Emergence of Dual VEGF and PDGF Antagonists in the Treatment of Exudative Age-Related Macular Degeneration

Matthew R Kudelka; Hans E Grossniklaus; Kenneth JMandell

Disclosures

Expert Rev Ophthalmol. 2013;8(5):475-484. 

In This Article

Abstract and Introduction

Abstract

Neovascular ('wet') age-related macular degeneration (AMD) is the leading cause of blindness among Caucasians over the age of 55 in the USA and is an important cause of ocular morbidity worldwide. Progress in oncology, and more recently ophthalmology, led to the development of VEGF antagonists, three of which are now approved for the treatment of wet AMD. Recent discoveries in ophthalmology and vascular biology, however, suggest that combined inhibition of VEGF and platelet-derived growth factor (PDGF) may be more beneficial than inhibition of VEGF alone. Accordingly, numerous studies are underway to evaluate the role of anti-VEGF/PDGF combination therapies for the treatment of wet AMD. This review discusses the biology of VEGF and PDGF and current preclinical and clinical data exploring the use of combined VEGF/PDGF inhibitors in the treatment of neovascular age-related macular degeneration.

Introduction

Age-related macular degeneration (AMD) is the leading cause of blindness among Caucasians in the USA and is a major cause of blindness among other ethnic groups. According to the 2000 US census data, AMD accounts for 54% of blindness among Caucasians, 28.6% among Hispanics and 4.4% among blacks.[1] Furthermore, the prevalence of AMD is expected to increase substantially by 2050.[2] Models indicate that cases of early AMD will increase from 9.1 million in 2010 to 17.8 million in 2050. Wet AMD, which accounts for 10–20% of AMD, is responsible for 80–90% of blindness associated with AMD.[3,4]

Pathologically, AMD is characterized by degeneration of retinal pigment epithelium (RPE) and/or fluid accumulation in the subretinal space.[5] The RPE supports photoreceptors and is separated from the choroid by Bruch's membrane. Changes in Bruch's membrane result in decreased diffusion of oxygen to the pigment epithelium, which leads to RPE degeneration and/or neovascularization of choroidal vessels. In conjunction, weaknesses in Bruch's membrane facilitate extravasation of choroidal vessels into the subretinal space, leakage of fluids and central vision loss. Central vision loss can also be caused by RPE degeneration in isolation.

AMD is classified into early, intermediate and advanced stages based on the Age-Related Eye Disease Study (AREDS).[6,7] This classification schema has been described extensively.[6,7] Of note, advanced AMD is characterized by geographic atrophy (advanced dry form) or choroidal neovascularization (CNV, wet form). CNV involves leakage of fluid, lipid and blood from chroidal vessels into the retina or subretinal space, which leads to scarring and reduced vision.[8]

Current US FDA-approved treatments for wet AMD include laser photocoagulation, photodynamic therapy (PDT) and injectable VEGF antagonists, though the latter is considered the first line of treatment.

Major technologic and biologic discoveries have advanced the treatment of wet AMD. The development of the argon laser in 1964 led to the creation and validation of laser photocoagulation in the 1980s.[9–12] This technology, which causes non-selective thermal tissue destruction,[13,14] was improved upon in the 1990s with the development of PDT.[14–18] PDT is more specific for vessels than laser photocoagulation because PDT uses light to excite a vessel-selective dye, resulting in destruction of blood vessels and immediately surrounding tissue.[19,20]

While laser photocoagulation and PDT were being developed, VEGF emerged as a key player in ocular disease.[21] The isolation of human cDNA clones encoding VEGF, the physiologic characterization of VEGF and the identification of the VEGF receptor in the 80s and 90s[22–24] facilitated the development of VEGF antagonists for the treatment of ocular and other neovascular disorders.[25–31] Although VEGF was initially discovered for its angiogenic properties, additional studies have suggested that VEGF also contributes to inflammation/immune dysregulation in CNV lesions. Hence, VEGF antagonists likely target multiple and distinct processes in wet AMD.[32] A number of VEGF antagonists for wet AMD have been FDA approved, such as pegaptanib,[33,34] ranibizumab[35–40] and aflibercept,[41] or are in late stage development, such as MP0122.[42–44] Currently, ranibizumab or closely related bevacizumab, but not pegaptanib, is used as first-line therapy in wet AMD.

Although targeting VEGF for the treatment of wet AMD has marked an important advancement in the field of ophthalmology, retina specialists acknowledge the need for other targets in the treatment of wet AMD.[45] In fact, growing clinical and laboratory evidence suggest that dual inhibition of VEGF and PDGF may be more effective than targeting VEGF alone. Angiogenesis requires coordinated activity of VEGF and PDGF, but PDGF may also contribute to distinct aspects of wet AMD pathology, such as fibrosis. Studies examining postnatal remodeling of the retina provided initial clues as to the importance of VEGF and PDGF in wet AMD,[46] while work in cancer models provided the final push to pursue anti-VEGF/PDGF combination therapy for the treatment of wet AMD.[47,48]

Clinical trials for dual therapy look promising although, to date, no dual VEGF/PDGF antagonist has received FDA approval for ocular disease. This review describes preclinical and clinical evidence for dual VEGF/PDGF inhibition in the treatment of wet AMD.

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