Real-World Wet AMD Outcomes Still Lag Trial Results: Carl Regillo, MD

Two decades after anti–vascular endothelial growth factor (VEGF) therapy transformed the treatment of neovascular age-related macular degeneration (wet AMD), the gap between clinical trial outcomes and real-world results remains stubbornly wide because sustaining the treatment regimen newer drugs require is harder than the trials suggest, explained Carl Regillo, MD, FASRS, chief of Retina Service at Wills Eye Hospital and professor of ophthalmology at Sidney Kimmel Medical College, Thomas Jefferson University.

Regillo traced the arc from first-generation agents like ranibizumab (Lucentis; Genentech) and off-label bevacizumab (Avastin; Genentech) to second-generation options such as faricimab (Vabysmo; Genentech) and high-dose aflibercept (Eylea HD; Regeneron Pharmaceuticals), explaining how each new class has bought patients greater durability and, in some cases, modestly better disease control. But he was equally candid about what hasn't changed: a meaningful share of patients remain suboptimal responders, and even those who respond well initially often see vision decline over the long term due to recurrent disease activity, fibrosis, or geographic atrophy.

In part 1 of his interview with The American Journal of Managed Care® (AJMC®), Regillo also unpacked the everyday realities that separate clinical trial protocols from his own examination room—how often patients are actually able to sustain treatment, and the logistical, financial, and caregiving burdens that drive some patients to fall behind on injections or abandon treatment altogether.

AJMC: Anti-VEGF therapy transformed neovascular AMD when it arrived 2 decades ago. Looking at the full arc from ranibizumab to faricimab to high-dose aflibercept, what has changed for patients in clinical practice, and what has stayed stubbornly the same?

Regillo: There’s been a lot of progress over the last 2 decades, with the introduction of new anti-VEGF biologics—faricimab and high-dose aflibercept, most recently introduced, which we call second-generation drugs, because there are some potential benefits over the first-generation drugs. For patients, there has been much better disease awareness, which allows for better engagement in the treatment programs that are necessary to get good results. The average patient now knows what wet AMD is, for example, and that was not the case 2 or 3 decades ago before the anti-VEGF era. They’re familiar with injections, and they’re less fearful because they know people getting them and they know they’re generally well tolerated.

Over the past 2 decades, our anti-VEGFs have improved. They’re more durable, there’s even evidence for slightly better efficacy with some of the newest agents, such as with better drying, and all this helps with outcomes. But what is stubbornly the same? There’s still a relatively high treatment burden. There are still scenarios of patients who are suboptimal responders, and the anti-VEGFs don’t necessarily improve vision or achieve very good vision outcomes. Even in patients with initially well-controlled disease, we still see relatively poor long-term vision outcomes. All the real-world studies show it, and that’s for a variety of reasons, including disease recurrence, which leads to progression or even some fibrosis that nibbles away at vision over time, or the development of geographic atrophy in patients actively being treated for wet AMD.

AJMC: Faricimab targets both VEGF-A and angiopoietin-2, and high-dose aflibercept pushes for longer intervals. How are you using these agents differently from each other and from older-generation options, and for which patients does the distinction matter most?

Regillo: Faricimab is unique in being dual-acting: it’s called a bispecific antibody because it targets not just VEGF-A but also binds and inhibits angiopoietin-2, which does appear to play a role to some degree in the pathogenesis of wet AMD and other conditions like diabetic retinopathy. Both faricimab and high-dose aflibercept give us greater durability; they have that in common. The added mechanism of action of faricimab might also allow for a bit better drying in the setting of wet AMD, although we’re seeing that benefit more so in diabetic macular edema.

There may be a little better efficacy for both drugs compared with first-generation drugs and may be a little better drying that favors faricimab, but both give us greater durability and greater duration of action, and that does help to decrease treatment burden for our patients with wet AMD.

AJMC: Clinical trials for anti-VEGF agents show strong visual acuity gains, but long-term real-world data consistently tells a different story. Where does the disconnect come from? Is it undertreatment, patient dropout, variable biology, or something else?

Regillo: You certainly named a few factors, because they’re all probably playing a role to some degree in giving us these disconcerting poor long-term vision outcomes. That’s not across the board for everybody. When you look at the long-term vision outcomes over 4 or 5 years of anti-VEGF biologics in practice, a lot of patients still do really, really well and maybe up to half or so at 20/40 or better. We saw that in the extension trial of the Comparison of Age-related macular degeneration Treatments Trials (CATT) study. But unfortunately, a lot of patients do have a decline in acuity, and it’s multifactorial.

Probably at the top of the list of factors that lead to vision loss over time is some degree of relative undertreatment. It’s nobody’s fault. We do our best to try to stay on top of the disease, but these are older patients with comorbidities, and life gets in the way. They may find themselves in a hospital or have trouble getting to the office because of other illnesses. Some of these patients need injections pretty frequently, every 4, 6, or 8 weeks, and that’s really hard to sustain over many years. Basically, our drugs have limited durability in many of our patients, and with frequent treatments, we’re more likely to be at risk for relative undertreatment and disease recurrences. Every recurrence, especially multiple over a long timeframe, tends to nibble away at vision and can lead to fibrosis.

The other major source, which we don’t have control of, is geographic atrophy, which definitely contributes to some of the long-term vision loss that appears in some patients, especially between years 3, 4, and 5 into therapy.

AJMC: In your own practice, what does the injection interval look like for most of your patients with wet AMD in the maintenance phase? Are you realistically achieving the intervals we see in the pivotal trials?

Regillo: We’ve done studies to look at exactly how durable our first- and second-generation drugs are. Based on everything that’s been published—pro re nata studies, treat-and-extend studies, variable treatment approaches, and real-world studies—first-generation drugs like bevacizumab off-label, ranibizumab, and 2-mg aflibercept have a mean or median durability in the maintenance phase of about 8 to 9 weeks, with a range of about 4 to 12 weeks. Very rarely do these drugs consistently control disease much beyond 12 weeks.

Second-generation drugs shift that to the right of the curve. If you think of a bell curve distribution, we’re talking mean/median durability in the maintenance phase for faricimab and high-dose aflibercept more in the range of 10 to 12 weeks, with a range of 4 up to 16 or more weeks and even longer in some patients with less aggressive disease. In general, we are seeing second-generation drugs lasting longer on average.

Now, are we achieving what we saw in pivotal trials? For the most part, yes, but there are some distinct differences in the way we practice versus how the clinical trials were designed. In practice. Most retina specialists still strive for zero tolerance for exudation. We call these disease-free or exudation-free treatment intervals. We don’t like to see recurrent exudation, so we adjust the treatment interval so that we don’t see recurrent disease activity. That will translate into more frequent treatments compared with the trials, because the trials allow for some disease recurrence before the treatment interval is adjusted, which makes the product look more durable. I call that the fudge factor—it’s about a couple of weeks. In general, yes, we are achieving longer treatment intervals with second-generation drugs, but just not quite as much as the trials would necessarily suggest.

AJMC: Treatment burden in wet AMD goes beyond just injection frequency. What does the non-clinical burden look like for your patient population, and which factors drive dropout most?

Regillo: There are a lot of factors that drive dropout, and the non-clinical burden is quite high and multiple in nature. Think of the logistics of getting to the office on a frequent and regular basis. If you’re elderly and have compromised vision, you’ll need assistance: family, friends, and transportation to get to and from the office. Comorbidities and medical problems also get in the way and interfere with treatment.

Then there’s cost. There can be significant out-of-pocket expenses for patients, both direct costs like co-pays, which can be quite high for the drugs, and indirect costs. Getting to and from the office, traveling in rural America, could take a few hours and be quite expensive. All of these factors contribute to patients being late for treatments, missing treatments, or sometimes discontinuing treatment altogether.