2009, Volume 16, Supplement 2: Maximising safety and efficacy in the treatment of wet AMD

The prevalence of neovascular age-related macular degeneration (wet AMD) is predicted to rise to more than 300,000 patients in the UK alone by the year 2025. The personal and economic costs are considerable. It leads to worsening of vision-related function and overall wellbeing, with one third developing clinical depression. The majority of patients progress to legal blindness in the affected eye within two years of diagnosis, and healthcare utilisation costs are seven times higher in affected patients compared to age-matched controls. Thus, the development of new treatments for wet AMD, and of access to such treatments, is clearly important....

Age-related macular degeneration (AMD) is a common ocular condition that may destroy central vision and has a devastating effect on the patient’s quality of life. More than eight million Americans, particularly those over the age of 55 years, suffer from age-related macular degeneration, and the overall prevalence of advanced AMD is projected to increase by more than 50% by the year 2030.1 In the UK, the annual incidence of neovascular AMD was calculated to be around 24,000 in 2005, with a prevalence of 243,000; this is predicted to rise to over 300,000 by 2025.2 The majority of patients with neovascular AMD progress to legal blindness in the affected eye within two years of diagnosis, and there is a 43% probability of progression to neovascular AMD in the other eye within five years.1 Until recently, the only pharmacological-based therapy for treatment of patients with neovascular degeneration has been photodynamic therapy with verteporfin. Although the pathophysiology is still poorly understood, it is increasingly clear that vascular endothelial growth factor (VEGF) plays an important role in promotion of the neovascularisation and vessel leakage that lead to loss of central vision. Therefore, intravitreal antiangiogenic therapy (injection of antiangiogenic agents directly into the vitreous) is currently the primary therapy for neovascular AMD. Currently, the most common therapeutic agents are ranibizumab, pegaptanib and bevacizumab (used off-label). Anti-VEGF agents administered systemically for other indications in oncology have been associated with serious systemic adverse events and death.3 Since breakdown of the blood-ocular barrier is common in wet AMD, repeated intravitreal anti-VEGF therapy may lead to a small amount of systemic VEGF inhibition, possibly resulting in serious long-term adverse events, though these have not yet been shown in clinical studies.4 We here review the pathogenesis of the disease, the therapeutic options currently used in clinical practice and the possible safety concerns about anti-VEGF therapy in patients with neovascular AMD....

Vascular endothelial growth factor (VEGF) plays a pivotal role in stimulating abnormal neovascularisation, a key characteristic of neovascular age-related macular degeneration (so-called wet AMD).1 VEGF is a secreted protein that is able to diffuse and trigger mitogenic activity in endothelial cells.2 It is produced by multiple retinal cell types, and blood vessels in the retina have several receptors for VEGF. It is known that VEGF inhibition can both prevent and reverse breakdown of the blood–retinal barrier.3 Indeed, elevated VEGF levels have been linked to neovascularisation and vascular permeability.(4-8) Consequently, it is proposed that VEGF inhibition could block the underlying pathogenic process of wet AMD. However, VEGF is an intercellular signalling factor with numerous functions throughout the body. These functions can be both physiological and pathological: examples of these functions are provided in table 1....

In 1971 Folkman proposed that tumour growth was dependent upon angiogenesis, and consequently suggested that preventing angiogenesis might prevent tumour growth.1 This concept led to research into manipulating angiogenesis in order to influence tumour progression, and subsequently other therapeutic areas, including cardiology and ophthalmology. In 1983 vascular permeability factor (VPF) was discovered, followed by vascular endothelial growth factor (VEGF) in 1989. It later transpired that they were in fact the same molecule. ...

Introduction Pegaptanib sodium (Macugen®) was approved for the treatment of neovascular AMD (wet AMD) in Europe in 2006. It is administered by intravitreal injection into the affected eye once every six weeks at a dose of 0.3 mg.1 Pegaptanib is a pegylated modified oligonucleotide that binds with high specificity and affinity to extracellular vascular endothelial growth factor (VEGF) isoform 165, inhibiting its activity. VEGF is a secreted protein that induces angiogenesis, vascular permeability and inflammation, all of which are thought to contribute to the progression of wet AMD. VEGF165 is the VEGF isoform preferentially involved in pathological ocular neovascularisation. In animals, this selective inhibition with pegaptanib proved as effective at suppressing pathological neovascularisation as pan-VEGF inhibition; however, pegaptanib spared the normal vasculature whereas pan-VEGF inhibition did not.1 ...