Residual Edema With Ranibizumab 0.5 mg and 2.0 mg for DME
Residual Edema With Ranibizumab 0.5 mg and 2.0 mg for DME
Purpose To compare the efficacy of ranibizumab 0.5-mg and 2.0-mg intravitreal injections for persistent diabetic macular edema (DME) previously treated with bevacizumab.
Methods In all, 43 patients with residual center-involved DME following intravitreal bevacizumab were included in this 12-month prospective, nonrandomized, multicenter study. Enrolled patients received three monthly ranibizumab 0.5-mg injections. At month 3, patients with residual macular edema switched to three monthly injections of ranibizumab 2.0-mg. Assessments included monthly visual acuity and spectral-domain optical coherence tomography.
Results Mean visual acuity improved by +6.4 letters at month 3 and +8.8 letters at month 6. Mean central subfield thickness (CST) decreased by –113 μm at month 3 and –165 μm at month 6. Before enrollment, 29/43 (67.4%) patients showed <10% CST reduction following monthly bevacizumab treatment. After three monthly ranibizumab 0.5-mg injections, 22/29 (75.9%) patients showed >10% reduction in CST, whereas 6 showed <10% reduction. Of these six, three (50%) showed >10% reduction in CST after switching to three monthly ranibizumab 2.0-mg doses. No serious adverse events were observed to month 6.
Conclusion Ranibizumab 0.5-mg or 2.0-mg may improve visual and anatomic outcomes in patients with DME who demonstrated minimal or no response to bevacizumab therapy. Moreover, increased dosage of ranibizumab (2.0-mg) may provide additional benefit over ranibizumab 0.5-mg in some patients. However, 2.0-mg ranibizumab is not currently commercially licensed or available.
Vision loss associated with diabetic macular edema (DME) is a significant public health problem that affects individuals psychologically, socially, and economically. In developed countries, DME is among the most common sight-threatening complications of diabetic retinopathy. The incidence of DME increases with severity and duration of diabetes, ranging from 3 to 20%.
The pathogenesis of DME is not wholly understood. Histological findings include loss of pericytes and endothelial cells, together with capillary basement membrane thickening. Eventual microaneurysm formation paired with breakdown of the blood–retinal barrier lead to vascular leakage and macular edema. Vascular endothelial growth factor (VEGF) is believed to play an important role in the pathogenesis of DME.
The Early Treatment Diabetic Retinopathy Study (ETDRS) provided strong evidence for the treatment of clinically significant DME with macular laser therapy. This treatment was shown to reduce the risk of moderate vision loss by 50%; however, significant visual gains were not common. VEGF inhibition for the treatment of DME has shown promising results with significant visual gains, resulting in a paradigm shift in the treatment of DME.
Bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, USA) is a fully humanized recombinant antibody that binds all isoforms of VEGF-A. Bevacizumab is currently used off-label to treat DME. Several studies support the efficacy of bevacizumab compared with focal macular laser. In the BOLT trial, patients with persistent DME following macular laser therapy were randomized to bevacizumab vs continuing laser therapy. Patients treated with bevacizumab gained 8.6 letters vs 2.5 letters in those receiving macular laser therapy (P=0.005). Despite favorable results, there remain patients who either do not respond or only partially respond to intravitreal bevacizumab treatment.
Ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA, USA) is a monoclonal antibody fragment derived from the same murine antibody as bevacizumab, but with a different development path than bevacizumab. The goal in the development of ranibizumab was, in part, to produce a molecule that could diffuse more efficiently through the retina after intraocular injection for the treatment of age-related macular degeneration (AMD). Decreased systemic half-life and resulting systemic toxicity of an antibody fragment relative to a full-length antibody was another driving force in the development of this molecule. Relative to bevacizumab, ranibizumab has been reported to have a somewhat shorter vitreous half-life, but has 5- to 20-fold higher biologic activity. This increased activity, coupled with the smaller molecular size of ranibizumab, may further benefit eyes with DME. The US Food and Drug Administration approval for ranibizumab 0.3-mg for the treatment of DME was granted in August 2012.
Ranibizumab has been shown to be efficacious in the treatment of DME in numerous clinical trials. The REEF study was designed to evaluate visual and anatomic outcomes with intravitreal ranibizumab 0.5-mg in patients with DME who partially responded to or failed to respond to treatment with intravitreal bevacizumab 1.25-mg. Patients who failed to respond to ranibizumab 0.5-mg after 3 months were further treated with ranibizumab 2.0-mg to determine whether a higher dose of ranibizumab provided additional treatment benefit. Higher-dose ranibizumab has previously been shown to be effective in recalcitrant cases of other VEGF-mediated diseases including exudative AMD and radiation retinopathy.
Abstract and Introduction
Abstract
Purpose To compare the efficacy of ranibizumab 0.5-mg and 2.0-mg intravitreal injections for persistent diabetic macular edema (DME) previously treated with bevacizumab.
Methods In all, 43 patients with residual center-involved DME following intravitreal bevacizumab were included in this 12-month prospective, nonrandomized, multicenter study. Enrolled patients received three monthly ranibizumab 0.5-mg injections. At month 3, patients with residual macular edema switched to three monthly injections of ranibizumab 2.0-mg. Assessments included monthly visual acuity and spectral-domain optical coherence tomography.
Results Mean visual acuity improved by +6.4 letters at month 3 and +8.8 letters at month 6. Mean central subfield thickness (CST) decreased by –113 μm at month 3 and –165 μm at month 6. Before enrollment, 29/43 (67.4%) patients showed <10% CST reduction following monthly bevacizumab treatment. After three monthly ranibizumab 0.5-mg injections, 22/29 (75.9%) patients showed >10% reduction in CST, whereas 6 showed <10% reduction. Of these six, three (50%) showed >10% reduction in CST after switching to three monthly ranibizumab 2.0-mg doses. No serious adverse events were observed to month 6.
Conclusion Ranibizumab 0.5-mg or 2.0-mg may improve visual and anatomic outcomes in patients with DME who demonstrated minimal or no response to bevacizumab therapy. Moreover, increased dosage of ranibizumab (2.0-mg) may provide additional benefit over ranibizumab 0.5-mg in some patients. However, 2.0-mg ranibizumab is not currently commercially licensed or available.
Introduction
Vision loss associated with diabetic macular edema (DME) is a significant public health problem that affects individuals psychologically, socially, and economically. In developed countries, DME is among the most common sight-threatening complications of diabetic retinopathy. The incidence of DME increases with severity and duration of diabetes, ranging from 3 to 20%.
The pathogenesis of DME is not wholly understood. Histological findings include loss of pericytes and endothelial cells, together with capillary basement membrane thickening. Eventual microaneurysm formation paired with breakdown of the blood–retinal barrier lead to vascular leakage and macular edema. Vascular endothelial growth factor (VEGF) is believed to play an important role in the pathogenesis of DME.
The Early Treatment Diabetic Retinopathy Study (ETDRS) provided strong evidence for the treatment of clinically significant DME with macular laser therapy. This treatment was shown to reduce the risk of moderate vision loss by 50%; however, significant visual gains were not common. VEGF inhibition for the treatment of DME has shown promising results with significant visual gains, resulting in a paradigm shift in the treatment of DME.
Bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, USA) is a fully humanized recombinant antibody that binds all isoforms of VEGF-A. Bevacizumab is currently used off-label to treat DME. Several studies support the efficacy of bevacizumab compared with focal macular laser. In the BOLT trial, patients with persistent DME following macular laser therapy were randomized to bevacizumab vs continuing laser therapy. Patients treated with bevacizumab gained 8.6 letters vs 2.5 letters in those receiving macular laser therapy (P=0.005). Despite favorable results, there remain patients who either do not respond or only partially respond to intravitreal bevacizumab treatment.
Ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA, USA) is a monoclonal antibody fragment derived from the same murine antibody as bevacizumab, but with a different development path than bevacizumab. The goal in the development of ranibizumab was, in part, to produce a molecule that could diffuse more efficiently through the retina after intraocular injection for the treatment of age-related macular degeneration (AMD). Decreased systemic half-life and resulting systemic toxicity of an antibody fragment relative to a full-length antibody was another driving force in the development of this molecule. Relative to bevacizumab, ranibizumab has been reported to have a somewhat shorter vitreous half-life, but has 5- to 20-fold higher biologic activity. This increased activity, coupled with the smaller molecular size of ranibizumab, may further benefit eyes with DME. The US Food and Drug Administration approval for ranibizumab 0.3-mg for the treatment of DME was granted in August 2012.
Ranibizumab has been shown to be efficacious in the treatment of DME in numerous clinical trials. The REEF study was designed to evaluate visual and anatomic outcomes with intravitreal ranibizumab 0.5-mg in patients with DME who partially responded to or failed to respond to treatment with intravitreal bevacizumab 1.25-mg. Patients who failed to respond to ranibizumab 0.5-mg after 3 months were further treated with ranibizumab 2.0-mg to determine whether a higher dose of ranibizumab provided additional treatment benefit. Higher-dose ranibizumab has previously been shown to be effective in recalcitrant cases of other VEGF-mediated diseases including exudative AMD and radiation retinopathy.