Macular degeneration is a form of age-related blindness that develops over time. One cause of the blindness is neovascularization (i.e. new blood vessel growth) of the eye. In 1997, vascular endothelial growth factor (VEGF) was found to be over-expressed in patients with wet macular degeneration (macular degeneration caused by choroidal neovascularization). Since that time, anti-VEGF therapy has been studied to prevent and reverse the progression of macular degeneration.
Targeting angiogenesis
The process of blood vessel growth is called angiogenesis. VEGF-A has been found to play a key role in this process. Thus, inhibiting the actions of this molecule inhibits angiogenesis and prevents neovascularization from proceeding. Antibodies and protein fragments that bind VEGF-A can prevent it from binding its receptor, which prevents it from activating the various chemical pathways that initiate the processes necessary for blood vessel growth. A diagram of the VEGF pathway is available from SA Biosciences. Targeting VEGF-A clearly cuts off the process of angiogenesis at its starting point. Thus, VEGF-A antagonists are inhibitors of angiogenesis. The lack of blood vessel growth blocks further neovascularization, reduces vessel leakage and halts the progression of blindness caused by the abnormal vessels.
Limiting treatment to the eye
However, VAGF-A is involved in both pathological and normal blood vessel growth. In order to limit the actions of the antagonists to VEGF molecules in the affected eye (and ensure the drug reaches the retinal vessels), macular degeneration treatments are injected into the vitreous humor, the jelly-like fluid behind the lens and in front of the retina. Many treatment sessions are needed because the over-expression of VEGF-A is not addressed by the drug – it simply reduces the actions of the VEGF molecules that are present in the eye. Approximately one-half of patients do not improve with treatment, though one type of injection, the drug marketed as Lucentis, halted the progression of vision loss in 95 percent of patients in clinical trials.
Anti-VEGF treatment options
According to the American Macular Degeneration Foundation, three anti-VEGF drugs are on the market and used to treat wet macular degeneration. The first to receive FDA approval was pegaptanib in 2004 (marketed as Macugen), which is an RNA aptamer that targets the primary subtype of VEGF-A, known as VEGF 165. However, the first drug approved for treating wet macular degeneration that also improves vision in approximately 40 percent of patients is Lucentis (approved in 2006), which contains ranibimuzab, a fragment of a humanized IgGI kappa isotype monoclonal antibody that targets all forms of VEGF-A. Bevacizumab (Avastin) is a full-length humanized monoclonal antibody against VEGF that is used in cancer treatment to prevent angiogenesis, but it is used off label for macular degeneration and not yet approved for such use. In a two-year trial reported in 2011, Avastin was found to perform as well as Lucentis.
Use in wet macular degeneration
VEGF antagonists are successfully used to treat wet macular degeneration. Injection into the vitreous humor targets the treatment to the blood vessels of the retina, preventing further neovascularization and slowing the progression of blindness caused by blood vessel growth. Studies are still aiming for better success rates and to broaden the drug choices available as treatment options.
