This month's issue of Ophthalmology features two reports from a phase 2 study of VEGF Trap-Eye for wet AMD, showing the new treatment offers more sustained and comprehensive VEGF suppression than may be achieved with currently used anti-VEGF agents.
The first report established the safety and efficacy of repeated monthly dosing with VEGF Trap-Eye over 12 weeks, with patients showing significant reductions in retinal thickness and improvements in visual acuity. In this fixed dosing phase, patients received one of five regimens of VEGF Trap-Eye for 12 weeks, followed by as-needed (PRN) dosing from weeks 16 through 52.
The second report details the PRN dosing phase, exploring whether the high affinity of VEGF Trap-Eye for VEGF-A and PlGF could translate into the maintenance of initial visual acuity gains through one year with less frequent injections.
This study was a double-masked, prospective, randomized, dose- and interval-ranging study in which five groups of approximately 30 patients each were assigned to a fixed-dose of intravitreal VEGF Trap-Eye in the study eye during the first 12 weeks of dosing, followed by PRN dosing from weeks 16 to 52. The VEGF Trap-Eye regimens were 0.5 mg or 2 mg at four-week intervals (0.5q4 or 2q4 on day 1 and at weeks 4, 8, and 12 for a total of 4 treatments) or 0.5, 2, or 4 mg every 12 weeks (0.5q12, 2q12, or 4q12 on day one and week 12 for a total of two treatments). During the PRN dosing phase beginning at week 16, patients received the same dose of VEGF Trap-Eye (0.5, 2, or 4 mg) as received during the fixed-dosing phase.
The clinically significant improvement in visual acuity achieved at 12 weeks (5.7-letter gain) was maintained to 52 weeks (5.3-letter gain), accompanied by a decrease in central retinal thickness (-119 μm at week 12 and -130 μm at week 52). Among patients in all treatment groups combined, 22 percent experienced a gain of ≥15 letters and only 8 percent had a loss of ≥15 letters at the end of the study period. These improvements were achieved with an average of only two additional injections over the 40-week PRN phase; notably, 44 percent of patients required either no retreatment or only one reinjection, suggesting a long duration of effect in these patients.
Treatment was generally well-tolerated, with a safety profile similar to that previously reported with other intravitreal anti-VEGF agents.
The most robust improvements and consistent maintenance of visual acuity generally occurred in patients initially dosed with 2 mg every four weeks for the first12 weeks. This difference was apparent at 12 weeks and was maintained throughout the 40-week PRN phase, despite the fact that all patients were treated as often as necessary during this phase, leading the authors to conclude that initial sequential monthly loading doses seem to provide better control of neovascular leakage and lead to superior gains in visual acuity that can be subsequently maintained with less frequent dosing.
The authors believe that the high binding affinity of VEGF Trap-Eye, its presumed long intravitreal half-life, and activity against multiple VEGF family members, including PlGF, may contribute to more sustained and comprehensive VEGF suppression than may be achieved with currently used anti-VEGF agents. Based on its binding affinity and estimated intravitreal half-life in humans, a mathematical model has predicted that, after intravitreal injection, VEGF Trap-Eye would maintain biological activity for 10 to 12 weeks, whereas ranibizumab would maintain such activity for 30 days, supporting the concept of less frequent dosing with VEGF Trap-Eye.
This month the U.S. Food and Drug Administration's Dermatologic and Ophthalmic Drugs Advisory Committee unanimously recommended approval of VEGF Trap-Eye for wet AMD at a dose of 2 mg every eight weeks after three initial monthly doses. The committee's recommendation will be considered by the FDA in its review of the Biologics License Application for VEGF Trap-Eye, which the FDA expects to complete by August 20, 2011.