Abstract and Introduction
Abstract
Antivascular endothelial growth factor (anti-VEGF) therapy has revolutionised the treatment of wet age-related macular degeneration (wAMD). Recent research has focused on evaluating competing agents and alternative dosage regimens, providing evidence to help determine optimal treatment strategies. We therefore conducted a review of clinical research studies in wAMD published since 2008 that compared anti-VEGF dosing regimens and therapies; seven studies met our inclusion criteria. Data on baseline disease characteristics, disease outcomes, safety (ocular and systemic) and treatment burden (injection and visit frequencies) were extracted on patients treated with ranibizumab 0.5 mg, bevacizumab 1.25 mg or aflibercept 2.0 mg for up to 2 years. For ranibizumab and bevacizumab, visual and anatomical outcomes at 1 and 2 years were superior using scheduled monthly (or 4 weekly (q4w)) compared with as needed or scheduled quarterly dosing regimens. Treatment outcomes were generally better for both drugs when more aggressive retreatment criteria were used, which resulted in more frequent injections. Bevacizumab, however, was associated with a 30–35% elevated rate of serious systemic adverse events compared with ranibizumab, regardless of dosing interval; further study in larger patient populations will be required to determine the validity of this finding. Intravitreal aflibercept injection every 8 weeks was non-inferior to ranibizumab q4w on all visual and anatomical endpoints at week 52, had a similar safety profile and required five fewer anti-VEGF injections.
Introduction
Before the introduction of effective therapy, neovascular (wet) age-related macular degeneration (wAMD) was a leading cause of blindness among the elderly in the USA, Europe and elsewhere. The antivascular endothelial growth factor (anti-VEGF) treatment ranibizumab dramatically changed the prognosis of wAMD and significantly decreased the incidence of legal blindness in some countries: patients can now reasonably expect stabilisation of vision—and even improvement. Bevacizumab, which is approved for the treatment of some cancer subtypes, is also currently used off label to manage wAMD. Outcomes achieved with bevacizumab may be clinically similar to those attained with ranibizumab.
Recognising that once monthly treatment can be burdensome, physicians have used alternative dosing regimens, including quarterly and as needed (PRN). The benefit of less frequent dosing was shown in single arm studiesand in a drug and disease model that evaluated the impact of an individualised, flexible treatment regimen on disease progression, leading to current ranibizumab labelling in Europe and treatment practices worldwide. In contrast, randomised, controlled studies have shown that patients receiving ranibizumab less frequently than monthly may have poorer outcomes over the long term. Moreover, although injection frequency is reduced with PRN regimens, monthly monitoring is required to determine the need for re-dosing.
In addition to these new data on dosing regimens for ranibizumab and bevacizumab, intravitreal aflibercept injection was approved for the treatment of wAMD in the USA in 2011 and in Australia and Europe in 2012. Aflibercept is a recombinant fusion protein consisting of portions of the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of human IgG1. Unlike ranibizumab and bevacizumab, it binds to VEGF-A with 1:1 stoichiometry and to human placental growth factor. Aflibercept binds more tightly to human VEGF-A165 than either of the endogenous VEGF receptors (see online supplementary table S1), possibly leading to less frequent injections.
Given these new developments in the area of wAMD therapeutics since the American Academy of Ophthalmology and Royal College of Ophthalmologists guidelines were last updated, we conducted a review of major clinical studies comparing anti-VEGF dosing regimens and therapies.