Overcoming Treatment Plateaus in Chronic DME

Dr. Garg: 
Hi, I am Sunir Garg. With me is my good friend and colleague, Dr. Charlie Wykoff, and today we'll be discussing overcoming treatment plateaus in chronic DME. Here are our relevant financial disclosures. We'll do our best to hit these learning objectives as much as we can today. Charlie, this is a great case that you and Dr. Phan had seen in Houston. Would you mind taking us through this? 

Dr. Wykoff: 
This is a fascinating case, and controversial for many reasons. I'm super excited to present this to you, Sunir, and get your input and your guidance because I've learned a lot from this patient and the comanagement that many of us have put to this case. So the fascinating thing about this is that the patient's monocular, right? Their right eye has central retinal atrophy and also some optic nerve damage, probably a combined RVO and also DR process in the past. 
They have a long-standing history of proliferative diabetic retinopathy and DME. He's a 68-year-old gentleman, still actively working and his left eye is his better-sighted eye. You can see on this scan, he looks pretty good. He's 20/50. There's a little bit of DME, a little ERM there, some hard exudates, but overall pretty good. Photoreceptor layer looks pretty good and this is what he looks like a few years after that initial picture I just showed you. Now 9 years after receiving regular injections, and long periods of monthly injections, and you'll see why in a few slides. So he's 20/70 on this image because of the DME and he notices the medications wear off like clockwork. 

Dr. Garg: 
Typically, our data suggests that sugar control going crazy, blood pressure going crazy, kidney disease is going bad, doesn't typically associate itself with diabetic edema, but in somebody who's getting shot so frequently with this much edema, at least I would wonder is there something else going on that I'm missing? Is there some inflammatory processes? Whatever. So it really is very atypical. 

Dr. Wykoff: 
Yeah, completely agree. And their retina, when he's dry, if you look at the edges there, the nasal side of that OCT scan, there's not a lot of DRIL. His layers there look pretty good. The temporal side, there's a little more ischemia and such, but he has a relatively healthy retina when he does not have the fluid as you'll see. 

So this is 1 month later, he's receiving fixed aflibercept 2 mg injections now essentially monthly. And there are a few months of this because you can see how consistent it is. We'll pause in a couple slides and for real discussion point. Yeah, you can see at this point he's again stable. He's in that 20/50 to 20/60 range. Sometimes he gets down to 20/30 actually, but with this central fluid. But occasionally he is lost to follow-up because often he gets admitted for some other diabetes-associated complication to a hospital and can't get the care that he needs. And you can see what happens when he was delayed by a few weeks. 

So this is why he keeps getting the monthly injections. Because when he doesn't get treated, he has this really dramatic recurrence of the edema and he symptomatically gets tremendously worse. I mean, it's amazing his acuity as good as it is because I would believe it if it was 20/200 or 20/400, it's still 20/70, which is pretty good. But subjectively, he says he can't function at all. He can't drive at this point. He can barely read, he can't do his job, and that's why he's been so compliant coming in so frequently with monthly injections for so long. 

Dr. Garg: 
And that's one of the amazing things about folks with diabetes or even neovascular AMD to some extent, is they know how much these treatments will help them. And so people like this really will prioritize their eye appointments more than really any other thing in their lives because when this happens to them, they're dead in the water and they know it. 

Dr. Wykoff: 
Yeah, it's fascinating you put it that way because you're absolutely right. I completely agree. It's one thing to look at a spreadsheet with the numbers of injections we give patients and say, "Wow, that's a lot of injections." But then you talk to the patients and you see how valuable they really are. And patients don't like to get pokes in the eye and the Betadine hurts and they're irritated for a while. But a lot of patients do that repeatedly because they actually directly benefit from the improvement in visual function. 

So the goal here, so this is when aflibercept 8 mg came out, and this is one of the early switchers that we had. And so we decided, hey, look, this could be a perfect patient for a longer interval here. So switch, gave them 8 mg here for the first time. And you can see a month later they are as dry as they've ever been. I don't want to say they're drier than they've ever been, but they look really good compared to where they had for a long time. 

And why is that? Is that just a higher molar dose of the same medicine? I guess so. That's just my explanation and I think what's happening here is just this patient's clearance of this medication is very rapid and/or their VEGF level is very high. It's probably a combination of both that determines a given patient's interval, and this patient is just one of our really frequent flyers and here with 8 mg, they're able to go longer. 

Dr. Garg: 
This is an amazing response. I would've predicted meaningful improvement, maybe a smidge better than they had been with 2 mg every 4 weeks, but I wouldn't have guessed this. 

Dr. Wykoff: 
Yeah, agreed. And then this was them another month later. Again, consistent 8 mg dosing. You can see their ellipsoid zone centrally has a few little areas of breakdown, but overall is pretty good. And you can see that's why that they notice when the fluid comes back. And here they're 20/50, but again, subjectively, dramatically better than where they were at 20/70 with all that massive amount of fluid a couple months before. So we continued monthly, aflibercept 8 mg at this point, saw them again in a month and then at this point, decided to go longer. 

Now the goal here was not to go 8 weeks after this, it was to go 5 or 6, but there was a delay in the patient getting back. And so you can go to the next visit, but we were surprised to see that there was beginning to be a little bit of recurrence, but really nothing dramatic at this point. Of note, the patient, I find this fascinating, it's not a lot of my patients, but some patients will start to notice vision, the drug wear off, particularly an RVO or DME before there's a dramatic amount of fluid. And that's what was happening at this patient at 2 months. They said, "Look, I noticed that it's starting to get blurry again," and that was before there was a meaningful amount of fluid. 

Dr. Garg: 
One of the things that I'll often ask them is, well, now that we're on this newer drug at every 8 weeks versus aflibercept 2 mg that you were on monthly, what do you think worked better for you, both in terms of the vision, in terms of frequency of visits and overall quality of life? Because some patients will be like, "Look, I'm just telling you that it's wearing off a little bit. As long as you're not worried about it, I'm cool coming in every 8 weeks." Other patients will say, "You know what? I like the way my vision was a week ago. I need to go back to that because that just kept me functioning better." 

Dr. Wykoff: 
Yeah, it is funny when that happens. Because I have patients that with RVO where they're very sensitive and they absolutely want to stay dry all the time, and I keep saying, "Let's push you out a little bit longer." But they notice it, so they want to stay. They know what their interval is, and this patient's exactly like that. So we decided to continue them at 8 weeks. And that's the other question I'd have for you, Sunir, is this someone that you would push longer? And I think, at this point, we've basically maintained them on every 7 to 8weeks, and when they go beyond that, they do tend to have a little bit of recurrence slowly just after 8 weeks. And so that's where we've maintained them. 

Dr. Garg: 
Yeah, I would do the exact same thing. I mean, getting this person who was at 4 weeks, who's doing pretty well, not great anatomically, to every 8 weeks with better anatomy to me is such a huge win. And the patients would probably say, "This was a huge win. For 9years, I was coming in every month and then now I'm every 8 weeks," that everybody's thrilled. That doesn't mean that I won't explore it. And I think once the eye proves to me that it's going to behave itself at every 8 weeks for a while, I don't have a specific number, maybe 6 months, 8months, then I will do what you had indicated in the previous conversation we had of let's go 8 to maybe 9 weeks. 

And maybe I'll stay at 9 weeks for a time or two, make sure everything's cool to try to get them out a little bit farther. But I wouldn't be very aggressive in pushing this person out probably because it's their better-seeing eye. Probably because they were just so stubborn for so many years that their eye behaves differently than other eyes, I would think. And so I think they just need more personalized attention than we might do for other people. 

Dr. Wykoff: 
Yeah, all really good points. I think the other thing you brought up earlier kind of resonated, which was especially in situations like this where it's hard to control, making sure the systemic factors are under control. And this patient had ups and downs on diabetes, but overall was doing pretty well. I think their HbA1c was 8 or 9, so it was reasonable. It wasn't terrible, and they had a consistent relationship with their primary care physician. They just had sort of a frustrating course of diabetes, and they had systemic manifestations also. 

Dr. Garg: 
How often do you bring up conversations of the importance of HbA1c and systemic management for patients who are in this situation, and what do you do with that conversation? Do you just kind of mentioned it with the patients? Do you have the in-depth conversation? To what extent do you engage other members of their healthcare team? 

Dr. Wykoff: 
I try to stay positive with HbA1c because I don't want to be negative with patients around their blood sugar, blood pressure, cholesterol control, but I try to bring it up in a positive way. So for example, if it's about 7.5 or better, so we always document the HbA1c and if it's 7.5 or better, I will almost always comment with something along the lines of, "Hey, I see your HbA1c is really good, you must be working at it." That's a phrase I use a lot. And then patients will light up and they'll say, "Yeah, doc, I'm trying," or, "It's hard." We sort of resonate around a positive message. 

And then if it's above that but not too high, let's say in sort of 8 to 9.5 range, it depends on where they were before. So if they were above that before, let's say the 10 range and they're down to 8.5, I'll similarly be positive. I'll say, "Look, you're in a good trajectory here. It looks like you're down." Then if we're above the 9 range, I tend to bring it up in a soft way and I say, "Man, I see your HbA1c is a little high. How are things going?" Because I feel like most of our patients know that their HbA1c needs to be lower and that it's important, and I try to bring it up in a nonthreatening way where they know that I know, and then I kind of have an open-ended conversation about it. What do you do? 

Dr. Garg: 
I do something similar. Whenever possible, I'll try to tie in improvements in their OCT to what's happening with them systemically as well. So if the HbA1c is pretty good or is better now than it was when we began, even if my anti-VEGF injections may be doing the lion's share of the work, I'll say, "Look, between the work you're putting in coming into the office and the work you're putting in at home with your sugars and blood pressure, we're in a lot better place today than we were a year ago." 

And I do try to be that cheerleader along the way because this is a tough lifetime disease for people, and it's a slog. And there's, I don't want to say a judgmental aspect to it, but especially if people are overweight too, they kind of get tied up in those feelings as well. And I think focusing on the things that people do have influence and control over, as you suggested, I think it's just a great way to go and it's a more humane approach in my opinion as well. 

Dr. Wykoff: 
That's a great point. The data that I think of with this, I think is fascinating. And I actually talk about this with patients, especially early in the disease course. There've been a lot of secondary and post-hoc analyses looking at HbA1c in our anti-VEGF trials. And overall, the two things that I remember from a lot of those analyses are that regardless of what your HbA1c is, you can have a good response to anti-VEGF, right? The response to anti-VEGF for DME does not appear to be dependent on HbA1c. So someone with great control, poor control have an equal chance of doing well. 

Really important for patients under poor control to understand that, because oftentimes they feel guilty, they feel like they caused this, and I try to take that off their shoulders. I try to say, "Look, regardless of your systemic control, that's super important. We're going to talk about that repeatedly, but regardless of that, we have a good chance of improving your eyes here." I think that's really important and positive for patients. 

And the only other thing I remember related to that is that in the control arm, I think it was VISTA and VIVID, that was the one place where HbA1c made a difference. So if you're at a really good HbA1c, you had a much better response to focal laser. I don't know if that's actually true, but that was the finding from the study. And I tend to think overall that probably just means that if your HbA1c is well-controlled, your disease is probably going to be a more benign course. 

Dr. Garg: 
Yeah, great point, Charlie. And this was a post-hoc analysis of the PHOTON study, and just to highlight a couple of things. Patients did really well out to 2 years with treatment, and I think that's important because patients want to know, "What do you mean I'm not getting just one or two shots, I have to do this for longer?" And so when I say, "Well, look, we have data right now, these newer agents are potentially able to keep your vision good for 2 years, with improved vision really through year 1, the maintained at year 2 is important." 

One of the other thing though that was important was when patients were previously treated with DME, those were the switcher patients that you had alluded to, it seemed like some of those patients may have needed more frequent treatment or may have benefited from more frequent treatment than patients who were treatment naïve. And I think that really ties in beautifully with your case. Somebody who was stuck at monthly shots for 10 years is probably going to behave differently, than somebody who just developed DME for the first time 2 months ago. And I think personalizing their treatment has really made a lot of sense, both in your case as well as being born out in the data as well. 

Dr. Wykoff: 
Yeah, really good point. I think these prospective trials are really important because it helped give us guardrails and discussion points with patients. I like the fact that this trial really pushed the envelope on durability. I think that that's useful. Aand I think that these newer agents probably can get patients to go a little bit longer, which is good. 

Dr. Garg: 
We are also fortunate to have other treatment options available for patients with diabetic edema. Faricimab is one of the other newer agents that's been approved for patients with DME. Similar kind of results that we're able to see with ongoing treatment. Patients have improved anatomic response as well as improved visual acuity over time. When you're in this space, we know from some of our earlier work, the DRCR.net trial that aflibercept seemed to be better than ranibizumab or bevacizumab, particularly for patients who had 20/50 vision or worse. Now with aflibercept 8 mg as well as other treatments, how do you decide which drugs to incorporate into your practice? And do you have one that you go to? Do you try different ones depending on the anatomy? 

Dr. Wykoff: 
Well, I have a low bar to switch. So I think the important thing is when, especially in diabetic macular edema, I tend to lean toward earlier treatment. We have the PROTOCOL V data, which is fascinating and a little bit controversial for many reasons. But you can have center-involved DME with good vision and they can do okay if you observe them until they lose vision and then you need to treat them. I think that that's reasonable. 

I tend to take a little early approach in routine clinical practice where if there is disruption of the photoreceptors centrally, I have a low bar to initiate therapy. Because I find that in that state of the disease, you don't need a lot of injections in most cases, to get rid of that central fluid, dry the central fovea, and then either stop injecting or do a rapid treat and extend, a long interval. So I tend to initiate earlier than PROTOCOL V would suggest, in my own hands. And in that state, especially in early disease states, I think most of the anti-VEGFs can do well. 

That said, when there is any evidence of persistent fluid after monthly injections, I do have a low bar to switch to one of the newer agents. I think I've had good experience with both faricimab and with 8 mg aflibercept and I think that both of them can meaningfully extend intervals. Although they don't, in my opinion, extend intervals quite as long as the clinical trial summaries would suggest. I think that there's an incremental benefit that is meaningful to many patients, and it all depends on what that starting timeframe is, right? 

The case here we just talked about, going from a month to 2 months, is fantastic, but that patient is not going to get to every 12 or 16 weeks, and that's okay. It's still a win for that patient to have an incremental benefit. 

Dr. Garg: 
Yeah, I saw a patient earlier this week who they were with their family member and the family member said, "Well, when is my loved one going to be getting the drug that lasts for 4 months?" And I said, "Well, you've been getting the drug that lasts for 4 months for the past year. Your disease just requires you to come in every 9 weeks." And they're like, "What?" 

I'm like, "Yeah. There are different things that we look for to keep people seeing well, and we're fortunate that we have flexibility in dosing intervals. And I have some patients whose disease really is pretty easygoing, and I can push them out very far. But the way that you see best is when you're coming in more frequently because when we tried to space you out before, your vision dropped off. You remember when that happened?" They were like, "Yep, I remember that because that scared the heck out of me." And so we really do need to tailor it to what the patient needs and not just to the top line data, although the top line data is really impressive. 

Dr. Wykoff: 
I love that. I think you summarized it perfectly. I love the individualized perspective. And I had that conversation with patients at the beginning and then frequently throughout. I say, "Look, these medications are great, and it's hard to predict. It's hard to predict exactly how much vision you're going to get back, exactly what your vision's going to be and exactly how frequently you're going to notice this. How frequently you're going to need the injections." But I say, "Look, we're going to optimize your vision, and then we'll go as long as we can in between the injections, and maybe that'll be a month and maybe it'll be 4 months, and we're going to have to wait and see." 

Dr. Garg: 
That's awesome. Well said as always, Charlie. It's a pleasure learning from you and spending time with you, and thank you all for joining us. 

Dr. Wykoff: 
I enjoyed the discussions, Sunir. Thank you.