The introduction of anti-VEGF drugs nearly 2 decades ago significantly changed the prognosis for preserving long-term vision for patients with neovascular age-related macular degeneration (nAMD).
However, the first generation of anti-VEGF agents to enter the market, including ranibizumab (Lucentis, Genentech) and aflibercept (Eylea, Regeneron), as well as the off-label use of bevacizumab (Avastin, Genentech), are not without their limitations. For example, results in real-world studies are considerably poorer that those reported in randomized trials of these drugs.1 The cause of the latter is multifactorial, but it is at least in part driven by the fact that real-world patients are often treated with regimens that differ from the fixed dosing used in pivotal trial programs. In one study analyzing data from 13,859 patients in the IRIS Registry, for instance, patients treated with bevacizumab, ranibizumab, or aflibercept received about six injections over a 1-year period.2
“With first-generation anti-VEGFs, the mean durability of the anti-VEGF agents we’ve been using is about 8 weeks, with a range of 4 to 12 weeks. So that means, on average, you’re injecting about every other month—and some patients can get to your office pretty easily every other month, and some can’t,” Dr. Regillo said. “We know that the reality is, in the real world, there are visual acuity declines on average, because we can’t really get the adherence we need to maintain the vision outcomes we get early on when we start treatment.”
According to Dr. Regillo, the cumulative evidence and experience in real-world settings has highlighted an unmet need for more durable VEGF inhibition, a treatment gap that appears to have been filled, at least in part, by the introduction of the so-called second-generation anti-VEGF inhibitors aflibercept 8 mg (Eylea HD, Regeneron) and faricimab-svoa (Vabysmo, Genentech) (Figure 1). Aflibercept 8 mg is the same molecule as in standard-dose aflibercept (2 mg), but the higher dose provides for longer duration of VEGF inhibition. Faricimab-svoa is a structurally unique bispecific antibody targeting both VEGF and angiopoietin-2, which is suspected to have a role in the pathogenesis of retinal vascular disorders.
Figure 1. Second-generation anti-VEGF agents offer the potential for greater durability, meaning longer intervals between injections.
In the phase 3 PULSAR trial, aflibercept 8 mg demonstrated non-inferior BCVA gains at 48 weeks compared to aflibercept 2 mg, which was the primary endpoint. However, patients in the 8-mg group were able to achieve significantly longer treatment intervals relative to what would be possible with 2-mg dosing (Figure 2).
Figure 2. Percentage of patients randomized to high dose aflibercept achieving extended dosing in the phase 3 PULSAR trial.
“It didn't give us, on average, better visual outcomes, but it did give us quite a bit better durability,” said Dr. Regillo. “When you compare the durability, we're looking at well over half the patients getting out to 16 weeks. And in year 2 of the study, we could even go 20 weeks, which is pretty darn impressive.”
Farcimab-svoa was studied in nAMD in the TENAYA/LUCERNE phase 3 clinical trial program. Each study demonstrated that farcimab-svoa was non-inferior in mean change in BCVA from baseline compared to 2-mg aflibercept. However, a significant proportion of patients were able to achieve those vision gains with dosing intervals of 12 weeks or greater (Figure 3).
Figure 3. Percentages of patients achieving 12-week or greater treatment intervals with faricimab at weeks 48 and 112 in a pooled analysis of the phase 3 TENAYA/LUCERNE study.
“And that's the beauty of what we saw in the phase 3 trials with three-quarters or so of patients being dosed at 12- to 16-week intervals at the week 48 primary endpoint, and over one-half at 16 weeks by the end of year 2. There's no way that we could have achieved that with first-generation drugs based on personal experience and what has been published to date,” said Dr. Regillo.
1. Chong V. Ranibizumab for the treatment of wet AMD: a summary of real-world studies. Eye (Lond). 2016;30(11):1526.
2. Rao P, Lum F, Wood K, et al. Real-world vision in age-related macular degeneration patients treated with single anti-VEGF drug type for 1 year in the IRIS Registry. Ophthalmology. 2018;125(4):522-528.
