Emergence of dual VEGF and PDGF antagonists in the treatment of exudative age-related macular degeneration

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.

Keywords::

• angiogenesis
• clinical trials
• combination therapy
• neovascular age-related macular degeneration
• ophthalmology
• preclinical studies
• PDGF
• VEGF
• wet AMD

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Age-related macular degeneration (AMD) is a major cause of visual impairment worldwide, it accounts for 54% of blindness among Caucasians in the USA and early cases are expected to increase from 9.1 million in 2010 to 17.8 million in 2050.

• • Although wet AMD accounts for 10–20% of AMD, it is responsible for 80–90% of blindness associated with AMD.

• • In wet AMD, changes in Bruch’s membrane lead to choroidal neovascularization (CNV) and leakage of fluid, lipid and blood into the retina or subretinal space.

• • VEGF antagonists are currently the preferred form of treatment for wet AMD; approved agents include pegaptanib, ranibizumab and aflibercept.

• • VEGF stimulates development of the endothelial plexus, while PDGF induces pericyte recruitment to vascular endothelium, facilitating vessel maturation.

• • Dual VEGF/PDGF therapies have been approved for the treatment of other neovascular diseases such as cancer.

• • In wet AMD, dual VEGF/PDGF inhibition offers the potential to induce vascular regression, which is not seen with current VEGF antagonists. PDGF inhibition could also reduce subretinal scarring that follows vascular regression.

• • Anti-VEGF and PDGF aptamers, sunitinib and pazopanib have been successful in animal models of ocular neovascularization.

• • Additional research should be conducted on non-VEGF/PDGF growth factors, such as PlGF, IGF-1, angiopoietin and pigment epithelium-derived factor (PEDF), to determine if these could be viable targets in the treatment of wet AMD.

• • Isolated case studies with sorafenib and early clinical trials with pazopanib and E10030, an anti-PDGF adjunct to ranibizumab, suggest that dual VEGF/PDGF inhibition has the potential for significant clinical improvement over VEGF antagonism alone in the treatment of wet AMD.