How MACUGEN^® (pegaptanib sodium injection) Works

Understanding the Pathophysiology of Neovascular (Wet) AMD

Neovascular AMD is characterized by the presence of choroidal neovascularization (CNV). In the CNV cascade, hyperpermeable blood vessels grow out through Bruch’s membrane into layers of the retina. These abnormal blood vessels can lead to retinal hemorrhaging, scarring, retinal pigment epithelial (RPE) detachments, and RPE tears.¹

Although all CNV shares a common pathophysiology, CNV has been historically divided into 3 subtypes, depending on fluorescein angiographic appearance:

• Predominantly classic — ≥50% of the lesion is classic CNV (classic CNV appears as a well-defined area of hyperfluorescence on a fluorescein angiogram)¹
• Minimally classic — <50% of the lesion is classic CNV¹
• Occult with no classic — none of the lesion has classic CNV (occult CNV appears more diffuse and less defined on a fluorescein angiogram)¹

Video: See How MACUGEN Works

Watch a video that illustrates how chronically overexpressed VEGF damages the eye and explains how MACUGEN therapy can help reduce vision loss from neovascular AMD. Choose your Internet connection speed in the space below.

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Evidence Shows VEGF₁₆₅ Is an Essential Signal in Pathologic Processes Underlying Neovascular AMD^1-4

• Early in neovascular AMD, several initiating stimuli trigger continuous overexpression of pathologic VEGF^3,5
• Reduction in choriocapillaris blood flow
• Accumulation of lipid metabolic byproducts
• Oxidative stress
• Alterations in Bruch's membrane
• Overexpressed VEGF binds to endothelial cells, promoting³
• Angiogenesis (new vessel growth with increased permeability)
• Expression of cytokines and proteases
• Overexpressed VEGF also binds to monocytes^3,6
• Resulting in chemotaxis
• Releasing additional VEGF, which further amplifies VEGF signaling
• VEGF cascade leads to CNV with breakdown of the blood-retinal barrier — the hallmarks of neovascular AMD^1,2

• MACUGEN selectively blocks VEGF₁₆₅, which interrupts the VEGF cascade and associated choroidal neovascularization. MACUGEN does not rely on physical destruction of vasculature to exert its effect⁸

MACUGEN Is the First Therapy Targeted to Treat Pathologic Processes Underlying All Subtypes of AMD^7,8

MACUGEN has a complex 3-dimensional structure that binds to upregulated VEGF, preventing it from binding to its receptors. This inhibits upregulated VEGF and slows the progression of CNV associated with all subtypes of neovascular AMD^7,8

Based on observations reported from in vitro or animal studies. The clinical significance in humans is unknown.

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References:

1. Ambati J, Ambati BK, Yoo SH, Ianchulev S, Adamis AP. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol. 2003;48:257-293.
2. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122:598-614.
3. Witmer AN, Vrensen GFJM, Van Noorden CJF, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res. 2003;22:1-29.
4. D'Amore PA. Mechanisms of retinal and choroidal neovascularization. Invest Ophthalmol Vis Sci. 1994;35:3974-3979.
5. Ferrara N, Gerber H-P, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669-676.
6. Ishida S, Usui T, Yamashiro K, et al. VEGF₁₆₄-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med. 2003;198:483-489.
7. Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR, for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805-2816.
8. Data on file. Pfizer Inc, New York, NY.