In Fort Lauderdale, Florida, Dilsher Dhoot, MD, gave a presentation: “Effects of Time Since Diagnosis to Intravitreal Aflibercept Injection and Baseline BCVA on Outcomes in CRVO: Post Hoc Analysis of the COPERNICUS and GALILEO Trials.” The study found that treatment soon after diagnosis resulted in better visual acuity gains.

So we did a post hoc analysis of the Copernicus and Galileo trials. These are the Phase 3 registration trials for macular edema in central retinal vein occlusion.

In this trial, patients are randomized to receive either aflibercept or sham injection. Aflibercept patients were treated every four weeks for 24 weeks, at which point primary end point, which was loss of three lines or more, was read out.

In this post hoc analysis, we were very interested to see if a delay in treatment resulted in differences in anatomy or visual acuity gains. And so patients were divided into one of three groups: patients who were enrolled in the trial within one month of diagnosis, one to three months of diagnosis, or greater than three months from diagnosis.

So the interesting part of this trial was that there was visual acuity differences. Patients who had the best visual acuity gains were those patients who were treated within one month of their diagnosis, compared to those patients who were treated after three months of diagnosis were the worst visual acuity cases. Interestingly, their anatomy was the same. So the anatomy improved in all groups, and there was no difference.

The second part of this analysis was looking at baseline visual acuity. And the baseline vision acuity had any bearing on final visual acuity. And in fact, those patients with the best baseline visual acuity have the greatest vision at the end of the trial. The greatest gain was in those patients with the worst baseline visual acuity. And this may have to do with ceiling effect. But it turns out that their final visual acuity were not as good as your counterparts who started off with good vision.

And so I think this trial provides information for our patients and physicians and helps manage expectations; namely, that if a patient is seen with macular edema secondary to central retinal vein occlusion, it really is important to get started on treatment right away.

This transcript has been lightly edited for clarity.

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Retina World Congress

Dilsher Dhoot, MD, discusses the post hoc analysis of the Copernicus and Galileo trials, which investigated if a delay in treatment would affect visual acuity gains or change in anatomy.

Copernicus and Galileo trials: Effect of time since diagnosis on BCVA outcomes in CRVO

In Fort Lauderdale, Florida, Aleksandra Rachitskaya, MD, presented, “End-of-Study Results from the Phase 3 Archway Trial of the Port Delivery System With Ranibizumab in Neovascular Age-Related Macular Degeneration.” The Port Delivery System (Susvimo, Genentech) received FDA approval in October of 2021.

Well, thank you so much for having me. And it's a pleasure to talk to you today about the presentation that I delivered at the Retina World Congress in Fort Lauderdale, Florida.

So what I focused on was the results of the end of trial for Archway. Archway, as you might know, is a study that focused on the Port Delivery System. And it's really a pivotal trial that compared the Port Delivery System for the treatment of neovascular AMD to monthly ranibizumab.

The way this trial was structured, it had the Port Delivery System that was surgically implanted, and then refilled every 24 weeks and the control group were the patients who received ranibizumab monthly. We know that the primary outcomes were at week 36 to 40, and those results have been released and showed that Port Delivery System is noninferior and equivalent to monthly ranibizumab.

So in this presentation, we focused more at the secondary outcomes. So we looked at the visual acuity outcomes at 60 to 64 weeks as well as 88 to 92 weeks. And we also looked at anatomic outcomes, patients who required supplemental ranibizumab in Port Delivery groups and also at the safety. So that's kind of the big picture of what we looked at.

And the Port Delivery System is a surgically implanted reservoir that allows for continuous delivery of ranibizumab in patients with neovascular AMD. In fact, based on the Archway results, we have approval, FDA approval, for patients with neovascular AMD to receive the Port Delivery System. And those are patients who have been treated with two or more anti-VEGF agents.

So looking at the results of—end-of-trial results showed that in terms of visual acuity, the Port Delivery System was noninferior to monthly ranibizumab. We also saw very nice OCT findings, they were consistent and showed drying of the retina.

The other interesting aspect that we saw is by the end of the trial patients were eligible for 4 refills, so refills occurred every 24 weeks. So they were able to get 4 refills. Before each of these refills, at several visits before, patients were eligible to receive supplemental ranibizumab if they needed it, based on particular criteria. And so the study showed that 95% of patients did not require any supplemental ranibizumab. So that's interesting information in terms of efficacy of the Port Delivery System.

And then finally, we looked at the safety because this is a surgical procedure. So safety, of course is extremely important. And we didn't see any new safety concerns compared to the primary outcomes. In particular, we looked at the conjunctiva retraction and erosion, endophthalmitis, implant dislocation and septum dislodgement.

So, in summary, the end-of-trial results showed that when it comes to Port Delivery System, it is noninferior to monthly ranibizumab in terms of visual acuity and OCT outcomes, and the adverse events were manageable, and we continue to learn how to improve this surgery and make this successful for our patients.

Aleksandra Rachitskaya, MD, discussed the Phase 3 Archway end-of-trial results for the investigation of the Port Delivery System with ranibizumab in neovascular AMD.

Phase 3 Archway end-of-trial results: Port Delivery System is noninferior to monthly ranibizumab

In Denver, Colorado, Richard Rosen, MD, presented a talk entitled, “Assessing vitreous cortex hyalocyte morphology and dynamics in the living human eye.” Rosen is a professor at New York Eye & Ear Infirmary of Mount Sinai.

Hi. I'm Richard Rosen. And today we presented from my lab imaging of hyalocytes from a series of control subjects.

So hyalocytes are resident macrophages within the vitreous gel, and they are responsible for keeping the vitreous clear. The vitreous is the clear space between the lens and the retina. And so the hyalocytes are type of macrophage that continually surveils the area and clears of any debris that blocks the light from getting to the retina. And also is responsible for maintaining the immunological privilege of the vitreous, keeping it from any inflammatory conditions.

The process we used was—we started out with OCT, actually looking at cells with commercial OCT, and then advanced to our adaptive optics scanning light ophthalmoscope. And we were able to image by taking sequences every five minutes over an hour, we can actually see these cells moving around and within the vitreous gel structure and actually watch their different activities.

So the paper itself was describing the different morphological features. So there are different stages of activation of these cells. And we looked at the series of different populations of the cells within each individual. And so we recorded basically the distribution of the numbers of the different types of cells and their various movement, the variety of the movement, the speed of the movement, and just the characteristics of how they move.

So these cells are very fluid, they have a lot of different processes, and these processes extend in and out, and they grab on to different factors and clear the space. And this is really the first time that these cells have been imaged this way in humans without any sort of markers or any sort of dye or anything like that. So that's basically the crux of the talk.

So these cells are implicated in formation of epi-cellular membranes, which cause macular pucker, which are involved in proliferative diabetic retinopathy involved in proliferative vitreoretinopathy. And so it's the first time we've really been able to see these cells, the same way that we can see them in a culture.

And so we're hoping that we'll be able to study subjects with actual diseases, such as diabetes, cell subjects with different types of epiretinal membranes, and characterize how these cells behave and what's their role, and how, how we can potentially change their behavior so that we can help to eliminate them in some way without having to necessarily do surgery.

ARVO

Richard Rosen, MD, shares insights on how imaging can capture hyalocytes and their movement without the use of dyes.

Morphologic features of vitreous cortex hyalocyte captured with OCT

In Fort Lauderdale, Florida, Steven Yeh, MD, dives into his presentation, “Front-line therapies and novel drug delivery for uveitis.” He outlines a few common therapies, such as methotrexate, mycophenolate mofetil (CellCept; Genentech), adalimumab, and fluocinolone acetonide via suprachoroidal delivery (Xipere; Bausch + Lomb).

I have the privilege, at the Retina World Congress, to speak to frontline therapies and novel drug delivery for the treatment of noninfectious uveitis. Within the field of uveitis, we're very excited about the different possibilities and the therapeutic alternatives in our armamentarium — both systemic therapies that have been shown through randomized controlled studies to be effective for the treatment of noninfectious uveitis. These include medications like methotrexate as well as mycophenolate mofetil, or CellCept, for the treatment of steroid-sparing agents for noninfectious uveitis. We also have level-one data related to adalimumab, which is a tumor necrosis factor alpha inhibitor, that's also helpful for the treatment of noninfectious uveitis.

Now, when we think about uveitic macular edema, which is the leading cause of vision loss in uveitis, we also know this is very important to target these as well, both from the standpoint of reducing complications related to structural deficits as well as improving visual acuity.

And there have been other randomized controlled studies that have also looked at both intravitreal therapies as well as suprachoroidal drug delivery for the treatment of noninfectious uveitis. Within the realm of intravitreal therapies, the fluocinolone acetonide 0.18 milligram dose has been shown to be effective for reducing the rate of recurrences of uveitis in randomized controlled studies and two large phase 3 studies.

Now with regards to other treatments in uveitis, suprachoroidal drug delivery is a nuanced innovative drug-delivery platform that allows the treatment of macular edema due to noninfectious uveitis. Xipere, which is administered via the suprachoroidal drug-delivery platform, delivers high levels of medication within the retina to the choroid for reducing levels to anterior segment structures. Within the PEACHTREE study, which evaluated suprachoroidal drug delivery compared to sham control, patients who received Xipere experienced a greater visual acuity gain with about 47% of individuals getting three lines or greater visual acuity over the 24-week endpoint. In addition, rates of cataract were comparable between sham control, as well as suprachoroidal drug delivery and intraocular pressure rates were favorable as well.

So, in summary, there's a lot to be excited about within the realm of treatment for noninfectious uveitis both within systemic therapies, we have randomized controlled studies with level-one evidence about their efficacy signals for the quality of life and the patient's visual acuity with noninfectious uveitis. And within the realm of local therapies, both intravitreal and via the superchoroidal route, there's a lot to look forward to with regards to drug delivery to improve visual acuity and the quality life of our patients.

 This transcript has been lightly edited for clarity.

Steven Yeh, MD, provides a brief overview of available therapies for noninfectious uveitis and uveitis macular edema.

Expanding the therapeutic arsenal for noninfectious uveitis, uveitic macular edema

In Fort Lauderdale, Florida, David Boyer, MD, presented a talk entitled, “OPT-302 Combination Therapy in wet AMD: Phase 3 program designed to assess superiority in mean BCVA over anti-VEGF-A monotherapy.” Boyer serves as a retina specialist at Retina-Vitreous Associates Medical Group as well as a leading investigator for various national clinical trials.

Yeah, it's my pleasure to present to you some data concerning a drug that actually will improve our present treatment of patients with wet macular degeneration.

When the anti-VEGF era began, we were told that the VEGF receptor 1 and 2 were the most important and VEGF receptor 3 and 4 were not. And everything was concentrated basically on VEGF-A, and then aflibercept came out, so VEGF-B became important. We were always told that VEGF-C and -D were unimportant, and they were probably related to lymphomagenesis.

Well, it turns out that that's not quite true, because when you administer the anti-VEGF to block VEGF-A, you also get an upregulation of VEGF-C and -D. And we find that when patients that have wet macular degeneration, they have an elevated level of VEGF-C in their plasma. There's a lot of evidence now that the VEGF-C and -D receptor via G3, it plays an important role and is able to promote leakage. So blocking VEGF-C and -D is a great place to improve the quality of the patient's vision and the anatomic outcomes.

There were several studies that were done in Phase 1-2A and a Phase 2B study and then a very large Phase 2B study with about 366 patients. The comparator was ranibizumab, and it was divided 1 to 1 to 1. And basically, the patients received ranibizumab every month for six months, ranibizumab every month plus OPT-302 0.5 milligrams or OPT-302 2.0 milligrams.

The study was very interesting. At the end of the study the high dose the two-milligram dose showed about a 3.4 letter improvement overall. And it was not only an improvement in the in the vision: There was a tendency for an improvement in the 5, 10, 15 Letter gainers, as well as a decrease in the patients who had loss of 5, 10, or 15 letters. And anatomically, there was also significant improvements in the retinal thickness, in subretinal fluid and intraretinal fluid.

There was a pre-specified analysis that was performed and basically this eliminated the RAP [retinal angiomatous proliferation] lesions. And that was still allowed 70% of the patients in the trial to be evaluated. When you evaluated those patients and eliminate the RAP lesions, you had a 5.7 letter improvement, you had a marked improvement both in the 5, 10, 15 letter gainers, the number of patients who received 20/40 vision, and all the anatomic endpoints that we look for—the reduction of subretinal fluid, intraretinal fluid, and retinal thickness.

Based upon this the study will continue into a Phase 3 trial, and you have basically 2 groups of patients: The one group of patients will continue to receive ranibizumab as given by label every month, plus 0.5 milligrams of OPT-302, or two milligrams of OPT-302. The other group will receive aflibercept according to label receiving monthly injections for 12 weeks, and then every eight weeks after that.

And again, the additional treatment is with 0.5 milligrams of OPT-302 or two milligrams of OPT-302 against the aflibercept alone group.

Based upon the results in the Phase 2, patients with RAP lesions were eliminated. And we're very hopeful that we will see the similar results of getting 5.7 letters in this subgroup.

The study is ongoing right now and is still enrolling and if you have patients that you feel would benefit from this, certainly contact the nearest investigator.

David Boyer, MD, discusses the Phase 3 investigation for OPT-302 combination therapy for wet AMD.

Phase 3 investigation of OPT-302 combination therapy assess superiority in mean BCVA over anti-VEGF-A monotherapy

Oscar Otero-Marquez, MD, a research fellow with the New York Eye and Ear Infirmary of Mount Sinai, discusses his poster presentation titled, “Retinal Blood Flow Measurements in Healthy Subjects with OCT Doppler,” that was presented at the ARVO 2022 annual meeting held in Denver, Colorado.

 Hello. So my name is Oscar Otero. I am a research fellow at New York Icahn Infirmary of Mount Sinai. I'm working at the Dr. Rosen’s lab. My poster presentation is titled Retinal Blood Flow Measurements in Healthy Subjects with OCT Doppler.

The purpose of our study was to assess retinal blood biomarkers using a new prototype OCT. The idea is that we can measure retinal biomarkers such as blood flow volume, average velocity, and vessel diameter with new prototype.

What we found is that there is no difference in the supratemporal, infratemporal arcades in healthy human subjects. The idea of doing this study is that so far, we do have data available in the U.S. population. All the previous studies have been done on Asian populations. So this is the first time that we can measure retinal blood flow biomarkers in a U.S. population.

The next step is to image subjects with retinal diseases or with glaucoma. The idea is to use this prototype to image subjects with glaucoma, or CRVO. We think that these conditions might predispose to less blood flow within the eye. That means it is not proven yet that, for example, subjects with glaucoma have less blood flow within the eye. And that is a theory that still needs to be proven. So with this device, we can measure the blood flow within the large vessels that are different with OCT-A.

With this prototype, we are measuring the blood flow within large vessels close to the optic nerve. That way, we can see if there is a decrease in the blood flow in conditions such as glaucoma or, for example, in patients with CRVO, and retinal vein occlusions. There is a difference between the non-affected and the affected brain. One good thing is that we expect to measure if there is a difference within the same eye, for example, before and after treatment. If we see we are treating a patient with glaucoma, and we see that with one of our treatments the blood flow increases with medical or surgical therapy, we can reassure the patients that the treatment is good for them. And we can expect to use this as a clinical tool for our patients or for monitoring all kinds of diseases.

The study assesses retinal blood biomarkers using a new prototype OCT, aiming to measure retinal biomarkers such as blood flow volume, average velocity, and vessel diameter with a new prototype.

Measuring retinal blood flow biomarkers using OCT Doppler

Sunir J. Garg, MD, FACS, discusses the benefits of hypersonic vitrectomy as a novel technologic advancement for retinal surgeons in a presentation at the 2022 Retina World Congress.

Yeah, so hypersonic vitrectomy is one of the really most novel ways we have of removing vitreous, and our traditional guillotine cutters are really amazing. And as they've gotten faster and faster, they take smaller bites of the vitreous gel. And as you take smaller bites of the vitreous gel, you reduce viscosity. When you have less viscosity, you're able to remove the gel a lot more efficiently.

And over the past 10 to 15 years, our cutters went from 2500 cuts a minute to 15,000 cuts a minute to getting closer to 30,000 cuts a minute. But there's certain inherent limitations. Smaller bites are still small bites, but they're not tiny particles.

One of the other limitations of our standard guillotine cutters is they're a needle and needle design. And as you may remember from high school physics, the smaller you make a lumen, the exponentially more resistance you have. Hypersonic vitrectomy not only takes small little particles of the vitreous gel, but it doesn't have a needle and needle design. So the single lumen gives you an effectively larger internal radius, enabling you to remove the vitreous gel a lot more efficiently.

So we looked at a bunch of different cases using this technology. And we found that we could do pretty much a whole host of retinal surgeries with it: retinal detachments, retain lens material, silicone oil cases. And for a lot of cases, it was really great. And surgeons found that was particularly advantageous for removing vitreous gel in mobile retina. So in retinal detachment cases it was terrific. We could use that same port to remove retain lens materials, we didn't have to open up a frag in these cases. And some of my colleagues actually used it to remove silicone oil.

And it was kind of neat to be able to do basically the entire surgery with one instrument. There was a couple of cases in which I don't think anything's going to be better than a guillotine cutter, particularly in really thick, dense diabetic membranes. Using scissors or guillotine cutters are really fabulous. And there's a couple of cases that had a really kind of glassy, thick vitreous gel, that this didn't work that great, but honestly, neither did my guillotine cutter so I think that was just those cases.

One of the other potential advantages of this is you don't need gas, so you don't need big gas tanks and you don't need to be tethered to an operating room. So whether you're in places around the world that don't have easy access to those things, or whether you're looking at doing vitrectomy outside of the traditional or this might be really advantageous.

There are some limitations about it, you know, we're still refining the different port technologies. So one of the great things about this is you can change the port. So you can make it into a teardrop shape; you can make it into a sigmoid shape, and some of our new iterations seem to be a lot more efficient than our old ones.

We're also adjusting some of the parameters of the handpiece. One of the things that we found is by increasing the frequency, we can dramatically increase the force or the ability of the instrument to cut the vitreous gel. And we're currently working on a new sigmoid shape, which seems to be a major improvement over what we had before.

But considering that the technology is really new, and there's only been hundreds or maybe 1,000 cases done, I'm really impressed with how dramatically better the technology continues to get. And as we use it more often, I think we'll continue to refine it.

Note: This transcript has been lightly edited for clarity.

Though the speed of traditional guillotine cutters has increased significantly in recent years, there are certain limitations. With the advent of hypersonic vitrectomy, Sunir J. Garg, MD, FACS, explains how retinal surgeons can remove the vitreous gel with more efficiency.

Hypersonic vitrectomy: Novel technology for vitreous removal

At Retina World Congress in Fort Lauderdale, FL, Carl Regillo, MD, presented a talk entitled, “Results of the KSI-301 Dazzle Neovascular AMD Pivotal Clinical Trial.” While the study failed to meet its primary endpoint, KSI-301 demonstrated good initial visual gains and anatomic effects as well as positive durability.

Dr. Regillo is the director of retina service at Wills Eye Hospital.

I had the opportunity to present the top line results of the Phase 2/3 pivotal study on the use of KSI-301 to treat neovascular AMD.

This is all very new information, so a lot of people are probably not aware of the results. Unfortunately, the study did not reach its primary endpoint in terms of KSI being noninferior in mean change BCVA from baseline to the primary endpoint compared to aflibercept.

So, we saw some initial visual gains that look good, in addition to some good anatomic effects early on during the induction phase, the monthly injections of the therapeutic, but some loss of vision over time. And so the amount of vision gain at the primary endpoint was not as much as aflibercept.

What we saw was very good durability, actually. And there's the positive aspect to the way KSI performed. Sixty percent of patients were able to be extended out or be treated as infrequently as every 5 months. So that is impressive, with 60% of patients going 5 months and doing very well, visually, anatomically, on par with aflibercept. It was the 30% of patients that were getting KSI-301, every 12 weeks or three months that didn't perform as well.

It is pretty clear from case studies in further analysis that those patients probably need to be dosed more frequently than every 3 months, because we saw a good initial drain 1 or 2 months after a given KSI dose. But then disease activity recurred significantly and that accounted for vision loss. It was that 30% of KSI patients getting treatment every 3 months that sort of brought the whole population visual acuity down over time to the primary endpoint.

While the DAZZLE trial failed to meet its primary endpoint, KSI-301 demonstrated good initial visual gains and anatomic effects as well as positive durability.

Carl Regillo, MD, outlines latest results of KSI-301 clinical trial

Rishi P. Singh, MD, FASRS, highlights the two-year results of the YOSEMITE and RHINE trials, in which patients were randomized to receive either faricimab or aflibercept, in a presentation at the 2022 Retina World Congress.

My presentation was on the two-year results of the YOSEMITE and RHINE trials. This trial enrolled patients and randomized them to receiving either faricimab or Eylea within the course of the trial. The patients in the faricimab arm were actually given either a personalized treatment approach after four loading doses or given the drug every eight weeks after loading period.

And what the study found was really quite interesting. The faricimab molecule, which is both a combined anti-Ang2 and an anti-VEGF, performed better than the aflibercept drug in the trial in many different ways.

First and foremost, the durability of the drug was significantly better in the faricimab study, with almost 79% of patients achieving acute 12 week of dosing and the personalized treatment approach during the end of the two-year study.

In addition, 60% of patients who received the drug every 16 weeks at the end of the two-year trial, and we found greater reductions in retinal fluid, especially intraretinal fluid, within the faricimab arm compared to aflibercept. As well as we saw better resolution of diabetic macular edema in a faster fashion within the faricimab arms compared to aflibercept during the two-year trial.

In the study, the faricimab molecule, which is a combined anti-Ang2 and anti-VEGF, performed better than the aflibercept drug in many different ways. Rishi P. Singh, MD, FASRS, summarizes some of these key findings.

YOSEMITE and RHINE trials yield durability, retinal fluid reduction, DME resolution with faricimab

At Retina World Congress, Harry W. Flynn, MD, presented a series of videos that illustrated vitrectomy techniques in endophthalmitis management cases. In the four cases he presented, Dr. Flynn described a variety of endophthalmitis management options for retinal surgeons.

Thank you. I was part of a symposium on uveitis, and I was specifically talking about endophthalmitis management approaches. My focus was on vitrectomy techniques in the management of endophthalmitis cases.

I started out with a case of endogenous endophthalmitis caused by Candida albicans. The traditional way of handling these cases is to perform a pars plana vitrectomy. But many of these eyes are prone to retinal detachment because of vitreoretinal traction. And because of large lesions that have organisms growing through the choroid into the retina and into the vitreous, these lesions are often highly elevated.

In a video, I showed a technique of laser treatment to surround the lesions first, and then to actually obliterate the lesion with direct focal laser. We still use intravitreal and systemic antifungals as part of the treatment.

My second case was a bleb-associated endophthalmitis, and I show 27-gauge vitrectomy techniques to enter the eye, especially when these eyes are very congested, and to remove the vitreous and allow injection of intravitreal antibiotics. It is important to avoid de-bleeding the bleb because these blebs are highly necrotic. And if you do so, the debris mot will leave a large hole in the sclera often with leakage … very difficult to close. So we just use subconjunctival antibiotics in these cases, which are usually adequate.

My third video was on a combined approach to keratitis-associated endophthalmitis. These cases are particularly tough because the cornea is opaque. There is no view of fundus details. So I showed a combined approach with 25-gauge surgery, a corneal transplant, removal of the intraocular lens, performance of a pars plana vitrectomy, and placement of fresh corneal tissue graft in place when finally with injection of individual antibiotics.

My last case was a suture removal-related endophthalmitis. These cases occur rarely, but they do occur when people forget to use povidone iodine on the ocular surface. And these are often caused by Streptococcus, which is a very virulent organism and it causes poor outcomes. I showed a technique of using 27-gauge vitrectomy in the anterior chamber to remove the fibrin clot, followed by a pars plana vitrectomy. again using 27-gauge techniques. The pictures that I showed were courtesy of David Jacobs, one of my former fellows who allowed me to use his slides.

In summary, I used my presentation as a way to present vitrectomy approaches for endophthalmitis in these very difficult and challenging cases.

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