Diana Do, MD

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I’ll bring up the question of this new category of AMD [age-related macular degeneration] that many have described. I really like the paper in particular by Dr Phil Rosenfeld talking about this nonexudative neovascular form of AMD. These type 1 membranes, these CNV [choroidal neovascularization] lesions that grow up between broken membrane between the RPE [retinal pigment epithelium], have been called confluent drusen for years. Just a double layer sign on structural OCT [optical coherence tomography] and then OCT-A could pick out the lesions, but there’s no exudation. There’s no subretinal fluid, and there’s no intraretinal fluid. There are typically no symptoms with these lesions. It turns out that 10% or 20% of patients with GAA and intermediate drying B may harbor these lesions. It’s fascinating to be able to pick these up clinically. When you see a lesion that might be this nonexudative form of neovascular AMD, do you think about those treating those eyes? How do you manage those eyes, Mark?

 That’s a great question. It shows how amazing it is to be in our field given this explosion of not only treatments but, as you are mentioning, the diagnostic capabilities we have with OCT-A and understanding things we didn’t know. You’re absolutely right: OC [optical coherence] angiography has allowed us to image and see these lesions. It’s not something I would go after if it doesn’t already have a neovascular exudative component, but I will follow them much more closely. Instead of bringing them back in 6 months or so, I am much more aggressive with my observation, I guess you could say. I would have them come back in just a few months and see how that’s going, and at the first sign of leakage, I would definitely initiate treatment early on. But it’s quite remarkable with the OCT-A and that we’re able to see these.

 Sophie, Charlie, I had a question about OCT-A. I know a lot of our friends and colleagues have these amazing OCT-A images. When I use it in day-to-day clinic, a lot of the images are challenging to interpret. I still rely on my good old fluorescein angiogram when I want to make the diagnosis of active wet AMD. Am I the only 1 who has trouble getting good OCT-A images, or do you have these cases too?

 I’m glad you brought this up for discussion, Diana. In most cases, OCT-A is difficult to interpret. You may see a lesion there, but you may not know if it’s leaking or not. I’m old-fashioned. I like fluorescein, and I like OCT. But in select cases that are leaking on fluorescein but perhaps the OCT doesn’t show the lesion as well, I get an OCT-A. The reason is that if I can see the lesion on OCT-A, then that is a noninvasive way of monitoring that patient, because I certainly don’t want to do serial fluorescents on my patients. I found it helpful in that situation. I found it helpful in other conditions such as CSR [central serous chorioretinopathy], which has given me some nice CNV membranes to look at and, in some cases, vitelliform dystrophy. But in run-of-the-mill wet AMD, I wish I could replace fluorescein angiography with OCT-A, but I don’t think we are there yet. There are few select individuals in the United States who have big OCT labs and an army of help to find that lesion. But that’s not routine practice.

 Something that can help, at least in my limited experience with OCT-A, is that when patients are getting the OCT-A, usually it’s their last test. Oftentimes their eyes can be even more dried out, especially in this older population that has such dry eyes. I’ll usually have them relubricate the eye, and then—also after the scan—I make sure the proper segmentation was done on the OCT-A itself. Sometimes that will bring out the lesion or whatever you’re trying to look for. It’s helped me in some cases. But as you said, sometimes it can be very challenging, and we just do the best we can with what we got.

 I agree with everything that’s been said. Diana, I have the same challenges. I’m used to being efficient looking at our structural images on OCT. You can glance at an OCT efficiently and interpret it. But with OCT-A, it takes a long time to resegment and to correct and look at the different layers. It’s a very time-consuming effort to look at those. Unfortunately, I find myself moving away from fluorescein. I say 

 because I wholeheartedly agree with Sophie. Before the COVID-19 era, I would get a fluorescein on almost all my patients at baseline, and then rarely after that unless there was some change. Even now, I must admit, if it’s obvious I often will skip the fluorescein. I feel a little guilty saying that because I enjoy having those baseline images. I’m just trying to be efficient. I look forward to OCT-A software catching up with the structural OCT software that we have.

Videos

A panel of experts discusses nonexudative neovascular AMD and challenges associated with diagnostic imaging such as OCT-A and fluorescein angiography. 

Diagnostic Imaging of Nonexudative Neovascular AMD

VEGF agent, 1 of the big 3 that you laid out. And you treat them monthly. They’re compliant, as Sophie brought in—great point. You’re 3 or 4 injections in, and there’s persistent fluid. They’ve gotten better, but they’re not 20/20, and their symptoms haven’t totally resolved. At what point do you think about switching agents? What’s your driver for switching? How do you switch agents in clinic?

 This is a common clinical scenario that we face as retina specialists. Often we may, for insurance purposes, start a patient with bevacizumab because of step therapy that’s being employed in a lot of insurance plans. If the patient in my hands does not have a good clinical response—defined by resolution of active fluid compartments on the OCT [optical coherence tomography] or significant improvements in vision—then I would like to switch to an FDA-approved rapid agent if possible. I tend to try to switch them to aflibercept because there are robust efficacy and safety data that suggest that it is a good therapeutic agent for patients. We’re able to extend patients every 8 weeks or longer with aflibercept therapy. I usually wait 3 to 4 months if I had started them on bevacizumab before seriously switching to a different agent.

Very reasonable. Is there such a thing as a nonresponder? If this is wet AMD [age-related macular degeneration] and not a masquerade syndrome—we’re not talking vitelliform dystrophy that someone misdiagnosed; you really got wet AMD—is there such thing as a nonresponder? What’s an incomplete responder or poor responder? What are the words you use?

 That’s a great question. I wish there was a better way to figure out who these patients are going to be. Ultimately, you’re trying to do every 28 days—as frequently as you can get with bevacizumab—and it’s just not getting results, or the resolution of the fluid or improvement that we’re really looking for. As Diana just pointed out, for a lot of these patients, we convert them to aflibercept, and there is an improvement in vision. There definitely is a role for that switching and with the different agents. To get that really aggressive treatment, it can really get some good success with that switching.

 Sophie, what’s your goal? We talked about how you communicate goals to patients early on, but you have a little puddle of subretinal fluid in the center. It’s stable with monthly dosing. The patient is happy; the vision is OK. Do you ever tolerate fluid and begin to extend, or are you a treat-to-dry physician? What do you think about fluid?

 I’m definitely a treat-to-dry retina specialist. Sometimes you learn that based on 1 case. The reason we treat to dry is because we have drugs that are just about controlling the disease in those who have a little fluid. If you extend by another month, you may tip the balance into getting a lot more fluid and vision loss. It’s important to understand that we’re about keeping them stable if they have a little fluid. In my opinion, they’re not the ones to extend.

The question of how much we discuss with patients depends on how much they want to know. Some patients want to see the OCT and they want to see each kind of fluid, and they ask you to pull them up and compare them. Others just say, “My vision is fine,” and they may be doing well on whatever regimen of injections they’re used to. Everyone is different, and you have to cater to each patient’s needs because if someone is generally happy with their vision and is doing fine on injections—say, every 4 or 6 weeks, and they come in for a quick injection—perhaps they don’t want to know all the details of the OCT. And vice versa for the other kinds of patients when you just say, “You’re vision is great.” They really want to see their OCT. Every patient is an individual, and it’s important to understand what they want to hear about as well.

 Great comments. Diana, this is a little philosophical, but what about PDT [photodynamic therapy]? Is there any role for verteporfin? We have the EVEREST II trial that suggests maybe at least with ranibizumab it adds value. But you have the PLANET trial, which suggests that with aflibercept, it doesn’t really add much value. Is there a role for PDT in IPCV [idiopathic polypoidal choroidal vasculopathy] cases?

 A lot of retina specialists are not keeping their PDT machine. It’s at some select centers, but it’s not widely used. I use PDT most of the time for central serous retinopathy but not wet AMD because it’s effective in stopping leakage from that. Some physicians still think polypoidal choroidal vasculopathy if you aren’t getting the response you want with monotherapy intravitreal anti-VEGF agents; the combination may be helpful in select patients. PDT’s role in wet AMD is much smaller and maybe just for a few niche patients.

Key opinion leaders discuss factors to consider when selecting treatments in wet AMD including insurance considerations and degree of clinical response.  

Factors to Consider When Selecting Therapy in Wet AMD 

Mark, you were our safety guy before, so I’ll come back to you for another safety question. We’re all aware of the injection safety risks you described. What about this theoretical systemic safety risk? You have data that you can inject anti-VEGF agents in 1 eye and see a contralateral effect? You can measure decrease in system VEGF levels with some drugs at some points in some patients. Does it play a role in your clinical management in any way? If I had to pressure test that, especially in the high-risk patients, the patient says, “I just had a stroke 2 weeks ago,” or “I just had a heart attack, the vascular path.” Are there certain populations for whom we should think about this theoretical risk?

It’s a great question you’re mentioning because so far, in the data we have nothing is substantiating that. There’s clearly a systemic risk from it but at the same time, there’s certainly experimental and theoretical risks. We have noticed that there are anti-VEGF levels in the bloodstream, in the plasma, that have been detected experimentally and clinically. It’s there, and it’s getting outside the eye, but is it to a clinically meaningful level? I’m not sure we know the answer, but we are more confident.

In a lot of these large major studies, we’re not finding clinical end points. They’re suggesting that we’re causing danger issues to these patients. Based on some of the quantitative data in terms of levels in the blood, ranibizumab seems to clear faster than the other drugs. Presumably because it doesn’t have that Fc component on the molecule itself. As you said, these high-risk patients, ones who had a stoke maybe, if they’re really pushing for it, there might be a conversation in which you’d try ranibizumab if they’re worried about it. Another is not necessarily in the wet AMD [age-related macular degeneration] category, but there are other indications where we might worry more about systemic bloodstream. If we had a pregnant patient with diabetic retinopathy or myopic CNV [choroidal neovascularization], that would be someone for whom we might consider ranibizumab if you had to do anti-VEGF. But I don’t think it’s super compelling to be driven that way.

Great comments. You guys summarized the state of play extremely well. I learned a lot. Thank you.

Panelists consider the theoretical systemic safety of anti-VEGF agents in wet AMD and discuss their role in the management of patients with risk factors.  

Theoretical Systemic Safety of Anti-VEGF in Wet AMD

What is the largest unmet need that you see on a day-to-day basis? I’ll make it a 2-pronged question. The biggest unmet need, and then how do you think that need is going to be filled over the years to come as our field continues to evolve? Mark, I’ll start with you.

: All these treatments are exciting on the horizon, I think we’re hitting that unmet need, which is trying to increase the efficiency of our treatment, to decrease the burden of the treatment but also increase the efficacy at the same time. COVID-19, looping back a little, has showed us that patients are scared to come in, but they’re also scared to lose their vision. It’s not only going to be a huge success for treating our patients during this pandemic, but even beyond that, and the future is bright for a lot of these new treatments that will transform the way we give them.

: I agree, treatment burden, obviously. In efficacy, we have reached very high efficacy, but then we have to think, what limits vision? It’s atrophy and fibrosis. And yes, those are other things that need to be worked on with regenerative therapies. There’s a lot of potential there as well.

: I’ll unpack that for a second. You bring up the gorilla in the room in many ways, which is this concept of atrophy. We have the final common pathway for many of these eyes, which is where they become atrophic, whether you call it GA [geographic atrophy] or MA [macular atrophy], now we’ve got cRORA [complete retinal pigment epithelium and outer retinal atrophy]. We’ve got all these terms for this issue where the retina basically becomes atrophic. There is a lot of activity there, too much research to unpack in this short period. But it is exciting. We’re going to have phase 3 data from an inhibitor of C3 cleavage coming out in the second half of this year. And let’s say theoretically, that does become approved, and we have a molecule now that’s on label to slow geographic atrophy progression. How do you see incorporating that into your practice? Diana, I’ll refer that to you.

: It would be great to actually preserve vision before it’s lost. Of course, a lot of these clinical trials involve patients who already have center-involved geographic atrophy, so there’s really no chance of improving their vision. We’re just trying to limit the growth of the atrophy. You almost want to try the agent in people who have geographic atrophy that has not moved to the center, that might be juxtafoveal or extrafoveal, to try to preserve their central vision. I would be inclined to perhaps try it in that subset of patients who can benefit from stopping atrophy.

: Very insightful. Mark, what’s your thought on how these inhibitors of GA progression will unfold clinically?

: Diana brings up a good point, the exact location of the atrophy. And as Sophie was saying, it’s trying to understand the atrophy process itself in terms of increasing our efficacy for treating these patients with wet AMD [age-related macular degeneration]. I do think there will have to be something in the pipeline later on that address’s other parts downstream or upstream that are leading to these unfavorable aspects of the disease in these patients. As soon as we can target those in addition to VEGF, we’ll be going in the right direction, and giving the most preservation of vision for these patients. If we continue to keep our eye on the prize in the research realm, we’ll be headed in the right direction.

: Super comments. Diana, I’ll bring it back to you then. The largest unmet need and how we’re going to fill that need over time.

: For me, the unmet need in most of my patients is durability of action. We’re seeing with a lot of these new agents in clinical trial development, that companies are trying to address that. When we look at real-world data, we see that a lot of patients in clinical practice receive on average 5 injections of VEGF inhibitors over a 1-year period. That’s why we’re not seeing the terrific visual acuity outcomes we would expect in patients who participate in clinical trials. If we can develop new agents that need to be injected 5 or fewer times a year in the office, that would be a game changer.

: Thanks again to all of you, and thanks to our viewing audience. We hope you found this 

 discussion to be useful and informative. Thank you.

Expert panelists provide an overview of current unmet needs in wet AMD care and discuss the potential for improving clinical outcomes and treatment burden.

Unmet Needs and the Future of Wet AMD Care

: Diana brought this up, but let’s come back and talk directly again about faricimab. I’m curious about everyone’s perspectives here. This is the latest and greatest phase 3 data we have to digest; it just came out publicly a couple weeks ago. It blocks angiopoietin-2 in addition to VEGF-A. We have the neovascular AMD [age-related macular degeneration] data as well as the DME [diabetic macular edema] data. It’s unusual to have 4 phase 3 trials to digest at once, 2 in wet AMD and 2 in DME. We heard Diana’s perspective. I completely agree with that. Sophie, what was your takeaway from the faricimab data that were presented?

: Certainly in AMD, faricimab [Genentech] was compared to Q8 [every 8 weeks] aflibercept. And yes, about half of the patients on faricimab could go out to Q16 [every 16] weeks. I just know that from our clinical practice, that does not occur. Even though in the trial, technically, they didn’t compare 16-week aflibercept to 16-week faricimab, most of us who have treated a lot of patients are very hopeful when we see those numbers and that extension. It holds great promise. I’m looking forward to its approval.

: Yes, exciting. Let’s talk about the other non–VEGF-A targets from the other molecules. You have OPT-302, briefly, which is targeting inhibition of VEGF-C, and D, in addition to VEGF-A, with concurrently administered either ranibizumab or aflibercept. There was a large phase 2 trial that suggested superior vision outcomes. That’s moving forward in a pair of phase 3 trials, a global phase 3 program is initiating enrollment supposedly soon. Any hope, Mark, that blocking additional VEGF family members is going to add value in this disease phase?

: We see it now with the agents that we have, the more different VEGF molecules we get, potentially the more robust the response. And as you pointed out with the trial data so far, it hasn’t been disappointing. It’s helpful. There have been some preclinical data with some other molecules as well, showing that ultimately VEGF is a beneficial target for us. But at the same time, we do have the capability of looking at other ways to target the neovascular disease. The more molecules we can target, certainly the better, and maybe even new pathways as well. For example, there’s the Runt-related transcription factor 1, it came out in 

, and it seemed like a robust target potentially for another agent down the line as well. It’s exciting to see everything that’s coming out.

: Charlie, it’s always interesting when you’re employing combination therapy because the OPT-302 requires a separate injection from the anti-VEGF agent. It’ll be interesting to see if it does show some added benefit such that patients would want 2 injections in 1 visit.

: Yes, great comment. Diana, take us even further downstream. Now we have all of these TKIs, these tyrosine kinase inhibitors, in the space. The theory here is to block intracellular signaling from all of the VEGF family members. You get the effect of OPT-302 plus Eylea or plus Lucentis, or whatever other medication blocking VEGF you’re going to use. Do you think these TKIs have a role in our space? We’ve talked about them for years.

: Yes, I know TKIs, tyrosine kinase inhibitors, are being evaluated by several companies. axitinib is being evaluated by Clearside [Biomedical] as a suprachoroidal injection that could have beneficial effects and long duration of action. In addition, Graybug [Vision, Inc] is evaluating sunitinib as a long duration, every 6 month-administered intravitreal injection. And of course, EyePoint [Pharmaceuticals, Inc] is evaluating their drug as well looking at a sustained delivery of a TKI inhibitor. All these in theory have the potential of working and will be put to the test when they go against our current anti-VEGF therapies.

: It’s exciting. There is a tremendous amount of activity in trying to achieve better and more sustainable outcomes for our patients.

Key opinion leaders in ophthalmology comment on the potential role of alternative targets beyond VEGF-A including VEGF-C/VEGF-D and tyrosine kinase inhibitors. 

Clinical Trials of Alternative Targets in Wet AMD

: Let’s look at the future. Many of you have already begun to touch on these topics. Diana, you are the leader in clinical trials. I love watching you present; I always learn from you. Tell us about the molecules in development specifically targeting this concept of durability of anti-VEGF agents. We’ll talk about the surgical stuff later, but specifically new molecules on the horizon in clinical trials. What do we have?

: There are a lot of exciting developments in [retinal disease treatments]. And certainly, one of the new highlights that was presented recently was faricimab, which is a bispecific molecule that inhibits both VEGF and angiopoietin-2. The top-line results were presented for the phase 3 clinical trials in wet AMD [age-related macular degeneration] and showed that faricimab was effective and safe and was noninferior to aflibercept in their patient population. In addition, faricimab was able to be dosed every 16 weeks in about 45% of the subjects. That suggests that faricimab does have the extended durability to inhibit CNV [choroidal neovascularization] activity. That’s an exciting development for an in office-based treatment. Additionally, new results were presented for KSI-301, which is an intravitreal anti-VEGF agent built on an antibody biopolymer conjugate platform, an ABC platform, from Kodiak Sciences Inc. This agent is also engineered for extended durability. And the phase 1b data were presented in 121 treatment-naïve patients with either wet AMD, diabetic macular edema, or retinal vein occlusion. Interestingly, the data showed that 2 out of every 3 patients treated with KSI-301 could have a 6-month treatment-free interval after receiving 3 loading doses and 1 year of follow-up. Those are very encouraging results on their ABC platform, and they’re in pivotal studies as well. Sophie could probably allude to some other agents in clinical practice and clinical trials right now. But it’s a very exciting time in retinal disease treatment.

: It’s a great outline of the horizon. Sophie, tell us about the update now on the Port Delivery System [PDS]. We’ve been talking about this PDS surgical implant for a long time, years. Now we have high-quality phase 3 data assessing the efficacy compared to the monthly gold standard ranibizumab dosing for wet AMD. Tell us about your interpretation of the PDS data to date.

: The data are really promising. The Port Delivery System is a port that’s implanted surgically, and ranibizumab is injected through the port every so often. In the phase 3 trial that was every 6 months, and the results were comparable to monthly ranibizumab. In the phase 2 trial, there were many patients who were able to be injected even longer than [every] 9 months, some every 15 months. The data are very promising. Now, this is a surgical procedure, and it does involve coming in for refills. And as you know with any surgical procedure, there are some complications. Potential complications could include vitreous hemorrhage, but the surgical techniques have evolved such that the vitreous hemorrhage rate now is much lower. Another concern is endophthalmitis, with having a port placed in the eye waiting for a refill. There’s still a lot that we will learn about, and right now it’s being evaluated by the FDA for consideration for use.

: Great comments, a fascinating new approach. Mark, a lot of people are interested in this one-and-done approach. Could we use that word cure for some of these patients? That’s obviously an overstatement, but I used it to be a little provocative here. Let’s talk about gene therapy. We have 2 programs now, with many months, over a year of data. And both programs are now in humans, RGX-314 and ADVM-022. What’s your perception of these gene therapy programs? Where are we, and what can the field expect?

: I think both drugs have a good shot at being transformative for our field. The RGX-314, like you mentioned, now it’s under phase 2b and 3 clinical trial with enrollment. And after a year of data, like you were saying, most patients were essentially injection free for a year. The anti-VEGF molecule can create on its own in the tissue with the subretinal delivery, or with the gene therapy, being able to make it itself is phenomenal. Who would have thought we’d be doing this 20 or 30 years ago? Being able to do that, and have it sustained, and not having to have injections or refills after that, is quite exciting. Then along with that, we have ADVM-022, which is also gene therapy. Unlike the other, it’s just a single intravitreal injection. The 1-year results from that showed promise in one of the cohorts, with not having any rescue injections needed for them as well. It’ll be exciting to see how the rest of the trials and data pan out for these 2 systems. It could be something on the near horizon for us in our arsenal.

A panel of expert ophthalmologists provides insight into emerging clinical trial data on new molecules, surgical implants, and gene therapy in wet AMD. 

Diana Do, MD

Articles

Unmet Needs and the Future of Wet AMD Care

Clinical Trials of Alternative Targets in Wet AMD

Emerging Treatments for Wet AMD

Diagnostic Imaging of Nonexudative Neovascular AMD

Factors to Consider When Selecting Therapy in Wet AMD

Theoretical Systemic Safety of Anti-VEGF in Wet AMD

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