Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration.
BACKGROUND
Angiogenesis is a key aspect of the wet form of age-related neovascular (AMD), the leading cause of blindness in the elderly population. Substantial evidence indicated that vascular endothelial growth factor (VEGF)-A is a major mediator of angiogenesis and vascular leakage in wet AMD. VEGF-A is the prototype member of a gene family that includes also PlGF, VEGF-B, VEGF-C, VEGF-D and the orf virus-encoded VEGF-E. Several isoforms of VEGF-A can be generated due to alternative mRNA splicing. Various VEGF inhibitors have been clinically developed. Among these, ranibizumab is a high affinity recombinant Fab that neutralizes all isoforms of VEGF-A. The article briefly reviews the biology of VEGF and then focuses on the path that led to clinical development of ranibizumab.


RESULTS
The safety and efficacy of ranibizumab in the treatment of neovascular AMD have been evaluated in two large phase III, multicenter, randomized, double-masked, controlled pivotal trials in different neovascular AMD patient populations. Combined, the trial results indicate that ranibizumab results not only in a slowing down of vision loss but also in a significant proportion of patients experiencing a clinically meaningful vision gain. The visual acuity benefit over control was observed regardless of CNV lesion type. Furthermore, the benefit was associated with a low rate of serious adverse events.


CONCLUSIONS
Ranibizumab represents a novel therapy that, for the first time, appears to have the potential to enable many AMD patients to obtain a meaningful and sustained gain of vision. On June 30 2006, ranibizumab was approved by the US Food and Drug Administration for the treatment of wet AMD.
Ferrara
Napoleone
N
Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. nf@gene.com
Damico
Lisa
L
Shams
Naveed
N
Lowman
Henry
H
Kim
Robert
R
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology*; D008268:Macular Degeneration / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D000069579:Ranibizumab; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*; D014792:Visual Acuity
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab