Jury’s Out

The treatment of neovascular age-related macular degeneration (nAMD) has been transformed by the introduction of intravitreal anti-VEGF therapy. Since the introduction of this class of treatment in 2005 with off-label bevacizumab, the field has both embraced anti-VEGF therapy but also continuously tried to reduce the frequency of injection treatments, while maintaining the very good visual and anatomic results demonstrated in fixed-interval treatment protocols. It has been demonstrated that, in aggregate, converting patients in a given population to a less-frequent, 12-week injection schedule has not shown nearly as much benefit as higher-frequency, 4- or 8-week treatment (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). When study populations that did well in high-frequency dosing groups are allowed to follow-up in extension trials at infrequent intervals and receive few injections, visual acuity drops off fairly quickly over time. Real-world data also supports the finding that infrequent injections of available anti-VEGF injection therapy correlate with decreased acuity, whereas more frequent injections correlate with better vision (10).

Recently, Novartis presented data from the HAWK and HARRIER trials (11), which showed that 57 percent and 52 percent of subjects, respectively, maintained vision at 12-week injection intervals following a 3-injection monthly loading phase. In the protocols, patients were assessed monthly and could be treated at either 8- or 12-week intervals depending upon the presence of disease activity.

The question that was not directly challenged in the HAWK and HARRIER studies is whether or not the current commercially available agents (bevacizumab, ranibizumab, and aflibercept) have similar efficacy when subjected to the same dosing protocol. HAWK and HARRIER used aflibercept as an active control agent in half the randomized patients, but the aflibercept could only be dosed at 8-week intervals – without an option to extend to 12-week intervals, which the brolucizumab subjects enjoyed. Fortunately, ranibizumab and aflibercept have been extensively studied in a variety of less-frequent injection dosing protocols, and we can look at the patient populations in those previously published studies for some illumination regarding whether the HAWK and HARRIER results imply that a meaningful advance with regards to dosing frequency has been made.

In PIER (3), patients received 3 monthly loading doses of 0.3 mg (n=60) or 0.5 mg ranibizumab (n=61) then quarterly dosing through month 12. Fifty-four percent of patients at month 12 maintained their initial visual acuity gains enjoyed over the 3-month loading period (4). In CABERNET (10), the control group (n=163) received 0.5 mg ranibizumab quarterly after 3 monthly loading doses. At month 12, 71 percent of these patients required no additional therapy and gained a mean 8.2 ETDRS letters from baseline. In EXCITE (5), most patients were randomized to quarterly dosing after a 3-month loading phase. At month 12, approximately 41.6 percent of patients receiving quarterly ranibizumab 0.3 mg (n=120) and 0.5 mg (n=118) maintained their initial gains in BCVA. During weeks 52–96 of the VIEW trials, a subset of patients achieved a dosing interval of ≥12 weeks from the 0.5 mg ranibizumab q4 weeks (n=218; 43 percent), 2 mg aflibercept q4 week (n=284; 54 percent), and q8 week (n=245; 48 percent) groups. At week 96, these patients gained a mean 9.2 (AFL2q8), 8.8 (AFL2q4), and 8.5 (RBZq4) ETDRS letters from BL (6)(7).

Cross-trial comparison of over a decade of anti-VEGF studies suggests that approximately 50 percent of patients with nAMD perform well with a 12-week dosing schedule of ranibizumab, aflibercept, or brolucizumab. Our subspecialty is certainly seeking a therapeutic that can reduce the burden of treatment for our patients, and we will welcome brolucizumab as an additional treatment option. However, we need to look at its data in the context of our maturing compendium of knowledge studying anti-VEGF biologics in nAMD before we conclude that brolucizumab will provide an actual reduction in dosing burden.