Finding the Optimal Treatment Plan for Exudative AMD

A Review of Current Anti-VEGF Dosing Regimens

Avni V. Patel, MD, MBA; Scott M. Barb, MD; Lucy H. Young, MD, PhD


Int Ophthalmol Clin. 2015;55(4):103-112. 

In This Article


Age-related macular degeneration (AMD) is the leading cause of severe central visual acuity loss in people over 50 years of age in the United States. Approximately 1.75 million North Americans are estimated to have AMD and an estimated 200,000 new cases of exudative (also referred to as neovascular or wet) AMD develop each year.[1] This number will increase to almost 3 million by 2020.[2] Macular degeneration is a complex spectrum of normal age-related changes including reduced photoreceptor density, ultrastructural changes in the pigment epithelium, formation of lipofuscin granules, accumulation of basal laminar lipid-rich deposits, and progressive changes in the choriocapillaris. These changes may cause disturbances in Bruch's membrane allowing vessels originating from the choriocapillaris to form a new and abnormal fibrovascular complex. This fibrovascular complex or choroidal neovascularization (CNV) is the hallmark of exudative AMD.

It is well-established that vascular endothelial growth factor (VEGF) plays a major role in the neovascular or exudative form of AMD by aiding in the induction of angiogenesis and enhancing vascular permeability.[3,4] Consequently, intravitreal injections with medications targeting VEGF have become the standard of care for exudative AMD. Currently there are several anti-VEGF drugs that are used in the treatment of exudative AMD: pegaptanib (Macugen), bevacizumab (Avastin), ranibizumab (Lucentis), and VEGF Trap (Eylea).

Pegaptanib, or Macugen, was the first VEGF inhibitor approved for use in macular degeneration. It is a modified oligonucleotide that binds only to VEGF isoform 165 and not to other isoforms or receptors. This anti-VEGF therapy has largely been replaced due to more favorable results utilizing bevacizumab, ranibizumab, and aflibercept.[5–7] Bevacizumab, or Avastin, is a humanized monoclonal antibody against VEGF-A, and is comprised of an amino acid sequence which is 93% human and 7% murine. It was initially approved in 2004 for use in the treatment of colorectal cancer as it was shown to inhibit tumor growth through antiangiogenesis.[8] Ranibizumab, or Lucentis, is a humanized antibody fragment (Fab) that binds VEGF-A. It binds to and inhibits all forms of VEGF-A and their active degradation products.[5,9] VEGF Trap, or Eylea, is a soluble protein that acts as a VEGF receptor decoy. It is a fusion protein combining the ligand-binding elements from extracellular components of VEGF receptors 1 and 2. It can bind both VEGF and placental-like growth factor and penetrate all layers of the retina.[7,10]

The efficacy of anti-VEGF therapy in AMD was initially demonstrated with ranibizumab in 2 landmark trials: the Minimally Classic/Occult Trial of Anti-vascular Endothelial Growth Factor Antibody Ranibizumab in the Treatment of Neovascular Age-related Macular Degeneration (MARINA) and Anti-vascular Endothelial Growth Factor Antibody for the Treatment of Predominantly Classic CNV in Age-related Macular Degeneration (ANCHOR). In the MARINA study, patients received monthly intravitreal injections of 0.3 or 0.5 mg of ranibizumab or a sham injection over 2 years. Overall, 90% of the ranibizumab-treated patients lost <15 letters on the ETDRS chart compared with 53% of the sham-injection patients and vision improved by at least 15 letters in approximately 33% of the patients treated with 0.5 mg ranibizumab compared with 4% in the sham-injected patients at 2 years.[6,11] In the ANCHOR trial, patients were randomized to monthly injections of either the 0.3 or 0.5 mg ranibizumab injection or to verteporforin photodynamic therapy. The study demonstrated 95% of ranibizumab-treated patients maintained vision (lost <15 letters from baseline) compared with 64% of PDT-treated eyes at 12 months. Furthermore, about 40% of the patients treated with 0.5 mg ranibizumab gained at least 15 letters of vision compared with only 6% of the PDT treatment group at 2 years.[6,12] These 2 breakthrough studies changed the landscape of current AMD treatment.

While intravitreal anti-VEGF treatments successfully work to stabilize and even improve vision in patients with exudative macular degeneration, controversy still remains regarding the optimal treatment plan for patients. The question of how frequently to treat patients is important as many practitioners and patients alike recognize the burden of monthly injections. This paper seeks to review the data for current anti-VEGF treatment regimens to help elucidate the optimal treatment plan to maximize visual outcome and minimize burden to the patient and health care system.