity.

44:14 Steroid adjuncts do carry a higher risk of cataract and intraocular pressure rise, and missed visits are associated with the worst visual acuity.

44:25 Thank you.

44:26 That's great.

44:32 So, a couple of good questions here.

44:34 What's the mechanism for ERM reduction for afarinimab, and does DME cause an ERM?

44:41 I don't know if we know that one, but certainly the afarinimab data is kind of interesting for that. Yeah.

44:45 So we really don't know.

44:46 There's some thought that maybe the Ang-II inhibition plays a role.

44:51 You know, any of the eyes that have breakdown of the blood retinal barrier, including eyes with retinal vein occlusion, eventually, we start seeing epiretinal membrane formation, and then we ask ourselves, "Hmm, should we do a vitrectomy and remove it?" because we know that the intravitreal pharmacotherapy doesn't, have the same duration and durability after a vitrectomy. Mm-hmm.

45:11 There's a good question here. Just I, I think it's a nice one to talk about because we just talked about two intravitreal drugs and GA and neovascular AMD.

45:19 What do we do for prep?

45:20 Do you do lid scrubs?

45:22 Do we do betadine?

45:23 There's, chlorhexidine.

45:24 Is there any consensus you want to talk about for that?

45:27 Oh, yeah, I can, mention, and then Steve- Yeah ...

45:29 If you'd like to chime in.

45:30 I think, I am a betadine, betadine, betadine person.

45:35 Even in those that get-- You know, people are never allergic to betadine, right?

45:40 They are, have sensitivity to it in terms of irritation.

45:44 So I love my betadine, and I think it's really important to use some sort of antiseptic.

45:50 And recent studies have come out that's shown that, you know, others, like chlorhexidine and others, may indeed be, you know, close- Mm-hmm ...

45:57 To betadine.

45:59 And, once PDR develops, there's, there's no difference in efficacy between the anti-VEGF agents. I think that's the question. Mm-hmm.

46:06 Is there a difference, you think, in the, the difference in the anti-VEGF agent?

46:10 I don't think that there's much of a difference, or at least we don't know yet.

46:13 Yeah, we really don't know.

46:14 I think any anti-VEGF, can be used for, you know, trying to treat PDR and keep it quiescent. I feel like every maybe four months, you could get away with that, or even just twice a year, if you didn't want, or the patient, for some reason, didn't want, PRP.

46:31 But then they get lost to follow up and come back, and we're never happy.

46:35 And I, and I would just add that, perhaps because it's the durability question and related to patient follow-up and some of these very important, really, really important iss- issues you mentioned related to access follow-up, that, that even if they get treated, then then to know that that their follow-up is also very important and really just, just figuring out how to manage that. Yeah. Okay.

46:52 And then the last question was related to my talk, but I think, Steve, you're better suited for this because it's a Uveitis question.

46:58 So if you have a patient with IOI after intravitreal injection Actually, both the talks might have had that. If you have IOI, their IOIs are low in AMD, the DME population, but may be higher in the, the, GA drugs we talked about.

47:11 What do you do, number one?

47:13 What's the consensus, how you take care of these patients, and what percentage of patients, you know, get better, if you know that?

47:19 Yeah, so I mean, I, I would say that, very, very important question because we, we think about IOI after any intravitreal injection.

47:25 And so the first thing I always think about, is there any chance this could represent an infection? Mm-hmm. versus we talk about IOI-associated, IOI/vasculitis. But I, I've seen some patients who were referred in for a, an immunologic phenomenon, but they ended up having, like, a staph infection. So I, I exclude that, and then I treat with a topical corticosteroids if once we've excluded infection.

47:45 And I think then the next question is, what agent, you know, do we use?

47:48 Do we go back to the same agent?

47:49 Do we switch?

47:51 I, I-- Sometimes I, I will lean towards switching, in these situations, but if this is a medication that's been helping them, then I'll just talk to them about the risk-benefit profile and then move forward.

48:00 Mm-hmm. Yeah. Great. I'll just chime in. I'll just add- Yeah ... You know, if a patient comes into your clinic, you know, and your retina specialist down the hall is not available and had, they had just gotten an injection, and you see anterior chamber cell, you can say, "Oh, it's probably sterile inflammation.

48:15 Maybe it's IOI, intraocular inflammation," but you never want to miss endophthalmitis.

48:21 So I'll-- In that situation, when I see a patient like that, and I don't know what you all do, but I would perhaps start a topical steroid- Yeah ...

48:29 And then maybe have them wait until the end of the day and see me or stick around, and then, it'll usually declare itself, but follow them very, very closely.

48:39 That's great. Thank you.

48:40 Great job. ...Okay, so I'm gonna focus on, new and emerging treatments for neovascular AMD.

48:52 First and foremost, thank you for coming.

48:55 I know the Bills game is on right now.

48:57 It's twenty-four, twenty-three, in case anyone wants to know the update.

49:00 It's fourth quarter.

49:01 I think everyone wants to watch the Forty-Niners game at three thirty, so we'll try to get you out for the Forty-Niners game.

49:06 My apologies to the speakers after me.

49:08 But, I'm gonna talk about the new and emerging treatments for neovascular AMD, what we've learned. Here are my relevant financial disclosures for the presentation.

49:16 So what we've learned in neovascular AMD treatment is that, first of all, frequency matters. The number of injections that are given within the first year of this treatment are, are quite, ah, differential.

49:27 If you look at this from the IRIS registry, we see this retrospective analysis that patients can get anywhere from, from, a single injection all the way up to thirteen injections in a single year.

49:37 So they-- there are a lot of people that get a high frequency, but the mean tends to be about seven or eight within the first year, and that every injection really matters in regards to visual acuity. So I just showed you the, the number of injections they get, and here's what the outcome is in regards to mean improvement in visual acuity.

49:53 In order for you to even maintain vision, you have to get six to seven injections per year.

49:57 And in fact, I did a retrospective analysis a while ago on some of the VIEW data and saw the same trend. If you got patients who had, in the second phase of the study, really high levels of PRN therapy, they were the patients who actually did the best, versus those patients who were on the lower end of the scale, actually did the worst as far as visual acuity.

50:16 What, what are the, ASRS questions in regards to unmet needs in this category?

50:20 It's just like, Sharon, as, Sharon had said.

50:23 They didn't ask the question about, prior authorization, though I'm sure that would have ranked up as number one.

50:28 But the great, really big issue was, greater durability was the biggest problem that we all face, and long-term anti-VEGF suppression is one of the other ones faced.

50:37 And again, we have all these new drugs that have come out recently.

50:39 Brolucizumab was out for a while for better fluid control.

50:43 Faricimab, obviously, we've shown some data on better fluid control for DME.

50:46 I'm gonna talk about AMD now.

50:48 Aflibercept eight milligrams, we've had as well as, as well as port delivery system over time. Here are those three newer agents we have, FDA approved. They differ as far as their indication.

50:59 One update to this slide is ranibizumab port delivery is not only approved now for neovascular AMD, but it's also approved for diabetic retinopathy and DME.

51:07 So that's a little bit of an old, older, ar- area of the slide.

51:09 So we have to, That is a difference now with the new, new, approval.

51:14 But the rest of these drugs are all approved for their indications, and RVO obviously is forthcoming, for our aflibercept eight milligram groups as well.

51:23 So let's talk about eight, aflibercept eight milligram for neovascular AMD in the PULSAR study. This was sort of an interesting trial.

51:29 It was sort of a set it and forget it.

51:31 They compared two milligrams, given three initial doses by follow-up by every eight weeks, versus eight milligram groups, had three initial doses, even given, then given every twelve to sixteen weeks.

51:41 So a little bit different as far as their overall design, and you can see here the outcomes in regards to mean of visual acuity at, week forty-eight, which is the, primary endpoint, and then week ninety-six, which is the extension.

51:54 On the bottom, you see the anatomy improvements, again, pretty much equal across the board. So the big so what here is that these drugs performed equally as well with less frequent dosing with eight milligrams, which I think is very impressive to see, you know, twelve or even sixteen weeks of dosing frequency over the study. And in fact, they tested this even further in this PULSAR extension trial, which looked at long-term dosing these patients and really found the same continuation of improved visual acuity from baseline with less frequent dosing over the course of the trial.

52:25 The retinal thickness, again, nice response, seeing that i- infrequent dosing.

52:29 You might suspect in an infrequent dosing format, if it wasn't effective, you'd see sort of a seesaw pattern.

52:35 You didn't see that with these drugs.

52:37 So again, showing you both in the PULSAR and the PULSAR extension, that eight milligrams was able to cause enough retinal thickness suppression to keep that retinal thickness under control for the course of the study.

52:47 This is, I, I think, a really impressive slide, and I- I'll show you the one on the far right there, which is that the patients who ended the trial, at, at this hundred and fifty-six-week endpoint, which again is a, a long-term study, eighty-three percent of them who were in the study actually were Q twelve and beyond.

53:06 Sixteen percent actually were, were Q sixteen, thirty-seven percent were actually Q sixteen weeks and beyond, and there were actually proportions, even Q twenty and Q twenty-four weeks and beyond.

53:16 So really quite impressive data from aflibercept eight milligrams, which I don't think we've ever seen really in clinical practice per se, but nice to see that there is a trial benefit to show that there is patients who can be extended.

53:28 These are the ocular adverse events.

53:30 Thankfully, all very benign, related to the injection per se, not related to the study drug, but overall showing low rates of inflammation or uveitis.

53:38 Again, slightly different as far as the volume that's given for eight milligrams versus, the two-milligram dose, but again, no significant adverse events seen during the course of the study. ALLARA is a, trial that was conducted really to look at, the, increased frequency of dosing with eight milligrams and if there was, again, a safety signal or concern so that people could use this drug more effectively in the less than a week category.

54:03 And what they essentially did was the first, twenty-four weeks of the trial, they had-- they gave, these patients essentially, every four week injections and then went on to a treat and extend criteria per, disease, management at the course of the study.

54:17 And what they found essentially was, again, over twenty-four weeks, good improvement in visual acuity and good improvement in OCT thickness.

54:23 One main caveat of this study was these patients were previously treated, and that's why you don't see that big jump in visual acuity, and hence that's why you see a modest improvement only in visual acuity and OCT thickness, albeit it's quite meaningful to see this improvement over time....Spectrum is a real-world analysis of eight milligram, patients across many different countries.

54:45 Again, they're gonna be doing this study from a, a standpoint of looking at the, outcome for both DME and AMD.

54:51 They have some recent data, that's been shown with a mean improvement in visual acuity of those patients who switched to eight milligrams of about three point five letters better. Well, we-- after three injections, which is good to see. Again, the absolute vision is shown on the right, but the mean improvement, and, and net vision improvement is shown on the, on the right side.

55:09 And again, the OCT thickness showing you a, a greater reduction in OCT thickness, again, in a previously treated population, of patients who were there.

55:17 So, quite a nice, again, benefit to our patients to see eight milligram being very effective in the large patient populations.

55:24 And there's an ILLUMINATE study, which again, is a nice registry analysis of both AMD and DME with the IRIS registry.

55:31 A lot of patients here, forty-five thousand neovascular AM-- AMD patients, and when you break it down, you see a lot of them were switcher patients more than they were treatment-naïve patients.

55:40 And again, showing that there was a mean improvement in visual acuity of about four letters, and the mean injection interval was about twelve weeks.

55:48 So showing you again, in a real-world study of the IRIS registry, that there is benefit in these patients over time with, with eight milligrams as well.

55:56 And again, the intervals, of the injection are really Q12 and beyond in these patient populations you see after the course of the study, which again shows an extension of about two weeks per patient.

56:07 So every patient have pretty much experienced a little bit of a bump as far as their interval of extension prior, but about two weeks was the one that was seen.

56:15 Let's switch gears and talk about faricimab.

56:17 Faricimab, obviously, well, talked through by, by Sharon.

56:21 It's a bispecific, but TONI and LUCERN were our studies to look at for neovascular AMD.

56:27 A little bit different in design, but essentially against aflibercept, two milligram Q8 versus faricimab up to Q16 weeks, seeing that there was a nice improvement in visual acuity across the board, and again, a reduction in retinal thickness across the board, comparable to a more frequently delivered drug, which is good to see.

56:45 The average visual acuity at the end of the, a hundred and twelve weeks was about four letters. Some might say that this visual acuity is waning off, but I would also tell you that more-- many of these patients were twenty/forty or better.

56:57 We're enrolling studies now for neovascular AMD, where we see patients who are coming in with the better, best vision they ever have.

57:02 So these are tough studies to keep, patients with a, you know, gain of five or ten letters of vision. Sometimes they only gain four letters, and that's because a lot of these patients are in the twenty/forty or better category.

57:14 AVANELX was a nice extension study that was done up to four years out and has reported their results, and again, shown stability of visual acuity even up to four years out in these patient populations, with a really good follow-up in these patients over time.

57:27 And the retinal thickness, again, showing you that there's benefit in these retinal thicknesses, that still persist after four years.

57:33 So we finally have good, durable options through these both studies.

57:37 Again, Q12 and beyond, and about seventy-eight percent of patients in AVANELX with a, with, faricimab, showing you the benefit in those patient populations.

57:46 Again, with a fantastic safety profile.

57:49 Both these drugs, eight milligram, aflibercept and, faricimab, have very, very good safety profiles, very safe drugs without severe cases of IOI or endophthalmitis, so it's overall been quite good.

58:01 FAR RETINA is a study that I've been an author on with many different people, and this has looked at the IRIS registry, just like as, the prior study with eight milligram did.

58:10 This study looked at those patients who've been either prior treated or naively treated with faricimab and found some value in both the US and UK populations, which was done in the, UK EMR database.

58:22 And they found basically gains in visual acuity in those patients who are both treatment naïve, with stability of those patients who were previously treated.

58:30 And again, across all the studies, you see the, the extension occur within the first, few injections. You can see this is the improvement in visual acuity across these groups by about three letters in the treatment-naïve groups across the populations and, and as well.

58:45 And Retina Consultants America is really contributing a lot of data, and they have both AMD and DME studies going on, but they also did a study, an extension, and what they found is in their switcher populations, you saw again, that really great improvement as far as, visual acuity in these patient populations.

59:02 You can see that there was almost a, a five-letter improvement, depending on whatever drug they were switched to prior.

59:07 So seeing that benefit in those patients, and again, seeing that same signal, about two weeks of an additional extension was seen with these newer agents compared to the prior agents, which is good to see over, over the course of the study.

59:19 Port Delivery System was well discussed by, Sharon, but, but I'll talk about the fact that, you know, I think this is where we really see the value, right?

59:27 You can imagine that these patients get pulsatile therapy, which is on the top with their intravitreal treatment.

59:33 And on the bottom, you can see what port delivery system may offer our patients because it allows for them to get it, you know, at a much more steady state fashion over time and the release is over time.

59:42 And this is really platform technology.

59:44 I know it's been recently re-released in a new format.

59:47 There's been some benefits as far as, the, the, the septum, which has been strengthened, as well as the longevity, which has also been improved for some of the artificial studies that have been done.

59:59 And again, this, was recently rebooted, for, use in patient populations as well.

01:00:04 And what you saw from the trials was through Archway and then the Portal study, over about sixty, months, was a stability of visual acuity in these patient populations.

01:00:15 These are, again, prior-- previously treated populations, with very few patients getting, you know, the need for, for intravitreal therapy over the course.

01:00:24 And in fact, the number of, of, of injections range from one to two supplemental injections over the course of this entire study.

01:00:31 Again, this is showing you the OCT thickness, which was really well maintained over the course as well.

01:00:35 Those little, animal-looking things, those are all the refills that were done.

01:00:41 They were done every six months per protocol, and that was actually, the way that they were-- they essentially redelivered the drug over the course of the trial.

01:00:50 And so again, just in the supplemental treatment phase, ninety-five percent of patients didn't require any supplemental treatment.

01:00:55 Only a very small number of patients required supplemental treatment during the course....

01:01:00 And patients really love this.

01:01:01 I mean, when you did one, patients came in and asked for the other one to be done.

01:01:06 And again, many patients felt fewer treatments, less discomfort, were really positives, and, this is sort of that, population of patients, ninety-three percent, that preferred the PV- PDS, in their treatment, or memantarum.

01:01:20 Summit is a real-world efficacy of port delivery system, and this is patients who've, looked at, you know, just the re-- the real-world refill kind of, as- aspects of this.

01:01:31 They're finding a mean refill duration of about eight point six months, which again, is slightly higher than what we saw within the actual studies.

01:01:38 And again, supplemental treatments were really quite low.

01:01:40 This is forty-six patients.

01:01:42 Only two point two percent of patients or one patient essentially had a recurrence of disease and needed treatment.

01:01:48 That was a breakthrough between port delivery refills in this patient population.

01:01:53 So just to conclude, newer agents are out there.

01:01:56 They're achieving better control, but there's some real-world efficacy analysis really validating a lot of the data.

01:02:02 But let's now switch gears and talk about what's on the horizon, what's next?

01:02:05 And you're gonna hear a lot of those abstracts this week.

01:02:07 So this is a really quick preview of some of those abstracts you're gonna hear about and what we're hearing about. But we have two big categories of drugs we're looking at for future, options for durability.

01:02:18 The first is sustained-release tyrosine kinase inhibitors.

01:02:22 We're gonna hear a lot about OTX and, as well as Clearside has a, a product, axitinib, which they're using in a suprachoroidal fashion.

01:02:32 On the right side, you see gene therapy with, iXovic forty-one fifty and AbbVie RGEN-XIS-314.

01:02:39 Again, all in clinical studies and all being investigated currently over trial, the trials.

01:02:44 Let's look a little bit at tyrosine kinase inhibitors to start.

01:02:47 These are, multi-inhibitor VEGF, and, drugs.

01:02:51 So they inhibit both, obviously, VEGF-A, but they also inhibit, a lot of the i- intracellular and extracellular binding of these agents to VEGF-A.

01:03:00 So they not only inhibit VEGF-A, they also inhibit VEGF receptor one, two, and three.

01:03:05 So a little bit benefit there because it has the effect of VEGF-C and D inhibition, as well as placental like growth factors.

01:03:11 So these are really pan-VEGF inhibitors in comparison to our typical drugs, which have been all VEGF-A inhibitors or Aflibercept, which is for the first bispecific Ang- Ang2 and VEGF-A inhibitor.

01:03:24 So we have a little bit more, broader a- application.

01:03:28 And again, they're different in format, axitinib and the OTX format is in an injectable hydro, hydrogel.

01:03:35 And at EYP-1901, it's actually in the Durasert platform, which we're all well aware of from prior use of the, fluocinolone implant and the, Clearside application as a suprachoroidal delivery. Again, we're very familiar with this because we're doing this now with steroids, through a, a product that's already marketed, which, Steve will probably talk about in his UV eyes lecture.

01:03:55 But the suprachoroidal delivery pattern has been one, one to do that in.

01:03:59 OTX TKI has been delivering axitinib in this hydrogel format.

01:04:04 This shows kind of on, on the bottom, how it-- what it looks like and how it dissolves over time. So it kind of goes into, basically nothing.

01:04:11 You don't see any kind of, carcasses or any remaining material over that period of time, over nine months, and is effective to the, tissues, through al- almost, at, at levels that are, are significant all the way through month nine.

01:04:24 This is the trial that was the phase one, which really was just a single, randomization of OTX TKI, implant, plus one Aflibercept given four weeks later, compared to Aflibercept given every eight weeks.

01:04:37 And what you can see, essentially, pre- and post-treatment here, is that these patients were really heavily treated prior, and on the right side, you see what happens when they got the OTX TKI.

01:04:46 Now, they did get a single anti-VEGF agent, but you can't explain that alone to see that there's a great durability at tyrosine kinase inhibitors suppressing the number of supplemental treatments they got during the course of the study.

01:04:59 Here's the mean improvement in visual acuity.

01:05:00 Again, didn't really see a mean improvement, again, because these patients were previously treated, so that's expected.

01:05:06 And the retinal thicknesses remained quite stable.

01:05:08 You saw there was about a forty-micron change in retinal thickness over the course of the study. So not, not a huge change there, which is good to see, showing you good results.

01:05:16 And these are the two studies that are ongoing right now, SOL1 and SOLR.

01:05:20 They're both fully enrolled, but essentially, patients are randomized in the same way that they were in the first phase one, to, to OTX TKI and then given a, a single intravitreal injection, prior to that and the loading period that, that's shown there.

01:05:35 And they, they looked at the same with Aflibercept eight milligrams in, in that as well. Now, the differences in these two studies is SOLR is a non-inferiority trial design, so they're looking at, again, redosing OTX TKI in six-month intervals, as you can see there.

01:05:50 On the top one, you see SOL1 is actually a superiority study.

01:05:54 So they're waiting for patients to essentially lose, ten letters of visual acuity to then look at that endpoint, which is the primary endpoint at month thirty-six, and to see when those patients fail, assuming that the TKI patients will have maintained vision over the course. So quite different approaches in two studies, again, that are ongoing and currently fully enrolled.

01:06:15 EYP-1901 has done the same with the Durasert implant.

01:06:19 This is volimab, different, tyrosine kinase than axitinib.

01:06:23 It's biodegradable, and it does, dissolve completely over time.

01:06:27 This is the, DURAVYU Phase 2 study, which was, two, loading dose-- three loading doses of anti-VEGF plus EYP-1901.

01:06:35 Again, similarly followed over the course of the study, to see what the effect was in comparison to eight milligrams, two milligrams of Aflibercept.

01:06:44 A very stable visual acuity over the course of the study, very stable OCT.

01:06:48 These are prior treated patients and nothing exciting to see here.

01:06:51 However, look at the durability and look at the reduction and overall need for supplemental treatment. There's a huge reduction, about eighty percent of patients not needing supplemental therapy....

01:07:01 So this becomes part of bolt-on therapy for a lot of our patients.

01:07:05 As you can tell, there, increases the durability in our patient populations.

01:07:09 And this is LUGANO and LUCIA, which are very similarly designed, studies, which are non-inferiority trial designs.

01:07:15 Both of them are exactly the same in comparison to the ones I showed you just a moment ago, and they're both given, three loading doses of, of, the two milligram aflibercept, and then followed, without any treatment in the EYP-1901 arm to see what supplemental treatments were needed.

01:07:31 And again, and they were compared to the eight-- the two milligram, eight, eight, eight q eight-week drug on the bottom.

01:07:37 So we're expecting results hopefully by Q2, Q3 of this year, which will be exciting to see.

01:07:42 That will, again, help to validate some of the results we're seeing overall.

01:07:46 And finally, we have, Clearcide's drug, which again, shows very similar results, albeit in a shorter timeframe, with a, a stabilization of visual acuity and improvement in retinal thickness. Let's switch and talk about gene therapy for just a quick moment.

01:08:02 This is a really exciting area and a lot of interest, and, we actually at, at Harvard, have a entire lab, labs.

01:08:09 There are, there are eight of them. They're essentially working together on sort of the next generation of these, but there are some really good shots on goal here with the earlier-phase drugs.

01:08:17 They use the same vector suppression systems, and they're delivering these intravitrally, subretinally, or supracochleally.

01:08:24 The-- it's, there's a-- they're obviously releasing, having this, transcription factor, which can be, it can be aflibercept, it can be ranibizumab, it could be any of those drugs and to help with that process.

01:08:35 And there's just a difference as far as how they're applied.

01:08:39 There's obviously inter-- in-office based, which is sort of the forty MT platform and the ig- and the ixabec platform, and then you have the subretinal base, which is really the RegenxBio, AbbVie platform, which is present there.

01:08:53 And then there's also the suprachoroidal, which has been studied obviously by RegenxBio as well. And this is some of those, drug studies that have shown, Regenx, three one four.

01:09:02 This is again given through, neovascular AMD patients.

01:09:05 This lasts up to three years in those patient populations.

01:09:08 They've had multiple different cohorts, multiple different payloads that have been delivered to these patient populations, and the reduction in injection bur- burden is quite significant.

01:09:17 This is, a really, long-term studies that are being done here with Atmosphere and Ascent, which are the first subretinal delivery studies, and the suprachoroidal studies are the Altitude and Aviate studies over time.

01:09:29 These are the, those studies as well.

01:09:31 And these are the kind of those injection-free burden, seeing seventy-eight percent of patients not have supplemental treatment during the course and stable vision during the course of it as well.

01:09:39 Ixabec is, intravitreal delivered.

01:09:41 This is, again, a capsid delivering aflibercept.

01:09:45 Quite a different approach, but again, the patients are given some amount of, of local immunosuppression, usually with topical Durezol during the course of the study.

01:09:55 And, you can see the corticosteroid prophylaxis, which is, diflunisal, given for twenty-two weeks, plus or minus oral prednisone.

01:10:04 But, this is a-- they've had long-term studies in these patients, looking out even out to five years.

01:10:09 But they're, obviously, LUNA phase II study was a fifty-two-week primary endpoint, and this is showing you that injection-free status.

01:10:15 So again, a one-and-done therapy could be possible for our patients, albeit, that there, there's more studies to be done here beyond fifty-two weeks, showing about a seventy-five percent reduction in injection interval.

01:10:27 And this is, again, that stabilization of visual acuity and OCT, which we expect to see in these patient populations.

01:10:33 This is the Artemis Phase III design, which is ongoing right now with ixabec, showing you again that there is, a th- three loading doses of aflibercept given first, and then you get a single dose of a fix, ixabec versus nothing at all, and the patients are followed for their, mean improvement in visual acuity over the course of the study.

01:10:52 And the last trial I'll talk about is this one, which is the forty MT trial.

01:10:56 Again, this is a trial that's, that's actually delivering a, a capsid, which has aflibercept coded for this, and we're well familiar with aflibercept and what it can do.

01:11:05 The Phase I, Phase II trials have shown really fifty-seven percent were injection-free, which is quite good to see.

01:11:12 And again, this is the forefront, Phase III study, which is ongoing right now and enrolling. This, again, patients were given a Durezol taper, during the course of the study, so very important to see this patient population being treated this way against aflibercept over time.

01:11:27 So again, that's a lot of data.

01:11:28 I'm sorry, it just-- it's, it's overwhelming, but essentially, we have very good second-generation options.

01:11:35 We've got, tyrosine kinase inhibitors, and we have gene therapy around the horizon.

01:11:40 A lot of these seem, you know, somewhat similar, but they're different in many ways in far as their delivery patterns, what we're doing as far as immunosuppression in these patient populations.

01:11:50 And again, it'll be interesting to see kind of the longer-term data to see what the outcomes might be. So thank you very much.

01:11:59 So let's just, we-- get to Steve's talk, but while we-- while Steve is up to the podium, we have a couple of questions here.

01:12:08 So can CST, central subfield thickness, and central retinal thickness all be describing the same thing?

01:12:16 Yeah, you know, I don't know if you heard the question about central subfield thickness and central retina, retinal thickness.

01:12:23 So they're, they're different, and they-- it really depends on what OCT machine you're using and the, the analytics and the output, since they're all automated.

01:12:35 Do you wanna add anything to that?

01:12:36 No, I, I think- Not exactly.

01:12:38 Center point thickness, central retinal thickness, obviously, the central subfield, right? Mm-hmm. So that's the one millimeter.

01:12:43 But I, I think the most important thing is none of these are, are related to fluid.

01:12:47 So if you actually look at the fluid levels or mana- manage, you know, use AI to measure them in nanoliters, they're not at all equivalent for each other.

01:12:55 So you have to think about that, that the retinal thickness is different from fluid.

01:12:58 They don't actually even correlate very well at all....

01:13:02 Great! Thanks. So we're gonna turn it over to Steve.

01:13:04 Steve's gonna take us through a, a uveitis update. great.

01:13:07 First of all, again, thank you to, Dr.

01:13:09 Singh and Dr. Fechner. It's really fantastic to be a part of this program, and also to, all the great organizers from the Hawaii Eye and Retina Meeting. We're gonna be take-- actually take a, take a peer into some cases related to uveitis, and we've had some really fantastic, clinical trial data, and I'll be speaking to that, in just a bit related to vein occlusions.

01:13:28 These are my financial disclosures.

01:13:29 First of all, I'd like to start off with a case.

01:13:31 First, I wanna give a big shout-out to, Dr.

01:13:33 Terry Wood and also Emily Kang, who's a medical student, first year, who's here with us today, and they helped with this-- the, really gave me the information for this case I'd like to present to you.

01:13:42 So this is a thirty-three-year-old, thirty-three-year-old female patient from Samoa, diagnosed, with uveitis in 2023.

01:13:49 Treated with topical corticosteroids and a cycloplegic agent, and developed recurrences, many uveitis patients often unfortunately do.

01:13:57 And was sub- subsequently referred for a second opinion in Honolulu with Dr.

01:14:01 Wood, at the Hawaii Eye Center.

01:14:03 Interestingly, as you think about the patient's review of systems, I want you to be thinking about this case and how you would work it up.

01:14:08 But the patient also had some tinnitus, which was a little bit protean in the manifestations, as well as some skin induration involving, some tattoos.

01:14:19 Her visual acuities were twenty/thirty in the right eye, twenty/fifty pinhole into twenty/thirty in the left eye, and the slit lamp examination was just notable for mild to moderate anterior chamber cell in the right eye and trace cell and flare in the left eye.

01:14:30 There were some posterior sneak in the right eye, indicative of, some degree of chronicity or perhaps recurrence, and her fundus examination was notable for mild, disc edema.

01:14:38 You can see the nerve fiber layer, edema on the OCTs, of the nerves.

01:14:43 And she had several workups, that were performed, initially in April of 2025.

01:14:48 You can see her elevated ESR.

01:14:49 CSF of five point seven is markedly elevated.

01:14:52 Her radiology was also noted for an empty sella.

01:14:55 She had subsequent workup, including a cortisol, which was low, and her ESR seems to be increasing, and her ACE level was also elevated at nearly a hundred.

01:15:03 She also has toxo IgG positive, which we, can certainly see in some individuals of a certain age group.

01:15:11 And her external examination, you can see some induration of the tattoos.

01:15:14 This is on her forearm.

01:15:16 You can see these, slightly elevated areas next to those linear areas of the tattoos.

01:15:20 And, and her, other tattoos were also, mildly elevatedas well.

01:15:25 You can see the blurring of these Roman numerals of April 14th of 2024, for those of you who, who like to do Roman numerals.

01:15:32 So this is just not a bad tattoo, it's- ...

01:15:34 Actually, that's, ele- No, that's right.

01:15:36 These, those are actually elevated, right, so blurring of the Roman numerals.

01:15:39 And so, the differential diagnosis won't get, give you the answer just yet, but we're thinking either sarcoidosis, perhaps VKH, with that history of tinnitus.

01:15:48 Is this tattoo-associated uveitis, very recently described in the last seven or eight years, or is there potentially an infectious process?

01:15:55 And we'll come back to that after we talk about the tools needed to work up our uveitis patients. And so we're really looking for these pearls amongst these perils in patients with uveitis.

01:16:05 There are certainly multiple uveitis syndromes that have kind of vision-threatening consequences if they're not recognized and treated.

01:16:11 We work both in the retina space as well as the anterior segment, as well in infectious uveitis, certainly, the viral retinitis, such as acute retinal necrosis, can lead to, vision loss and even blindness.

01:16:23 Birdshot, which is thought to be autoimmune in nature, can also be very protean in its manifestations with its characteristic oval cream-colored lesions, and, there is a broad idiopathic, category.

01:16:34 So as uveitis res-- and retina specialists certainly start feeling comfortable with uncertainty. When we look forward at the anterior segment, we also have to think about herpes simplex.

01:16:44 Varicella-zoster, CMV can oftentimes lead to a heterochromic appearance with transillumination defects.

01:16:51 A hypopyon uveitis can be indicative of B27-associated uveitis or endophthalmitis in some clinical settings.

01:16:58 And also, there is this idiopathic category.

01:17:00 Some patients can have chronic anterior uveitis without a definite cause.

01:17:05 So how do we approach, the cases?

01:17:07 Well, the, the pa- the patient that I showed is very illustrative.

01:17:10 We're thinking about the history, the review of systems, ultimately, I'm zooming in at the slit lamp examination to classify the anatomic location of uveitis, assessing structural damage, looking for cataracts and steroid macular edema, and also very important to rule out infection.

01:17:26 With ocular fluid sampling, there really is an array of testing that we can do now, including PCR testing, and I'll talk a little bit further about genomics work that's ongoing.

01:17:35 Very exciting, to try to uncover some of these, pathogens, that previously were una- unidentified. And ultimately, we work with our consultants to identify important systemic disease associations, and the, the patient on the right-hand side actually had varicella zoster virus, retinitis in the context of shingles, so very devastating retinitis infection.

01:17:57 One question that I get is, that I often get is: What is a, quote, "standard uveitis workup?" Is it all of the above?

01:18:03 And it sometimes can be tempting just to, just to order an array of labs, but you really wanna be directed in how you order labs because of the risk of, false positives and also leading you on a rabbit trail that you don't necessarily wanna go, go down.

01:18:17 And so I, I really encourage, people to avoid a shotgun workup because your predictive value of a test is really dependent on your pre-test likelihood, of disease.

01:18:27 Really, this is predicated on your clinical suspicion and what you're seeing at the slit lamp. So keep We'll bear that in mind as we think about various diagnostic tests.

01:18:36 And so a- acute anterior uveitis, we're often taught in our textbooks that an acute unilateral first episode may not need a workup....

01:18:44 But there is literature now that shows that if you pick up ankylosing spondylitis, detect HLA-B27 positivity in an individual with back or hip pain, you can really change the quality of life of patients.

01:18:54 And so this is important as we think about the systemic manifestations that can be associated with acute anterior uveitis.

01:19:00 We've talked a bit about hypopyon and tattoos.

01:19:03 Some of the labs that I will order for individuals with bilateral or recurrent disease include B27, syphilis IgG, and also Quantiferon TB.

01:19:12 But there are some labs, labs that are not, particularly helpful, including ANA, rheumatoid factor, and ANCA, but certainly looking, very carefully for transillumination defects. This is one example of a patient that I shared with Dr. Jessica Shanta at Emory University.

01:19:27 Now, this is a thirty-year-old patient who had acute hypertensive anterior uveitis and developed a stroke, two days after presentation.

01:19:34 You can see on her slit-lamp photographs that she has these areas of iris stromal atrophy and transillumination defects as well.

01:19:41 And she ended up being PCR positive for varicella-zoster virus, and her stroke was actually attributed to a CNS vasculopathy that we can sometimes see in the context of varicella zoster, and she had a full neurolog- neurologic recovery after antiviral therapy.

01:19:56 Focusing a bit on HLA-B27-associated anterior uveitis, which can very-- be very common.

01:20:03 It's commonly bilateral and can, and can be asynchronous.

01:20:06 We manage these symptoms and signs oftentimes with rheumatologists.

01:20:09 You can see that, while most patients will present with an anterior uveitis, about fifteen to twenty percent actually will have posterior segment findings.

01:20:17 This patient actually had macular edema associated with non-infectious, uveitis.

01:20:21 As Dr. Singh, alluded to, a really nice candidate for suprachoroidal corticosteroid, for the treatment of macular edema in this individual and other corticosteroid preparations, as well to treat the anterior uveitis.

01:20:35 Related to hypopyon uveitis, there's some really nice epidemiologic data that's shown that hypopyon uveitis can oftentimes be associated not only with B27-associated disease, but also Behçet syndrome.

01:20:47 So very important to ask about genital ulcers, oral ulcers as well, and also res- assess patient for risk factors, for endophthalmitis, including recent trauma and also immunosuppression, because, again, very important to distinguish between infection and autoimmune-based, inflammation.

01:21:04 Now, what about syphilis? This is a, a condition that is certainly on the rise. Actually, in Atlanta and also in Baltimore, there actually are billboards related to eye syphilis, so syphilis that involves, that has ocular involvement. We see a fair number of these cases, on a yearly basis. Globally, over seven million cases of syphilis that have been reported since twenty twenty, and within the United States alone, over two hundred thousand cases in twenty twenty-three, which is actually the highest that it's been in over seven decades, with an increased portion of males versus females in about a two-to-one ratio. Also, recall that there's a very high rate of syphilis and HIV co-infection, so very important to check HIV, status in an individual-- any individual that you diagnose with syphilis.

01:21:48 And there are a number of reasons, that we think that syphilis may be on the rise, including reduced, funding globally, and also there was a drug shortage of penicillin back in twenty twenty-four.

01:21:59 And currently, from a testing perspective, the CDC guidance is that the, the-- what they call the reverse screening algorithm, where previously RPR was the initial test that was performed, and now it turns out that treponema pallidum IgG, this is an enzyme immunoassay, is actually a very, sensitive and specific test, to establish a diagnosis of syphilis.

01:22:19 And the RPR is done, reflexly to follow, the response to therapy.

01:22:24 Again, this is a reverse screening algorithm that's largely available in many of our laboratory- laboratories.

01:22:31 This is a case of an HIV-positive male patient, had syphilitic, syphilitic retinitis, and this is a case where, the imaging can be very helpful.

01:22:38 If you look at the nasal retina, there are these superficial retinal precipitates that are actually quite characteristic of syphilis, very nicely treated with IV penicillin.

01:22:47 You can see how nicely the retina- the retinitis has, cleared.

01:22:52 In addition, another characteristic imaging finding, this is a syphilitic posterior plaquoid chororetinopathy.

01:22:58 You can see the very, very well-demarcated plaque within the posterior pole that we see, in patients with syphilis.

01:23:04 Patient presented with finger counting, visual acuity initially, and an OCT, you can see these excrescences at the level of the outer retina, just elevation of the RPE and outer retinal change. And, and what's fascinating about this condition is that patients can re- return to twenty/twenty vision.

01:23:20 So some of these patients are some of our happiest patients in the clinic, at, at least after they've been diagnosed and properly treated for syphilitic uveitis.

01:23:30 I did want to mention, metagenomics, because this is increasingly used.

01:23:33 There are a number of labs, that we're, utilizing and working with to think about metagenomic testing.

01:23:39 Essentially, in terms of workflow, after an aqueous humor specimen or a vitreous humor, humor specimen is, is, harvested, it's actually run through a wet li- lab pipeline, where the genomic material, either the DNA or, or the RNA, are amplified.

01:23:54 Subsequently, the amplified DNA is run through an, a bioinformatics pipeline, subtracting out the human DNA to identify, different pathogens, either the pathogen of interest that's known or al- as- also other pathogens that haven't yet been identified, and can also trace the lineage of these pathogens to other, other, sites and other infections that have been observed. And this is one case that I found particularly fascinating. This is from our friends from the UCSF Proctor Foundation. This is a forty-year-old gentleman, actually had a twenty-year history of idiopathic, quote, "idiopathic anterior uveitis." he had metagenomic deep sequencing of his aqueous humor, and it turns out that he had a strain of rubella virus that actually dated to another strain that was identified in Germany about two decades prior, when he initially developed the uveitis syndrome.

01:24:45 So really fascinating where this technology can go....

01:24:48 So now that we have all the tools that we need to solve this case, we can go back, to the case from, from, Emily and also Dr. Wood.

01:24:56 And so again, we talked about the differential diagnosis, sarcoidosis, VKH, tattoo-associated uveitis, or infectious process.

01:25:02 And so Dr.

01:25:03 Wood, sent the patient to a dermatologist.

01:25:06 The-- again, this tattoo was elevated, so there were these granulomatous-type, appearing lesions, and a biopsy was performed in an area where there was some, discharge.

01:25:17 But it turns out that there were non-caseating granulomas.

01:25:19 You can see the interspersed, pigment.

01:25:21 It's been a long time since I've done, pathology, but, you know, I think you can still recognize probably those granulomas and an elevated ACE level.

01:25:28 So is this sarcoidosis?

01:25:29 Are we done, with the diagnosis and on to rheumatology for immunosuppression?

01:25:35 Well, let's take a look at the next step.

01:25:36 So it turns out that not only did they identify these non-caseating granulomas, but when they looked further, they also used a Fite stain, which helps to identify these acid-fast bacilli.

01:25:47 So there were actually acid-fast bacilli within the granuloma, this non-caseating granuloma, and using 16S sequencing, this is a targeted form of metagenomics, actually to target bacteria, to look at specific species that can, lead to infection, identified this, and I'll try very hard to pronounce this.

01:26:05 This, I think this is Mycobacterium ironicum, but this is atypical mycobacteria. And so what's the relationship between atypical mycobacteria and tattoos?

01:26:16 Well, if you look at the literature, you, you really need to actually look at the infectious disease literature because this is where, mycobacterial tattoo outbreaks have been reported. The CDC has investigated, some of these outbreaks in addition to, other state public health authorities, and there are multiple case reports in the literature related to non-TB mycobacterial infections, also multiple mycobacterial species, chelon mycobacterium, chelonae, fortuitum, and abscessus.

01:26:43 And it turns out then, when they looked and, and tried to investigate this further, they were identifying mycobacteria species also within tattoo ink and also some gray tattoos because these were actually diluted with some of the water, actually were diluted with water that was unfortunately infected with mycobacterium.

01:27:00 This is a, a case, fairly dramatic.

01:27:01 This patient actually had corticosteroids applied to this area that unfortunately had, an infection and had mixed acute and chronic inflammation.

01:27:10 So you can see how in the, in the setting of lower grade inflammation, you wouldn't see necessarily this severity, can certainly be, easy to miss.

01:27:18 Now, what's the relationship between non-TB mycobacteria and sarcoidosis?

01:27:22 This is actually If you look at the literature, for, for many decades, people have looked at this notion of potentially how atypical mycobacteria may be associated with sarcoidosis. And recent studies have shown, with biopsies of cutaneous lesions with, quote, "sarcoidosis," that actually one study showed that eighty percent actually showed atypical mycobacteria by PCR.

01:27:42 And there is, literature in the, in the uvea-- There is uveitis literature that suggests a strong relationship between tattoos and also sarcoid uveitis, as well as systemic sarcoidosis, as well.

01:27:53 So this really brings me back to this, really this triangle as we think about infection, immunity, and this category of idiopathic, that we do see these relationships of how mycobacterial infection could trigger a sarcoidosis-like, reaction.

01:28:06 It's important to continue to understand these diseases because they, because they may have broader implications for other autoimmune conditions like sarcoidosis, in the future.

01:28:16 And I thought this was really fascinating, when we think about, tattoos in general, that it's important to consider the sociocultural context, which related to the type of tattoos that males and females in Samoan culture, can have.

01:28:29 They have very sign-- They have a very significant, meaning to the individual.

01:28:35 For males, it can be related to character, family, and culture.

01:28:39 For females, protection, status, and readiness, for adulthood.

01:28:43 Again, thank you to Emily for, these slides and also talking us through important considerations related to, both what's seen in Hawaii and in Samoa as well.

01:28:51 And this can actually impact her care in terms of how we interpret, these findings, acknowledging this is a treasured part of their identity and not merely decorative, or body art. And w- when we're communicating, these, risks, important to, emphasize avoiding language that blames, poor hygiene or traditional practices, as well. So I know there's a lot of information here, but as we think about identifying the pearls amongst the per- perils, again, thinking about a targeted history review of systems and the clinical patterns of uveitis that can help with selective confirmatory testing.

01:29:26 And also very important to evaluate for infectious disease processes, as in, the patient that, we showed, and also important to use caution with corticosteroids and certainly to avoid empiric steroids if infection is suspected.

01:29:39 That's great. Thank you.

01:29:45 Very nice. So, so, you know, I, it was an case 'cause, you know, is that mycobacterium like universally found in, in, You said it was the water dilution, more so that than the actual pigment, right? So is- we have to actually just have sterile water when we get tattoos?

01:30:01 Just 'cause I've got to get a tattoo tomorrow, and I- Okay ...

01:30:04 Just make sure I have this right. Yeah.

01:30:05 No, it's a great, great question.

01:30:06 So I think that what we've, at least in some of the, some of the, the papers that I looked at- Right ... Again, the, the, the thought is that, that this, that the sterile wa- the sterile water, whether it's distilled water or whatever process there, there may be, may, may, may be, may be contaminated with mycobacteria.

01:30:21 But that being said, it's also a possibility that, that I was talking to Emily about just mycobacteria in general, whether there's higher rates, in the region because of the tropical nature or whether- Yeah ...

01:30:32 And this is something that I've been hearing as well.

01:30:33 So, lots of different factors, but again, when you think about Miami-Dade County as another area where this was identified, a lot of these haven't necessarily been investigated the same way with- Yeah ... Whereas a rigorous, CDC goes in or public health goes in to evaluate.

01:30:46 But this is something that I think is important to, to consider....

01:30:50 Great! That's awesome.

01:30:52 Any other questions from the audience?

01:30:53 Feel free to submit the app.

01:30:54 Why don't we, have you guys switch out?

01:30:56 And I know that Sharon is gonna talk about common pitfalls in imaging diagnosis.

01:31:01 This is gonna be a neat talk, I'm sure, to, to learn more about retinal imaging. Great.

01:31:06 Thank you so much.

01:31:08 So here, we'll start this off.

01:31:10 We have this picture right here, and I always ask myself: Where's your A-scan vector? Yeah.

01:31:15 Even though here we can clearly see there's posterior hyaloid right here, retina, and then choroid.

01:31:24 So these are my disclosures.

01:31:27 So how often do we typically use our patients' retinal images to educate them about their condition? Very often.

01:31:35 So always or frequently is almost ninety-five percent.

01:31:42 So I'm gonna start out with this case.

01:31:45 So how long does it take a retina specialist to look at a fundus photo during a busy clinic? One, one-thousand; two, one-thousand; three, one-thousand. I think three seconds at the most, maybe one second. Okay?

01:32:03 So three to five seconds, but we're gonna go with three seconds.

01:32:07 So I'm gonna show you a fundus photo, and I'm gonna give you three seconds, and then at the end of the talk, I'll show you what the diagnosis is, okay?

01:32:17 So here we go.

01:32:19 One, one-thousand; two, one-thousand; three, one-thousand.

01:32:26 Does anybody know the diagnosis and wanna say something?

01:32:31 Okay, perfect.

01:32:33 You're following what I was hoping would happen.

01:32:36 I thought so. Okay. We'll, we'll circle back to it at the end. So there are many different retinal imaging modalities available in most retina clinics.

01:32:46 So fundus photography, fundus autofluorescence, OCT, OCT angiography, fluorescein angiography, and ICG angiography, and then some clinics may have other stuff.

01:32:59 So retinal imaging, you know, assists in diagnosis, you can monitor disease progression over time, and it can help guide treatment in some cases.

01:33:08 And often, we use more than one modality, and together, they're used in the decision-making. And even similar imaging systems, let's say OCT in one office and OCT in another office, are often different.

01:33:23 So we have different image acquisition interfaces, we have different segmentation algorithms, different embedded analytics, different outputs, and different tips and tricks to get good images and interpret them.

01:33:37 So all images must be good quality, and we must be able to compare them over time.

01:33:44 So image quality matters a lot.

01:33:46 You can see here A and B, because this happens to be from one of my papers, A and B as good quality, but then all the other ones have something going on with them, either motion artifact or they're decentered, or they have eyelid or lash artifact, or media opacity, or just challenges with acquisition.

01:34:07 Even blinking can cause artifact.

01:34:11 Our group, has dev-- we've developed a convolutional neural network-based automated quality assessment of OCT and OCT angiography images in particular.

01:34:22 We did it in individuals with neurodegenerative disease related to some of my research, but these-- this model performs very well with high AUCs close to one and above point eight.

01:34:35 That shows, that this could be a way to help sort images quickly for image quality, especially for research projects.

01:34:42 And, some of the computer science, undergrads on our team developed this really interesting app that can be used on airplane mode, so you don't really need it connected to Wi-Fi or any sort of internet to, sort images for image quality.

01:35:00 So there are a lot of basic requirements for good quality images.

01:35:03 You need a skilled c- photographer, a cooperative patient, and of course, a clear cornea, clear ocular media, the ocular surface health needs to be good, and adequate pupillary dilation, usually, not always, and what the photographer sees is usually what you're gonna get in a busy clinic.

01:35:23 You can see here, pupillary dilation really helps get a stronger, OCT-saturated image.

01:35:29 So on the top is the same OCT as the bottom, but one is with the pupil dilated and the other is with the pupil undilated.

01:35:39 So there are many common pitfalls that we're going to go through, and some of it can relate to just the modality that the image is from and the interpretation.

01:35:48 So on an OCT, sometimes we can mistake shadowing or artifact for fluid.

01:35:54 On OCT angiography, such as the one on the bottom left, we can mistake a low signal flow, those voids, for retinal ischemia there in the PM bundle.

01:36:06 On color photos, we can have lid and lash artifact, which will pertain to the image I showed earlier, and areas of shadowing, and sometimes we may mistake staining of fluorescein with leakage.

01:36:21 On the right, that is geographic atrophy staining.

01:36:26 So there are also challenges with, acquisition of the images or technical, features.

01:36:32 So poor image quality from patient movement.

01:36:34 On the left, those are those horizontal bands.

01:36:37 So one way to decrease this motion artifact is help make sure the patient is comfortable and has their head against the bar there.

01:36:46 Media opacity, as you can see on the right, can also interfere with your, image, and sometimes if people are not that experienced, they may think that some of this could be fluid.... Also, the scan location and scan protocol are really important to help provide clinically useful images that we can use in-- during decision making.

01:37:08 So if you have an OCT that misses a certain slice or, you know, we really can benefit from some of the, radial rasters, we might miss a small macular hole, for example.

01:37:21 Artifact can also m- mimic pathology, as you can see there on the left.

01:37:26 This is in a highly myopic eye with a staphyloma.

01:37:29 Sometimes we get that artifact that you can see there.

01:37:34 And also, there can be segmentation errors.

01:37:37 So the posterior hyaloid on the image on the left is mistaken for the retinal surface, and you can see the red line, there is connecting to the hyaloid, whereas on the right, it's actually on the retinal surface, where it should be.

01:37:50 So one way to avoid this is to use enhanced depth, imaging.

01:37:54 Turn that on in an eye with vitreomacular adhesion or traction, so you get the correct placement of these auto-segmentation lines.

01:38:03 And sometimes you can have interpretation error, as we've touched on a little bit, like misreading some normal variations as pathology, overlooking really subtle findings if we're looking at the image too quickly, or confusing similar-appearing pathologies.

01:38:18 So right here, both of these images may initially look like cystoid macular edema if somebody's not, that familiar with looking at these images, and this is actually retained subretinal perfluorocarbon liquid, in an eye following retinal detachment repair.

01:38:33 I like to call it a post-op surprise.

01:38:37 So clinical correlation can be very helpful to avoid misinterpretation of what you're seeing.

01:38:44 And this is where multimodal images can really help you put it all together and figure out what it is if you can't see it on exam.

01:38:53 Also here, outer retinal tubulations, as you can see in both of these images, SORT, versus chronic intraretinal cysts.

01:39:02 So the outer retinal tubulations are a little more tubular shaped, and have these hyperreflective borders around them, as you can see.

01:39:10 They're often seen in eyes with advanced dry AMD and geographic atrophy.

01:39:16 And then also, you-- if you have an epiretinal membrane, you can either have cystoid macular edema, as on the right, or schisis cavities, which you don't really need to treat.

01:39:27 And so the schisis cavities are these hyperreflective spaces that you can see at the level of Henle's layer.

01:39:34 And then, of course, there's no leakage on a fluorescein angiogram with the schisis cavities, usually, but eyes with CME will have leakage on your additional imaging modality that you might get, to put this together, the fluorescein.

01:39:51 Also here on the right, there's top picture is silicone oil meniscus, and the bottom is an epiretinal membrane.

01:39:57 And one way you can tell the difference if you're not necessarily sure is you can see the, retinal distortion and the inner retinal r- wrinkling that the arrow shows at the bottom there in an eye with an epiretinal membrane compared to silicone oil meniscus.

01:40:15 Also, sometimes you can mistake subretinal fluid and think it's, wet AMD, when actually this eye has central serous.

01:40:23 And so you look for a pachychoroid, as shown with that white line in the top central image there, showing that the choroid is thicker in eyes with central serous.

01:40:32 There's no drusen in eyes with central serous.

01:40:35 And if you're lucky enough to see the rare smokestack on fluorescein angiography, you'll know that that is indeed central serous and not wet AMD.

01:40:47 Also, you don't want to rely only on imaging without correlating either with the symptoms or the clinical exam or other images, so multimodal imaging is very, very helpful, as seen here with all these images.

01:40:59 Can tell you that that on the bottom left is not central serous.

01:41:03 It's actually wet AMD, and so on the other OCT angiography images, you can see the choroidal or macular neovascularization.

01:41:13 And so multimodal imaging is l- very clearly helpful in these cases that all lead to cystoid macular edema to confirm what the diagnosis is.

01:41:24 So it, is it a branch retinal vein occlusion, diabetic macular edema, cystoid macular edema, or central retinal vein occlusion, among other things that can cause, CME?

01:41:36 Now, OCT angiography, in particular, is very susceptible to artifact.

01:41:41 You can have shadowing in any image, but here's a picture of it with OCT angiography.

01:41:46 Motion artifact, segmentation issues, so you think you're in one layer, but you're actually in a different layer, or projection issues, where the, overlying major retinal vessels are projected onto the deeper, retinal n- networks, really vascular networks, as you can see on the image on the right.

01:42:07 Usually, you just press a button to prevent, projection of the more superficial, vessels to deeper layers.

01:42:15 This is a really nice paper that looked at the identification of imaging features that can determine quality and repeatability or comparison of, retinal capillary density measurements on OCT angiography.

01:42:29 And they, try to define what a good image is because, as you know, it's very subjective often. So they look at fine vessel visibility, whether the scan is cent- centered on the fovea, tilt of the image, all sorts of motion and segmentation artifacts, and then the quality of the B-scan.

01:42:49 So I'll just show you some different things.

01:42:51 So these are considered poor quality.

01:42:53 You know, the fine vessels are not visible on the top left there.

01:42:56 There's motion artifact, which are those horizontal bands, and the B-scan quality, at the bottom is just not very good....

01:43:06 Here, this is a poor, image, a poor quality OCT image with a tilt that you see down there, and so there are corresponding, problems with the OCT angiography.

01:43:17 You can have a darker sector related to the tilt, as you can see in the image on the right, and that's actually not an area of retinal ischemia.

01:43:25 It's just what we call a low, flow void or signal.

01:43:32 Also, here's another, example of these flow voids due to the artifact, for a variety of reasons, with poor signal strength, and has what looks like apparent non-perfusion, but on the right, that is definitely areas of capillary dropout, and real areas of retinal non-perfusion for comparison.

01:43:54 So OCT angiography, as I touched on a little bit, is, particularly more susceptible to some of the artifact in the deeper layers.

01:44:02 Right here, there's projection artifact, mimicking choroidal neovascularization, up top that you can see.

01:44:10 And so you can get rid of the, projection by just clicking a button and cross-reference it with a structural OCT as well.

01:44:21 So here's motion artifact.

01:44:22 Here's another image that's decentered with some projection artifact of some of the larger vessels. Motion artifact, low flow signal, and just the list goes on. As you can see, it's very easy to get all kinds of artifacts with OCT angiography.

01:44:39 And here are just more images, and the motion artifact, is some of the more difficult to kind of, get past, especially when you're using these images for research.

01:44:52 This is considered good quality.

01:44:53 It's nicely centered.

01:44:55 The B-scan image is pretty good quality.

01:44:57 You don't see any significant, motion artifact, and then you can get your nice color vessel density map, on the bottom right.

01:45:06 These are also good quality.

01:45:08 You can see there's really nice detail of the fine vessels, and everything is very crisp. Here is some motion artifact that probably won't affect the image, where these arrows are pointing, some very s- subtle horizontal lines, and you could still use these for research when you're, you're actually quantitating some of the vessel density and perfusion density metrics. Now, ultra-widefield color photographs, the image on the left there is excellent.

01:45:39 The one on the right has some eyelid and eyelash artifact, not too much, and then also some face pad artifact, because if you've seen the Optos cameras, you know, sometimes you have to tilt the patient a certain way to get a really good image.

01:45:54 Also here for color photographs, you wanna make sure you have the correct magnification.

01:45:59 Sometimes you get a very magnified image, and at the previous visit, it was appropriate, and it's very hard to compare, and look at the pathology you're trying to find.

01:46:10 Also, focus and clarity, you know, you wanna make sure both lids are pretty wide open.

01:46:15 You wanna pay attention to the tilt so that you don't see the face pad there, and you wanna always clean the lens, 'cause you can get these little white circles on there, and the patient's trying to ask you what it is, and you're two hours behind, and you don't really wanna explain it at the moment.

01:46:32 Now, fluorescein angiography, there are also some things to be on the watch for, such as staining versus leakage, as I talked about earlier, and the picture on the left is actually staining of areas of geographic atrophy.

01:46:44 And so you wanna assess the late frames for increasing intensity if something's going to be leakage, and then it spreads, as we've all learned, in leaking fluorescein versus staining, and now we can always correlate with our OCT.

01:47:01 Sometimes you-- blocking of fluorescein can be misinterpreted as ischemia, as you can see the arrows on the right.

01:47:08 A lot of us know that's intraretinal hemorrhage, but sometimes people don't know, and that can be, misinterpreted for capillary non-perfusion.

01:47:17 And so you wanna correlate it with the earlier frames of the angiogram, the fluorescein angiography, or, your exam.

01:47:26 So how you can avoid some of these imaging pitfalls is you want to assure, ensure that you have proper image acquisition, some sort of quality control.

01:47:35 Usually, the photographers as the, as they get more experienced, can really help with a lot of these to produce a good image for you to review.

01:47:43 You wanna recognize the common artifacts and normal variants.

01:47:46 I have these pictures on the back of the slide because the one on the left is a retinal detachment OCT, and the one on the right is retinoschisis, where we use nowadays, compared to some of the older methods we used to use, with, measuring visual field defects and also seeing if laser would take in an area of schisis compared to not take in an area of retinal detachment.

01:48:09 Also, we use multimodal images to confirm findings.

01:48:12 We can compare with previous images when available.

01:48:16 We always wanna correlate with the clinical context and also keep up to date with continuous education and review of challenging cases, which we're all doing, here at this meeting. So future advances in retinal imaging is definitely going to change the way we practice.

01:48:34 As mentioned earlier, by Rishi, imaging tools to track and model geographic atrophy progression is coming soon, to the theater near you.

01:48:46 Enhanced wide-field color fundus photography, also peripheral or wide-field OCT.

01:48:52 AI is jumping into the mix to help us monitor fluid status, better resolution and enhanced depth macular OCT imaging, and improvements in OCT angiography technology....So how long does it take a retina specialist to look at a fundus photo during a busy clinic?

01:49:12 I would argue one second, two seconds, maybe, if the patient's talking.

01:49:18 And so does anybody know what the diagnosis is here?

01:49:26 I've shown this to a lot of people, but this patient had a choroidal melanoma hiding under the lashes and the lids.

01:49:33 And I think, you know, when you show this image to a technician or, somebody, a student, who's not used to looking at these, images, they see the choroidal melanoma.

01:49:44 But I think a lot of us are so busy looking at them, we've trained ourselves to block out some of the lid and lash artifact, and we might not see it right away.

01:49:54 This is that same patient four months earlier, so I think the clinical correlation is incredibly important.

01:50:00 If you see anything, even that shadowing on the left, which could be from the lens, you really have to do some clinical correlation, maybe get steered images to look at different, areas, make sure that you catch it.

01:50:15 So imaging is a very powerful diagnostic tool.

01:50:18 It can be prone to artifact.

01:50:20 You must interpret it with context and correlation and be aware of common pitfalls.

01:50:25 Reviewing the images very systematically can improve diagnostic accuracy and patient outcomes. Thank you.

01:50:33 That's great.

01:50:38 That's great. Why don't, we go to the next talk, and then we'll just wrap up with questions at the end?

01:50:43 I've got a lot of good questions come in.

01:50:44 So Steve's gonna take us home with, RVO management. Okay.

01:50:49 All right, thanks, Rishi. And now that I feel guilty about missing a melanoma, we'll switch gears and goback to talking about an update on retinal vein occlusions. And so what do we-- what's new in twenty twenty-six? First, I'd like to acknowledge, again, Dr.

01:51:01 Michael Singer. He, passed this talk to me when he couldn't make it, so we certainly miss him at the meeting, but we'll look forward to see him, seeing him soon, either, at future meetings or at Hawaii Eye next year.

01:51:12 These are my financial, disclosures.

01:51:14 And so in the way of background, retinal vein occlusions, we've talked a lot about diabetes macul generation, but retinal vein occlusions are very common, but do represent a heterogeneous group of retinal disorders, that are characterized by impaired venous return to the retinals- of the retinal circulation.

01:51:29 Very broadly, they're divided into branched retinal vein occlusions and central retinal vein occlusions. Oftentimes, from a clinical trials perspective, we classify hemiretinal vein occlusions, or HRVOs, with the CRVOs.

01:51:42 The incidence is estimated at one hundred and eighty thousand eyes per year within the United States, and branched retinal vein occlusions account for the majority of vein occlusions. It's important as we think about risk factors, to, recall and remember that, patients can have a number of systemic disease conditions that can also predispose them to developing these venous occlusive events, including hypertension, diabetes, arteriosclerosis, and locally, a, a risk factor includes open-angle glaucoma. So again, taking the whole patient, as well as local, local comorbidities, can also t- be very important for thinking about these conditions. And I'll talk very briefly about pathophysiology. Really involves, impaired venous return.

01:52:25 As you'll recall, retinal arterioles and ve- and veins share a common, adventitial sheath.

01:52:30 And what happens when you have arterial wall thickening is that this will actually compress on the veins and ultimately lead to a branched retinal vein occlusion.

01:52:38 You'll often see these vein occlusions at a junction of an arteriole and a vein.

01:52:42 And when we look at central retinal vein occlusion, this is a more complex process, but invo- can involve a variety of factors really related to venous compression or even thrombus found- thrombus, formation.

01:52:53 Thank you to Dr. Singh for providing these images.

01:52:55 But you can see this, classic retinal, these hemorrhages, and also macular edema in the context of central retinal vein occlusions, that can also lead to macular edema.

01:53:04 And as we trace through, vein oppression, narrowing, ultimately, this can lead to turbulent blood flow and thrombus formation.

01:53:11 We look at these wide-field fluorescein angiograms.

01:53:13 You can see this diffuse ischemia that ultimately leads to upregulation of vascular endothelial growth factor, that also mediates, this macular edema, in addition to a variety of other, factors, including inflammatory factors as well.

01:53:27 And all this will contribute to vision loss.

01:53:29 And so we know that macular edema is the leading cause of vision loss related to retinal vein occlusions.

01:53:35 And I just wanna take a step back as we think about all these anti-VEGF, injections that we're fortunate to have at our disposal.

01:53:43 And this is actually past the, the, the branch retinal vein occlusion and also the central retinal vein occlusion studies from BRAVO and CRUZ.

01:53:50 But in this study, the VIBRANT study, this actually looked at intravi- intravitreal aflibercept versus laser therapy for branched retinal vein occlusions.

01:53:58 There was a time, actually, when patients were diagnosed with branched retinal vein occlusions, where these patients were actually monitored for about three months prior to consideration of grid laser or focal laser.

01:54:08 This is prior to the anti-VEGF era.

01:54:11 So in this study, the VIBRANT study design, patients were randomized either to aflibercept or to laser therapy, with the primary endpoint at the week twenty-four, time point, looking at proportion of three-line visual acuity gainers.

01:54:25 Patients were subs- subsequently, dosed with Q eight-week aflibercept, up to week fifty-two, again, both the laser and the intravitreal aflibercept groups.

01:54:36 There was another study, the Galileo and the Copernicus studies.

01:54:39 This actually looked at intravitreal aflibercept for the treatment of macular edema associated with central retinal vein occlusion.

01:54:45 Patients were, randomized to either aflibercept or actually sham, because there was a time also where patients with central retinal vein occlusions were observed for the development of neovascularization, at which time pan-retinal photocoagulation was performed.

01:55:00 The, the primary endpoint at week twenty-four was a proportion of three-line visual acuity gainers, and patients received treatment up to a year.

01:55:09 And so when I look at-- show these studies, I wanted to show these together as we think about visual acuity improvement and the benefits that we've seen with intravitreal antiviral therapy.

01:55:18 With intravitreal aflibercept, at week twenty-four, patients gained, on average, seventeen letters of visual acuity improvement.

01:55:25 If you look at the laser group, still about seven letters in the branched retinal vein occlusion group. But what's remarkable when you look at week fifty-two is that patients who were treated initially with laser, not with anti-VEGF therapy, actually weren't able to achieve the same visual acuity improvement.

01:55:40 So delayed treatment un- with intravitreal anti-VEGF therapy, unfortunately, led to a ceiling effect with regards to their visual acuity.

01:55:48 We also found this to be, be the case in patients who were treated with aflibercept, for central retinal vein occlusion.

01:55:54 You can see in the, in the eye AI......

01:55:57 Group, patients who were treated with aflibercept gained about seventeen letters.

01:56:02 Patients in sham actually had lost visual acuity, and at week fifty-two, after both groups had received intravitreal aflibercept, again, you can see a marked difference in individuals who received intravitreal aflibercept versus those who, were observed initially. So early treatment, very important for central and branch retinal vein occlusions.

01:56:21 And we have a number of therapies on the market, as well.

01:56:24 We've talked about these a little earlier with Dr.

01:56:25 Fekrat and also Dr.

01:56:27 Singh's talks. And so we wanna know, how do these different anti-VEGF therapies, compare?

01:56:32 And the NIH-funded SCORE-2 study actually compared aflibercept given monthly versus be- bevacizumab or Avastin given monthly, with a primary endpoint at six months.

01:56:43 And it's important, again, to think about the differential comparative efficacy between these anti-VEGF therapies as we evaluate these therapies.

01:56:50 And what the study found was that intravitreal bevacizumab or Avastin was non-inferior to aflibercept with respect to visual acuity at six months after treatment.

01:57:00 You can see that in both groups, there's about an eighteen or nineteen letter visual acuity improvement. That's somewhere between three to four lines, so very impressive visual acuity related to treatment of macular edema due to central retinal vein occlusion. This is, again, at six months, that these therapies were indeed, comparable.

01:57:19 Ultimately, patients were then re-randomized to either monthly scheduled dosing versus a treat and extend regimen, same medication, and it turns out that when you look at the visual acuity endpoint at around, the, the twelve-month endpoint, there was no difference in visual acuity or OCT observed in this group of patients.

01:57:37 Again, these are mean values.

01:57:38 There certainly can be differences, and Dr.

01:57:40 Fekrat and Dr. Singh have published extensively on the importance of looking at different groups and risk factors for better or poorer visual acuity outcomes.

01:57:49 But what's also notable at the twenty-four-month time point, this is when patients actually were not on protocol.

01:57:54 They weren't on specifically a protocol-defined treatment.

01:57:57 Patients actually lost about a line of visual acuity.

01:58:01 And so whereas overall, over the twenty-four months, they improved, about fifteen letters, you can see that the curve actually dips down just a little bit at the twenty-four-month time point, and I'll come back to that in a second.

01:58:14 Now, LEVO actually looked at Lucentis, Eylea, and Avastin, and I apolog- apologize for using the brand names, but, this was for vein occlusion, so this was a LEVO study design.

01:58:23 This was deployed in the United Kingdom.

01:58:26 Over a hund- four hundred and fifty patients across the groups, ranibizumab, aflibercept, and bevacizumab.

01:58:32 And what I just wanted to mention is that the, that the, standard in this-- the standard reference medication in this ther- this trial was ranibizumab or Lucentis.

01:58:42 And what they showed was that aflibercept was non-inferior to ranibizumab, so Eylea and, Lucentis were comparable.

01:58:51 But, but it showed that there were differences, however, between Avastin and these other two anti-VEGF injections.

01:58:57 So we saw that both with the visual acuity as well as the spectral domain OCT outcomes.

01:59:04 And this is hot off the presses.

01:59:06 This was recently published in Ophthalmology Retina.

01:59:08 This is a paper by, Michael Ip, Yasha Modi, Sharon Fekrat, and others that had looked at a large retrospective observational study of the Vestrom, Health, Retina Database.

01:59:18 It included This used a, a big data informatics approach that included over twenty-two thousand eyes with branch retinal vein occlusions and over eighteen thousand eyes with central retinal vein occlusion, and seventy percent had at least twelve months of follow-up, whereas ten percent had at least, sixty months of follow-up.

01:59:36 So five-year follow-up, really fascinating as we think about how patients do, how patients are treated in real-world settings with the- with a Vestrom Health Retina Database within the United States.

01:59:48 Patients always wanna know what to anticipate, as they move forward with treatment.

01:59:52 In year one, patients who were diagnosed with central and bre- branch retinal vein occlusions received about seven injections in year one.

01:59:59 At year five, about four injections, so fewer injections, over time.

02:00:05 And in terms of visual acuity, you saw that the patients who were treated with anti-VEGF injections gained about twelve letters in the branch retinal vein occlusion group and about ten letters in the central retinal vein occlusion group.

02:00:17 And as you look at year five, as I ta- mentioned in SCORE-2, we saw a slight dip in the visual acuity. We saw this as well.

02:00:24 In year five, there were only about eight letters, as opposed to the twelve-letter gain in the branch retinal vein occlusion group and about five letters in the central retinal vein occlusion group. And I think this really, reflects our clinical experience, as well.

02:00:36 It's really important from this pers- perspective that patients are followed, and this does represent a chronic condition.

02:00:44 One really fascinating figure, and I encourage you, for those of you who are involved in residency education, this is a fantastic article, for a journal club.

02:00:52 But these patients were actually divided into tertiles by the number of injections that they received over the sixty-month period.

02:00:59 The first tertile, which is, which is the orange line, are individuals who received less than fifteen injections over the sixty-month period.

02:01:06 Patients in green were in between about fifteen to twenty-nine injections, and in blue, over twenty-nine injections.

02:01:11 So these are the patients that were treated probably the most assertively over the sixty-month time point, and this is actually a visual acuity curve.

02:01:18 And you can see that the patients who received a greater number of injections tended to do better from a visual acuity perspective in both the branch and the central retinal vein, occlusion groups. And I think that we're always thinking about ways that we can improve the quality of life for our patients through their vision, but also thinking about ways to reduce treatment burden.

02:01:37 But, we also have to think about how we can preserve visual acuity over the long haul as well. So again, it is a chronic condition that requires long-term monitoring, and patients do require anti-VEGF up to the sixty-month, time point, and there certainly are ongoing unmet needs.

02:01:52 And so that really brings me to, the second generation of anti-VEGF agents for retinal vein occlusion.

02:01:59 We have faricimab and aflibercept, with the Dr.- which Dr.

02:02:02 Fekrat and Dr. Singh nicely outlined, so I won't go into, their mechanism.

02:02:06 But the major trials that looked at-- that really was a Phase III, evidence for faricimab for retinal vein occlusion- were the CAMINO and the BALATON studies.

02:02:15 And I love when they have an easy way of remembering which name corresponds to which disease. So CAMINO is for central retinal vein occlusion, there's a C, and the BALATON is, is B for branch retinal vein occlusion.

02:02:27 Aflibercept, the QUASAR study actually studied both BRVOs and CRVOs, within the same study, looking at two milligram versus the higher dose, eight milligram, dose.

02:02:38 The study design, was a non-inferiority, trial, looking at faricimab versus aflibercept, as, to determine whether it was non-inferior to aflibercept for the treatment of branch and central retinal vein occlusions, again, in the BALATON and the CAMINO studies, respectively.

02:02:55 Patients subsequently rolled over into faricimab.

02:02:59 This is PTI, which means personalized treatment interval, for intravitreal injections up to week seventy-two.

02:03:06 So this is personalized for individuals related to when they need PRN doses of, faricimab. Again, the study design was faricimab versus aflibercept, with a primary readout at week twenty-four, rolled over subsequently to, faricimab with a personalized treatment, interval dose with a modified treat and extend protocol.

02:03:29 The, the differences that I'll mention is that patients with central retinal vein occlusion tended to have higher levels of, macular edema, exceeding seven hundred microns, so really thick, retinas.

02:03:40 And, you saw this with, as you compare the central subfield thickness between CRVOs and the BRVO category.

02:03:47 How did the patients perform?

02:03:48 Well, it turns out that in both arms, both with faricimab or aflibercept, there was improvement in visual acuity.

02:03:55 You can see that the visual acuity begins to improve at the week four time point and goes up to the week, twenty-four, up to s- sixteen to seventeen letters, with both, the cen- the CAMINO group and the BALATON cohort.

02:04:08 What was also interesting is that they also looked at fluorescein angiographic markers of macular leakage and found that there was a greater reduction of macular leakage observed in the faric- faricimab group versus the aflibercept group at the week twenty-four time point. These visual acuity improvements were sustained, for the seventy-two-week, doses, with the mean number of injections of about five injections, during that period.

02:04:35 And you saw these, reflected the visual acuity improvements that were, seen, in association with a reduction in central subfield thickness.

02:04:44 And what's important is that, nearly sixty percent of ind- individuals who were in the BALATON study for BRVO and more than forty-five percent, in the CRVO group were able to achieve greater than or equal to Q-twelve-week dosing.

02:04:58 So they were dosed at either three or four months, and you can see this very important durability signal that we're starting to see with the second generation of anti-VEGF agents.

02:05:08 And, this was very well tolerated, with no significant change in the safety profile.

02:05:14 Now, QUASAR looked specifically at aflibercept, a two-milligram dose versus the newer eight-milligram higher dose, and this was designed to look at non-inferiority of the eight-milligram dose, versus the two-milligram dose.

02:05:28 And so there are three arms, very similar to the study designs that you've seen, previously, either, aflibercept given two milligrams Q four weeks or given, as eight milligrams for three doses, every eight weeks after three initial monthly injections.

02:05:45 And there's also an eight milligram every week, eight-week dosing after five initial monthly injections, and you can see that, outlined here.

02:05:55 And overall, you can see the mean visual acuity, outcome was very favorable, with a nearly sixteen letter visual acuity improvement, overall.

02:06:04 And you can see this in both the branch retinal vein occlusion and central retinal vein occlusion groups, where both, groups are gaining a substantial level of visual acuity in all three treatment groups, again, showing that the higher dose was indeed non-inferior to, the two-milligram dose, with a fewer number of injections over time, again, dosed at every eight-week intervals versus every four-week, intervals after a initial loading dose. And s- the mean change in central subfield thickness was also encouraging and also reflected the visual acuity improvements as well. We're starting to think more about durability, as I mentioned before, and we're certainly seeing this as the vast majority of individuals were able to be at every eight weeks or greater, nearly ninety percent in the branch retinal vein occlusion, group, who were given, three, three, scheduled injections.

02:06:59 In individuals who were given five scheduled injections, you can see this rate is actually ninety-five percent, that were at least at the eight-week time interval.

02:07:07 And this is also very similar to what we find in the central retinal vein occlusion, population, being able to go out at least a week dosing.

02:07:15 And there will be results.

02:07:17 The week sixty-four results will be, shown at Angiogenesis, so which is in February, so please stay tuned for those results.

02:07:25 But again, very important to note that, the last assigned dosing interval, was, either Q-twelve or Q-eight weeks in a large proportion of individuals, as seen, on these pie charts. And again, we look forward to these results, early, actually coming up soon in the next one to two months.

02:07:44 And I'll just mention also that the ocular and non-ocular safety events through week thirty-six, showed a favorable, response with a very low rate of, adverse events and very similar to what we're seeing with the two-milligram dose.

02:07:57 And so I think that we're seeing a shift as we think about the treatment of retinal vein occlusion, very important related to early treatment, but also continuation of treatment for a longer period of time, ultimately increased durability signals with both, aflibercept milligrams and- faricimab, as well.

02:08:16 There's been a lot of data in this session, but again, we've shown that there's multiple randomized clinical trials that have shown excellent outcomes, with treatment.

02:08:25 There are some subtle differences that have-- that you've seen differ between different, studies, but very important to note that treatment delay beyond six months can be detrimental, and that long-term follow-up is certainly critical for retinal vein, management and as well as a risk factor modification and working with our care providers to optimize outcomes for patients.

02:08:46 So thank you again.

02:08:52 All right, so we've got about ten minutes left in this session, and we thought we'd just do the Q&A now. So these are some really great questions from the audience members. Thank you for submitting them.

02:09:03 Does multimodal imaging include using your indirect?

02:09:07 I think it does. I, I think that's a fair commentary.

02:09:10 What are your thoughts?

02:09:11 Well, yes, of course. Yeah.

02:09:12 We really can't, give that up, especially the younger generation.

02:09:17 These baseline skills are so important, and you sort of see it in primary care.

02:09:21 They basically don't examine the patient anymore. Yeah.

02:09:26 S- Steve, one of the comments about the CRVossa you mentioned in, in the initial s- slides was about the highest quartile of injections having the best outcomes.

02:09:37 Is that just the c- the cure or remedy to all of these things that can be used, just, you know, cheaper drugs or drugs that have been around for so long and just give them a lot more frequently, and is that the answer to these kind of conditions rather than just the durable drugs? Yeah, I think that's a great question.

02:09:52 I think that, I, I would say that the point of emphasis, is the importance of, of close follow-up and also, ensuring that they have anti-VEGF on board.

02:10:01 There's another study, that actually when we look about-- just look at just the patients who actually can have recurrent fluid despite anti-VEGF injections, it can be about ten percent, and about sixty percent will have recurrent fluid, and so these patients often need, you know, additional, more frequent dosing. Yeah.

02:10:17 And so whereas only thirty percent actually have-- can have r- complete remission of fluid.

02:10:20 So I think that it's important just to continue to treat.

02:10:23 I think that there are subtle differences.

02:10:24 We certainly can see anti-VEGF, a non-responder, spes-- I've seen this specifically with bevacizumab, that sometimes we need to move on to, something else.

02:10:33 Yeah, I agree. This is another one, with your patient with sarcoid, uveitis and the tattoo patient.

02:10:41 Can you treat this with s- with steroids, or is there concern around the mycobacterium being, worsening because of that?

02:10:48 Well, how, how does that treatment work with that sort of patient you had in that case?

02:10:52 Yeah. So I, I think that, that, that, ultimately, that's a great question because there is this balance between infection and, and immunity.

02:10:57 Yeah. Dr. Wood and Emily really I mean, it was really beautifulized- beautifully identified this infection.

02:11:03 So, so in this situation, they've-- they're looking at antibiotics, and because of the, the, the challenges with mycobacteria, these sometimes require longer courses of therapy, often in conjunction with ID.

02:11:12 But sometimes corticosteroids are needed to help dampen that immune response as well. Yeah.

02:11:17 Any tips on reducing artifacts from, wide-field images?

02:11:22 I think particularly because of that striking case you presented, and people are worried about this. Now, I'm going to be, like, searching- - all, all the lash lines in every patient that I see, like, so- I know.

02:11:31 You're forever changed.

02:11:33 I know.

02:11:34 Well, I think for, ultra-widefield, color photographs and autofluorescence in particular, I think, you know, you can hold the patient's lids open, so you can have your photographers do that. And I think with practice, it's just about getting the tilt correct, when you're obtaining those images.

02:11:53 That's- Of course, you can always put artificial tears in and other things- Yeah -to get better images.

02:11:58 I'll just chime in on one of the previous questions- Yeah ...

02:12:01 For non-retina specialists.

02:12:02 I think real-world outcomes are very different than clinical trial outcomes and for these, intravitreal injections.

02:12:09 So that's, you know, if we followed exactly the recommendations versus, you know, sometimes the real world, where the patient misses an appointment, or they get lost to follow-up, or we change our schedule.

02:12:23 I think that, you know, following the clinical trial advice, gives you superior outcomes. Yeah.

02:12:32 This is, another great question.

02:12:33 So right now, we have the faricimab drug approved for RVO, but we don't have aflibercept approved for RVO.

02:12:40 Is that right? And QUASAR is the study that they're doing for the registration. So do we have a anticipated date potentially of approval? Do you have an answer to that?

02:12:47 Oh, yeah. The, the date for that, for FDA approval of the aflibercept eight milligrams, has changed, and so we're hoping to get that soon.

02:12:58 I will say that I have treated patients, and their insurance has approved and paid for it, to use aflibercept eight milligrams.

02:13:05 So if interested in using it, you can always, you know, ask.

02:13:10 Shows you about the prior authorization process. Yeah.

02:13:17 Okay. As where it got approved.

02:13:19 Oh, interesting.

02:13:20 Oh, actually, I think it was just right before the holidays.

02:13:23 Oh! Yeah. We missed that. Sorry. Yeah.

02:13:25 I just wanted to make sure we clarified that.

02:13:27 So maybe we'll thank you for that. Yeah.

02:13:29 Thank you. And we'll- Yeah, thank you ... make sure that we, we have that in the next talk. Mm-hmm.

02:13:33 For GA, do you inject every other month or every month?

02:13:37 I'm an every other month person.

02:13:38 I think it gives you a little bit of flexibility.

02:13:40 I think the side effect profile, definitely better, less exposure.

02:13:44 Anyone else differently or- I will say- Yeah ...

02:13:47 A lot of people are, just picking the happy medium.

02:13:50 So if you're doing it every six weeks? Yeah.

02:13:54 Yeah, I think it's a little bit safer to, the safety profile improves for a, particularly for pegcetacoplan, when it's given every eight weeks instead of every four weeks, but the efficacy is not quite as good.

02:14:08 And I, I lean every, every other month, just risk-benefit analysis. Yep. Yeah.

02:14:11 Okay, last question, before 49ers game starts, so we can make sure we finish up.

02:14:18 How much GA do you, look at before starting injections?

02:14:22 So I don't think that there's a true, for me, measurement per se.

02:14:26 I think it's more of a patient discussion, fellow eye disease discussion.

02:14:31 Like, what's the fellow eye done?

02:14:32 Is it GA that's been lost?

02:14:34 There is patients who become very motivated.

02:14:36 What do you do, Steve?

02:14:37 And I, I agree. I mean, I think that it-- I think about proximity, to the, to the fovea and also the, their opposite eye, um- Yeah ...

02:14:44 As well in terms of what their history is.

02:14:46 I mean, and then sometimes patients, they, they, there's, there's quite a bit of direct consumer and advertising now, that they, they come with a, you know, the suggestion, if you will, as well, and so we'll certainly make the decision together.

02:14:56 So I think it really is a conversation. Yeah.

02:14:58 Sharon? Oh, yeah.

02:15:00 Well, so it is all about the patient conversation.

02:15:04 Sometimes, you know, a lot of the patients with geographic atrophy that's threatening the fovea, they're a lot older.

02:15:09 They're usually definitely in their eighties, usually their late eighties, and when you start describing what's involved, and they're functioning pretty well at the moment, they look at you, and they say, "Do I have to?" Yeah.

02:15:21 So I think there are a lot of factors that go into it. Yeah.

02:15:24 I'll just mention that, yes, aflibercept eight milligrams was approved right around Thanksgiving. Great. Okay.

02:15:30 Yeah. So that's great. Okay.

02:15:32 Well, that's the end of, this session.

02:15:35 I'm sorry to all the Bills, fans out there.

02:15:38 They lost in overtime.

02:15:41 Just what happened in Buffalo.

02:15:43 I'm sorry about that.

02:15:46 I'm, I'm-- I was a Browns fan, so it's even worse over there, so I feel for you.

02:15:50 Thank you to my co-presenters today, Dr.

02:15:52 Fekrat and, and Dr. Yeh.

02:15:54 You've been amazing. I thank you all for watching today, and, and we'll be starting back again in earnest tomorrow with some sessions, as well as, the keynote, Lindstrom Lecture tomorrow by Dr.

02:16:05 Peter-- by Peter Slack, which will be great to come and listen to tomorrow at ten thirty, I believe, today, tomorrow. So thank you, everyone.

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