A Prospective obsERvational Study to asSEss the Effectiveness of Intravitreal Aflibercept Injection in roUtine Clinical Practice in Treatment Naive patientS With Wet Age-related Macular Degeneration in Greece

Rationale and background Age-related macular degeneration (AMD) is the most common degenerative disease of the macula and the most common cause of legal blindness in the Western world. AMD is a disease of the elderly affecting 10% of individuals aged 65 to 74 years and 30% of those aged 75 to 85 years. Two forms of AMD can be distinguished. The dry form is more benign accounting for 90% of all AMD cases, but only for 10% of cases of blindness due to AMD. On the other hand wet AMD affects only 10% of AMD patients. However, it is more aggressive and rapidly progresses. Wet AMD (wAMD) accounts for 80% of cases of severe visual impairment and represents the majority of cases of legal blindness. Thus, wet or neovascular AMD is a disease with a great impact on both visual acuity and patients' quality of life.

About 1% of the population is affected by wAMD between 65-74 years of age, 5% between 75-84 years of age and 13% in people 85+ years. Given that wAMD is a strongly age-dependent disease its prevalence is expected to significantly increase in western countries (including Greece) in the near future. Therefore, early diagnosis and proper treatment will be a major public health concern.

AMD is diagnosed by stereoscopic biomicroscopy and additional examinations of the macula, such as fluorescein angiography (FA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT). The patient's visual status can be monitored with the Snellen chart and Early Treatment Diabetic Retinopathy Study (ETDRS) chart, the Snellen chart being most often used in Greece.

Wet AMD is caused by choroidal neovascularization (CNV) whereby new abnormal blood vessels spread beneath the retina. These vessels may rupture and cause retinal damage. In addition, vascular leakage may cause thickening and oedema of the retina, which is thought to contribute to vision loss. Vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) play a pivotal role in this scenario. VEGF-A and PlGF are members of the VEGF family of angiogenic factors that act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF acts via two receptor tyrosine kinases-VEGFR-1 and VEGFR-2-which are located on the surface of endothelial cells. PlGF binds only to VEGFR-1, which is also present on the surface of leukocytes. Excessive activation of these receptors by VEGF-A can induce pathological neovascularization and excessive vascular permeability. PlGF can synergize with VEGF-A in these processes, and is also known to promote leukocyte infiltration and vascular inflammation.

Treatment paradigms for wet AMD have changed tremendously since anti-VEGF treatment (inhibition of all VEGF-A Isoforms) was introduced. As a consequence, most previous therapy approaches lost significance and are applied in rare cases only. The pan-anti-angiogenesis treatment with ranibizumab was the first to show significant improvements in visual acuity of patients suffering from wAMD, thus becoming the first-choice therapy for most patients. The phase III clinical trials MARINA and ANCHOR have shown that ranibizumab applied every month is highly effective in improving visual impairment. However, in addition to the small risk of endophthalmitis associated with intravitreal injections, monthly treatment, which may continue for a patient's lifetime, is extremely burdensome to patients, their caregivers, ophthalmologists and the healthcare system. As a consequence, in clinical practice the monthly treatment regimen of ranibizumab is often altered to less frequent dosing intervals to reduce the associated treatment burden, although this may result in notably reduced efficacy.