Intravitreal Bevacizumab (Avastin) for Neovascular Age-Related Macular Degeneration

doi:10.1016/j.ophtha.2005.11.019

Ophthalmology

Volume 113, Issue 3, March 2006, Pages 363-372.e5

Presented in part at: American Academy of Ophthalmology Subspecialty Meeting, October, 2005; Chicago, Illinois.

https://doi.org/10.1016/j.ophtha.2005.11.019 Get rights and content

Purpose

To report the short-term safety, biologic effect, and a possible mechanism of action of intravitreal bevacizumab in patients with neovascular age-related macular degeneration (AMD).

Design

Interventional, consecutive, retrospective case series.

Participants

Eighty-one eyes of 79 patients with subfoveal neovascular AMD.

Methods

Patients received intravitreal bevacizumab (1.25 mg) on a monthly basis until macular edema, subretinal fluid (SRF), and/or pigment epithelial detachment (PED) resolved. Ophthalmic evaluations included nonstandardized Snellen visual acuity (VA), complete ophthalmic examination, fluorescein angiography, and optical coherence tomography (OCT).

Main Outcome Measures

Assessments of safety, changes in Snellen VA, OCT retinal thickness, and angiographic lesion characteristics were performed.

Results

No significant ocular or systemic side effects were observed. Most patients (55%) had a reduction of >10% of baseline retinal thickness at 1 week after the injection. At 4 weeks after injection, 30 of 81 eyes demonstrated complete resolution of retinal edema, SRF, and PEDs. Of the 51 eyes with 8 weeks’ follow-up, 25 had complete resolution of retinal thickening, SRF, and PEDs. At 1, 4, 8,and 12 weeks, the mean retinal thickness of the central 1 mm was decreased by 61, 92, 89, and 67 μm, respectively (P<0.0001 for 1, 4, and 8 weeks and P<0.01 for 12 weeks). At 4 and 8 weeks, mean VA improved from 20/200 to 20/125 (P<0.0001). Median vision improved from 20/200 to 20/80⁻ at 4 weeks and from 20/200 to 20/80 at 8 weeks.

Conclusions

Short-term results suggest that intravitreal bevacizumab (1.25 mg) is well tolerated and associated with improvement in VA, decreased retinal thickness by OCT, and reduction in angiographic leakage in most patients, the majority of whom had previous treatment with photodynamic therapy and/or pegaptanib. Further evaluation of intravitreal bevacizumab for the treatment of choroidal neovascularization is warranted.

Section snippets

Patients and Methods

Patients with AMD and subfoveal choroidal neovascularization were offered bevacizumab treatment if they had experienced continued visual loss or a worsening of anatomic appearance as determined by angiography or optical coherence tomography (OCT) despite standard therapy with photodynamic therapy and/or pegaptanib or if they deferred standard treatment. Patients were not offered treatment if they had uncontrolled hypertension or recent myocardial infarction or cerebral vascular accident. The

Results

Of the 79 patients, 50 were female and 29 were male. The mean age was 77 years. Follow-up ranged from 4 to 15 weeks. All 79 patients completed a 4-week follow-up visit, and 50 of 53 patients (94%) were scheduled to have an 8-week follow-up by the time of data closure completed this evaluation. The majority of eyes (63/81 [78%]) had received prior treatment with photodynamic therapy and/or injection of pegaptanib. Twenty-one of 81 (26%) had received prior photodynamic therapy alone, 24 of 81

Case 1

A 75-year-old woman with vision loss in her right eye for 2 years and recent gradual loss of vision in her left eye was diagnosed with bilateral neovascular AMD with occult choroidal neovascularization. Her VA was counting fingers (CF) at 6 feet in her right eye and 20/80 in her left eye. The patient received intravitreal injection of pegaptanib to both eyes, but her vision dropped to CF at 6 feet in the right eye and 20/100 in the left eye. Optical coherence tomography revealed increasing

Discussion

We acknowledge the shortcomings of this study: retrospective design, limited number of patients, nonstandard visions, and limited follow-up. Despite these limitations, this report confirms Rosenfeld’s initial single case report, and is proof of concept that intravitreally administered bevacizumab has at least a short-term biologic effect that is not consistent with our understanding of the natural history of subfoveal choroidal neovascularization associated with AMD.¹⁵ These anatomic

References (33)

F.G. Holz et al.
Pathogenesis of lesions in late age-related macular disease
Am J Ophthalmol
(2004)
A.P. Schachat et al.
Safe and effective
Ophthalmology
(2003)
M. Kamei et al.
A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits
Am J Ophthalmol
(1999)
N. Ferrara
Vascular endothelial growth factorbasic science and clinical progress
Endocr Rev
(2004)
A.P. Adamis et al.
The role of vascular endothelial growth factor in ocular health and disease
Retina
(2005)
M.G. Krzystolik et al.
Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment
Arch Ophthalmol
(2002)
E.S. Gragoudas et al.
Pegaptanib for neovascular age-related macular degeneration
N Engl J Med
(2004)
Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodiuman exploratory analysis
Retina
(2005)
P. van Wijngaarden et al.
Inhibitors of ocular neovascularizationpromises and potential problems
JAMA
(2005)
Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfintwo-year results of 2 randomized clinical trials—TAP report 2
Arch Ophthalmol
(2001)

Photodynamic therapy of subfoveal choroidal neovascularization with verteporfinfluorescein angiographic guidelines for evaluation and treatment—TAP and VIP report no. 2

Arch Ophthalmol

(2003)

H. Hurwitz et al.

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

N Engl J Med

(2004)

P.J. Rosenfeld et al.

Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration

Ophthalmology

(2005)

J. Gaudreault et al.

Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration

Invest Ophthalmol Vis Sci

(2005)

J. Mordenti et al.

Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration

Toxicol Pathol

(1999)

S. Michels et al.

Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degenerationTwelve-week results of an uncontrolled open-label clinical study

Ophthalmology

(2005)

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Manuscript no. 2005-1043.

Supported in part by the California Retina Research Foundation, Santa Barbara, California. Genentech did not sponsor this study.

Dr Avery has received consulting or advisory fees from the following pharmaceutical companies: Alcon, Eyetech, Genentech, QLT, and Neovista. Dr Pieramici has received research, consulting, or advisory fees from the following pharmaceutical companies: Eyetech, Genentech, QLT, and Neovista.

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Original ArticleIntravitreal Bevacizumab (Avastin) for Neovascular Age-Related Macular Degeneration

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Patients and Methods

Results

Case 1

Discussion

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Vascular endothelial growth factorbasic science and clinical progress

Endocr Rev

The role of vascular endothelial growth factor in ocular health and disease

Retina

Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment

Arch Ophthalmol

Pegaptanib for neovascular age-related macular degeneration

N Engl J Med

Enhanced efficacy associated with early treatment of neovascular age-related macular degeneration with pegaptanib sodiuman exploratory analysis

Retina

Inhibitors of ocular neovascularizationpromises and potential problems

JAMA

Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfintwo-year results of 2 randomized clinical trials—TAP report 2

Arch Ophthalmol

Photodynamic therapy of subfoveal choroidal neovascularization with verteporfinfluorescein angiographic guidelines for evaluation and treatment—TAP and VIP report no. 2

Arch Ophthalmol

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

N Engl J Med

Maximum tolerated dose of a humanized anti-vascular endothelial growth factor antibody fragment for treating neovascular age-related macular degeneration

Ophthalmology

Preclinical pharmacokinetics of Ranibizumab (rhuFabV2) after a single intravitreal administration

Invest Ophthalmol Vis Sci

Comparisons of the intraocular tissue distribution, pharmacokinetics, and safety of 125I-labeled full-length and Fab antibodies in rhesus monkeys following intravitreal administration

Toxicol Pathol

Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degenerationTwelve-week results of an uncontrolled open-label clinical study

Ophthalmology

Original Article
Intravitreal Bevacizumab (Avastin) for Neovascular Age-Related Macular Degeneration