Addressing Sub-optimal Response During the Treatment of Wet AMD

Dr. Kaiser: Suboptimal response to initial treatment of exudative AMD can be unpredictable, and can recur at different stages during treatment. Initial anatomic evaluation provides an essential foundation upon which decisions regarding changes in treatment can be made. We will begin with a discussion about sub-optimal response to treatment, monitoring of the disease and future treatments.

Sub-optimal Response to Initial Treatment

Dr. Kaiser: Dr. Kitchens, when do you decide that an initial treatment isn’t working and it’s necessary to talk with the patient about switching? Do you base your decision on vision alone, or do you refer to the results of OCT or a fluorescein angiogram?

Dr. Kitchens: My decision is almost always OCT-based, because I don’t necessarily believe you can trust the Snellen visual acuity test. A worsening OCT clearly indicates to me a suboptimal response. If I see worsening hemorrhage, then that’s definitely evidence of a suboptimal response.

Then there is a kind of gray area when it comes to defining a patient as an under-responder. I typically review a patient’s treatment from the first injection to the third injection, and if the patient’s subretinal fluid or vitreoretinal edema has decreased by 50% or more, I consider that to be a positive response. I don’t focus as much on a patient’s pigment epithelial detachment (PED), because I know it takes longer to respond. If the patient isn’t having a positive response after his third injection, I’ll start to talk about switching agents.

Dr. Kaiser: Do you have a preferred agent when you switch?

Dr. Kitchens: I usually switch to aflibercept (Eylea, Regeneron). If the patient isn’t responding to bevacizumab (Avastin, Genentech) or ranibizumab (Lucentis, Genentech), I think we need to go with the strongest thing that we’ve got and try to get the patient as dry as possible, as quickly as possible.

Dr. Kaiser: Dr. MacCumber, at this early switching point, do you also depend on OCT, or do you add fluorescein, ICGA, or any other diagnostic techniques at this point?

Dr. MacCumber: I think OCT is the most important study for determining the amount of residual fluid. However, with hemorrhage, ICG and angiography occasionally come into play. Sometimes when I detect a polyp, I will go with photodynamic therapy (PDT). Those pretty much make up my armamentarium, but I agree with Dr. Kitchens, my decisions are usually based primarily on OCT. Of course, vision is also important.

Dr. Kaiser: Dr. Brown, are there any features on OCT that would suggest to you the need to perform another type of imaging?

Dr. Brown: I think pure subretinal fluid in the absence of intraretinal cysts may make me consider that I missed a central serous retinopathy (CSR). If the patient has a thick choroid and pure, subretinal fluid, we’ll consider PDT. We rarely use PDT, but if a patient has a thick choroid, a PDT treatment can’t hurt, and if it works, that means CSR was missed.

Dr. Kaiser: I agree. Dr. Stewart, at what point do you become concerned about a lack of response to treatment, with any one of these drugs?

Dr. Stewart: I get concerned if I don’t see a good response after the first three injections. As the others have mentioned, at that point I consider switching drugs. Before doing this, however, I’ll re-evaluate my diagnosis. If I haven’t already performed a fluorescein angiogram, I will do one. If I have a baseline angiogram, I’ll re-examine it for signs of a masquerade condition.

So, the first thing I do is question my diagnosis.

And then my usual response at that point is going to be to switch drugs. And since I typically start with bevacizumab for most patients I’ll usually switch to ranibizumab or aflibercept, usually aflibercept, and then treat monthly. If, after an additional three injections, I still don’t see a good anatomic response, but I’m comfortable with my diagnosis, I’ll consider injections every 2 weeks. This regimen consists of bevacizumab alternating with ranibizumab or aflibercept. I generally don’t increase the volume of an injected drug because I think that increasing the injection frequency is more effective and safer. If the patient hasn’t responded to the second 3 months of injections, I’ll consider adding photodynamic therapy, though I’m frequently disappointed with the results.

Dr. Brown: One thing I like to try in cases such as the one that Dr. Stewart described — if I’ve switched therapy and I’ve gotten a suboptimal response again after three injections — I’ll consider giving a fourth injection and then I’ll bring the patient back 1 week later. This allows me another chance to see whether I can actually dry the patient out or not. If I achieve dryness after the fourth injection, I know it’s a matter of a frequency interval. If I can’t achieve dryness, then I just have to investigate another avenue.

Dr. Kaiser: Dr. Singh, do you try anything differently at that point?

Dr. Singh: I begin to consider switching when my registered change analysis OCT scans show worsening despite previous treatment. In addition, I have patients return 2 weeks after treatment to see if the treatment is at all effective by checking for a reduction in retinal thickness. The goal is to obtain a normal OCT with zero tolerance for fluid. However, the recent CATT analysis of predictive factors for OCT response showed that subfoveal intraretinal fluid appeared to be the single best predictor of visual response. Moreover, the results of CATT showed that time domain OCT is enough to guide treatment in a PRN fashion. Given all of this, I think this allowsretina specialists using SDOCT to accept more fluid.

I think that in using biologic agents to treat exudative AMD, we’ve come to understand that one of the long-term effects of these agents is tachyphylaxis, or a diminished therapeutic response to one of the drugs following repeated administration over time. Quantitative analysis of OCT volumes in patients with exudative AMD treated with ranibizumab and bevacizumab has shown a reduction in the ability to reduce retinal volume with repeated injections.¹ I believe there are a couple of studies that have shown at least a slight improvement in response after switching the agent.²

I think that too many practitioners may be too eager to switch. I guess the question is how much in the way of persistent fluid are you willing to tolerate, and how much does persistent fluid matter? The CATT study³ seemed to suggest that when it comes to persistent fluid, intraretinal fluid was the most worrisome type. Just a small amount of persistent subretinal fluid didn’t seem to affect visual acuity nearly as much. So, in my opinion, intraretinal fluid is the one big concern. If it consistently occurs, despite a repeated change of treatments, it’s a big ­problem.

Recognizing and Handling Tachyphylaxis

Dr. Kaiser: Dr. Singh, could you tell us how you recognize tachyphylaxis?

Dr. Singh: That’s a good question. I have to have seen a response to a drug beforehand in order to know whether I’m really seeing tachyphylaxis. It’s not an initial poor response, or incomplete response. With tachyphylaxis, you have to see at least a limited response first, or at least some significant improvement based on OCT and some improvement in the overall structure, before you can acknowledge a reduction in response.

Dr. Kaiser: Has anyone had a patient who was not responding well to aflibercept, who then switched that patient to, say bevacizumab or ranibizumab, with a good result?

Dr. Kitchens: Yes. I will occasionally switch patients back and forth if they’re struggling. I had one female patient who had received monthly injections of aflibercept in both eyes, over the past 6 years, and had persistent subretinal fluid. After switching to ranibizumab, she experienced an improved drying response. So, she felt qualitatively that her vision was better. I’ve had one or two patients like that. Most of the time I end up switching patients to aflibercept, because they started with bevacizumab or ranibizumab.

Dr. Brown: I think a selection bias may be introduced, because you never switch horses in the middle of the stream if the horse is pulling you through. So, if you only switch patients who are having trouble, you occasionally will have patients that perform better. I also have had patients that we switched from ranibizumab to aflibercept, who started getting more fluid, and then when we switched them back, they did better. I can’t be sure whether that can be attributed to improvement after a drug holiday or a similar phenomenon. I don’t know that I really believe in the theory behind tachyphylaxis. I can tell you I’ve had this discussion with a top expert Napoleone Ferrara, MD, a molecular biologist, on several occasions, and if he doesn’t know whether he subscribes to the theory, I’m sure I don’t know.

Dr. Kaiser: How would you define tachyphylaxis, Dr. Brown?

Dr. Brown: A true example of tachyphylaxis would mean shorter and shorter intervals between treatment — if, for example, I treat a patient every 6 weeks, and then the patient needs treatment every 5 weeks, and then every 4 weeks. But as Dr. Stewart said, the majority of patients develop a set interval and even years later, if I try to extend that, during vacation for example, they re-leak.

Dr. Kaiser: Dr. Singh, since you prefer to treat as needed, do you ever extend treatment beyond 1 month, with regard to your as needed treatment interval?

Dr. Singh: Not typically, unless the patient has been dry for many months in a row. I have a couple of patients who can go 6, 8, or even 10 months without an injection. We will talk about the risks of extending their visits, their risk of visual loss, and what sort of symptoms to watch out for. Sometimes I start with a 2 month interval and slowly extend it only after many visits show no significant injections or worsening of visual acuity. Dr. Stewart mentioned cases in which a patient only had three injections and didn’t require more — there are few patients like that. I’ve seen a couple who were able to end treatment after 10 injections, as well. I think extending the time between visits, with monitoring, can occur at some point, it just depends on your discussion with the patient.

Future Treatment of Wet AMD

Dr. Kaiser: I’d like to ask each of you to discuss what you think the immediate future may hold — the next 5 to 10 years — with regard to the field of wet AMD. What are you hoping to see?

Dr. Brown: It’s exciting that we now know the basic mechanism by which we can improve wet AMD, and that is with anti-VEGF suppression. We’ve already found agents that last a little ­longer, like aflibercept, and now the Holy Grail will be something that lasts for a significantly longer period of time — for 6 months or perhaps a year. I think it’s only a matter of time before that type of treatment will be available, either by means of a sustained-release device, or by means of a small molecule that can be deployed, perhaps in an eye drop. The progress will likely be similar to what we experienced with sulfonamides, or the first antibiotics. I think these are exciting times. We’re essentially curing blindness. I think in about 5 to 8 years or so, we’ll find ourselves saying, “I can’t believe we were giving shots every month.” At least I hope that will be the case.

Dr. Kaiser: We’d all be happy to see that.

Dr. Stewart, what are your thoughts?

Dr. Stewart: Of course I agree with Dr. Brown — anti-VEGF treatments have revolutionized our practices and changed the blindness patterns in industrialized nations. However, visual improvements with anti-VEGF therapy appear to have hit a therapeutic ceiling. Peak vision improvements reported by recent trials have not exceeded those from the ANCHOR and MARINA trials.^4,5 No matter what we do, we can’t seem to improve on the 8 to 11 letter average gains. I think that the only way to improve anti-VEGF therapy is to extend the duration of action beyond 4-8 weeks with sustained-release devices, refillable reservoirs or encapsulated cell technology.

Since we’ve hit this therapeutic ceiling, I’m pleased to see that we’re targeting other contributory molecules and moving toward combination therapy. By shrinking the neovascular complex or salvaging the RPE, we may finally break through the therapeutic ceiling and realize additional gains in vision.

Dr. Kaiser: We would be happy to see an effective combination therapy. Dr. Kitchens, what are you hoping to see?

Dr. Kitchens: I’m hoping to see developments in three areas. First of all, over the next year in imaging, I’m really looking forward to swept-source OCT. This technology should allow us to better define the choroid and maybe even the vitreous, as well.

The Holy Grail would be to stop progression of AMD and dry AMD in general. For dry AMD, Anti-factor D holds promise. If we can at least slow down atrophy, we can start to head off the second major cause of vision loss in macular degeneration.

Echoing comments by Dr. Brown and Dr. Stewart, I would say that I’m hopeful we’ll see a sustained-release device, but I think that will take a while because there are a number of challenges to overcome. Obviously, with other adjunctive therapies such as Fovista (anti-platelet-derived growth factor agent, Ophthotech), the bar is really set high. Getting two lines of vision out of people who have atrophy, and drusen, and 85-year-old retinas is a pretty amazing thing. It’s going to be hard for these other therapies to improve upon that.

I think that maintaining access to bevacizumab is going to be really important, because it continues to gives us an option in these challenging times of reimbursement.

Dr. Kaiser: Dr. Singh, what are your thoughts?

Dr. Singh: I expect that we’re going to have a sustained-release option, in some form, but that is not what I’m actually looking forward to most. The problem I foresee is that dry AMD will become as problematic as wet AMD. We have patients losing vision constantly. Even with the agents that are slowing progression of disease, we aren’t seeing a restoration of vision. I hope that with dry AMD patients, we’ll at least begin to see patients who have a lower rate of progression to legal blindness. We can effectively treat wet AMD, albeit with many visits, many injections, and many treatments, which takes a lot out of our practice and out of our patients.

So I hope the next big frontier will be vision restoration, however that will occur. Perhaps stem cell therapy, or maybe growth factors, will be found useful.

Probably the most important development would be a way to detect AMD much earlier. Genetics are likely to be only part of the answer. We have oxidative stress mechanisms in the body. We have proteomics. All of these have been shown in different studies to have predictive power^6-8 with regard to aggressiveness of disease and also with regard to the age that lesions will begin to occur. By investigating not just genetics but also proteomics, and the oxidative stress factor in the body, we may gain the ability to better predict what is happening in a given patient — I think that’s the next frontier.

Dr. MacCumber: I agree with that last point in particular. We don’t know why certain patients develop CNV, and we can’t predict when it will happen. We don’t know why certain patients develop geographic atrophy, either. I think we have to improve our understanding of macular degeneration, through genetics, through imaging, and through these other markers, so that we may be able to not only detect AMD in patients before they start developing vision loss, but also find some way to prevent progression to CNV or atrophy. It will be some time before we have this capability. I think a slow-release drug may be even more difficult, particularly with biologics. I think multimodal therapy, platelet-derived growth factor (PDGF) or other factors, combined with anti-VEGFs may improve our therapy for CNV. I also agree that we need some sort of treatment for GA because we really don’t have anything right now.

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