With the availability of pharmacologic treatment for neovascular age-related macular degeneration (AMD) in the past decade, the prospects for patients with choroidal neovascularization (CNV) secondary to AMD have vastly improved. Ophthalmologists can administer monthly intravitreal injections with the knowledge that the great majority of neovascular AMD patients will maintain their current visual acuity and many will show sustained improvement as a result of this treatment.
However, the burden of monthly visits and frequent injections on patients, physicians, retina practices, and the health-care system cannot be denied. As George A. Williams, MD, pointed out recently in these pages, the number of intravitreal injections performed in the Medicare population rose from 3000 injections in 2003 to more than 1 million in 2010, an unprecedented increase in utilization.1
As beneficial as the advent of ranibizumab (Lucentis, Genentech) and other anti-VEGF agents has been, it would be highly advantageous to have access to a therapy that requires less frequent treatment while retaining the efficacy and safety of the available agents.
Late last year, another pharmacologic agent received US regulatory approval for the treatment of neovascular AMD: aflibercept (Eylea, Regeneron Pharmaceuticals).2,3 Notably, the recommended dose for aflibercept is 2.0 mg every 8 weeks after an induction period of 3 monthly injections.3 The recommended regimen for ranibizumab is injection every 4 weeks.4
The US Food and Drug Administration approval of intravitreal aflibercept injection was supported by 2 randomized, multicenter, double-masked, controlled clinical trials, VIEW 1 and VIEW 2. The top-line results of these studies at 2 years (96 weeks) were recently presented and discussed,5 and this article summarizes some of the data presented.
The VIEW 1 and 2 studies were essentially identical in design.5-7 VIEW 1 was conducted in the United States and Canada by Regeneron, and VIEW 2 was conducted in Europe, the Asia-Pacific region, Japan, and Latin America by Bayer HealthCare. The primary endpoint of both studies was the percentage of patients who maintained visual acuity, defined as loss of fewer than 15 letters of best corrected visual acuity (BCVA) on the ETDRS chart (3 lines), at 52 weeks.
In each study, patients were randomly assigned 1:1:1:1 into 4 groups: 0.5 mg aflibercept every 4 weeks, 2 mg aflibercept every 4 weeks, 2 mg aflibercept every 8 weeks after 3 initial monthly injections, or ranibizumab 0.5 mg every 4 weeks.5-7 After the primary endpoint at 1 year, patients were treated under the same dosing assignment as needed (prn).5,8 Patients were evaluated monthly to determine the need for treatment and were treated at least every 12 weeks.
(Because the aflibercept 2 mg every 8 weeks regimen is the dosage that recently received regulatory approval, many of the comparisons below focus on this group and the ranibizumab every 4 weeks group, in order to compare the recommended regimens for the 2 drugs.)
In year 2, the study design was a capped prn regimen across treatment and comparator arms.9
In VIEW 1, 1217 patients were randomized, and in VIEW 2, 1240 patients were randomized.6,7 A total of 2412 patients in the 2 studies were treated and evaluated; 1817 were treated with aflibercept.2 Mean patient age was 76 years.
The primary endpoint, maintenance of BCVA, was achieved at 1 year. As has been reported previously,2 in the integrated analysis at 52 weeks, 94% and 95% of patients treated with 2 mg aflibercept every 8 weeks lost fewer than 3 lines of BCVA, as did 94% of patients treated with 0.5 mg ranibizumab.9,10
In an integrated analysis of VIEW 1 and 2, in eyes treated with 2 mg aflibercept every 8 weeks, mean change in BCVA from baseline was +8.4 letters at week 52 and +7.6 letters at week 96, with a mean 11.2 injections over the 2 years of the study, including 4.2 injections in year 2. In eyes treated with 0.5 mg ranibizumab, mean change in BCVA from baseline was +8.7 letters at week 52 and +7.9 letters at week 96, with a mean 16.5 injections over the 2 years of the study, including 4.7 injections in year 2. The results of each study individually were consistent with the integrated analysis.
During year 2 there were modest decreases of BCVA in all 4 treatment groups, ranging from 0.8 to 1.7 letters. The proportions of patients who maintained a gain of 3 lines or more of BCVA at 96 weeks were in the range of 30% to 33%, similar to the proportion seen at week 52 (31% of those receiving 2 mg aflibercept every 8 weeks).
Anatomic response was also strong at 2 years. The rapid decrease in central retinal thickness seen in the year 1 results was largely maintained over year 2 across all 4 treatment groups.
Over the course of 2 years, patients in the aflibercept 2 mg every 4 weeks group received a mean 16 injections, including 4.2 during year 2; those in the aflibercept 2 mg every 8 weeks group received 11.2 injections, with 4.1 in year 2; and those in the ranibizumab group received 16.5, with 4.7 in year 2. The percentage of patients who required frequent injections (6 or more) during year 2 was lower in the aflibercept every 8 weeks group (15.9%) than in the ranibizumab group (26.5%).
In patients who received the greatest number of injections, those in the aflibercept every 8 weeks group required 6.6 injections during year 2, and those in the ranibizumab every 4 weeks group required 8.0 injections, a difference of 1.4 injections. In the quartile that received the fewest injections, the average number of injections in both groups in year 2 was similar, at roughly 3 in each group, corresponding to the protocol-mandated quarterly injections.
Both drugs had a favorable safety profile in the studies. The incidence of serious ocular adverse events was balanced across all 4 treatment groups in both studies. The most frequent events were associated with the injection procedure, the underlying disease, or the aging process. The incidence of arterial thrombotic events was also similar among all 4 treatment groups: 3.2% for the ranibizumab group and 3.3% for the aflibercept groups combined. No dose-related adverse-event signals were seen among the aflibercept groups.
It is notable that there was a modest difference in the average frequency of treatment in year 2 of the study— 4.2 for aflibercept vs 4.7 for ranibizumab—and this appears to be driven by the fact that fewer patients needed more intensive therapy with aflibercept. That is, more patients in the ranibizumab group needed 6 or more injections in year 2 than in the aflibercept group, and, among the quartile receiving the most injections, patients receiving aflibercept every 8 weeks required fewer injections than those receiving ranibizumab.
There is no question that both aflibercept and ranibizumab are excellent treatments for CNV secondary to AMD, with a high degree of efficacy and safety now demonstrated through 2 years in large randomized clinical trials. In the VIEW 1 and 2 trials, visual and anatomic improvements were maintained through year 2 with capped prn dosing. No unexpected safety signals were seen with intravitreal aflibercept in the trials.
We are lucky to now have another excellent agent to add to our pharmacologic armamentarium for the treatment of neovascular AMD.
Jeffrey S. Heier, MD, is Director of Vitreoretinal Services at Ophthalmic Consultants of Boston. Dr. Heier has served as an advisor for and received research support from Regeneron and Genentech, and he chaired the VIEW 1 steering committee. Dr. Heier is a member of the Retina Today Editorial Board. He can be reached at email@example.com.