Retina Today - An Oral Drug for Treatment of AMD? (July/August 2016)

摘要

Age-related macular degeneration (AMD) is a leading cause of severe vision loss. In the United States, the estimated number of people with AMD is expected to more than double, from 2.07 million at present to 5.44 million by 2050.1 Although there is no treatment shown to prevent AMD, and no available treatment for the advanced dry form of AMD (geographic atrophy), the treatment of wet (neovascular) AMD was revolutionized by the introduction of intravitreal anti-VEGF agents a decade ago. AT A GLANCE • Standard of care treatment of wet AMD typically requires long-term intravitreal anti-VEGF injections at regular intervals. • X-82 is an orally administered small-molecule tyrosine kinase inhibitor derived from a cancer drug that inhibits VEGF and PDGF receptors without the toxicities of the parent drug. • A safe and effective oral agent that reduces or eliminates the need for intravitreal injections could be an attractive treatment option. Intravitreal anti-VEGF agents do a remarkable job of preserving and even improving vision in patients with wet AMD, but there is always room for greater improvement. For example, an effective oral treatment could reduce the need for intravitreal injections, thereby reducing the infection risk associated with injections and decreasing the burden of frequent trips to the office for patients and their family members who typically accompany them at each office visit. This article explores the only orally administered dual inhibitor of VEGF and platelet-derived growth factor (PDGF) in development for the treatment of neovascular AMD. AN ORAL TREATMENT FOR AMD? Following promising preclinical experiments and a phase1 study, X-82 (Tyrogenex) is being investigated in a double-masked, placebo-controlled phase 2 study as an oral treatment for patients with wet AMD.2 X-82 is a small-molecule tyrosine kinase inhibitor derived from sunitinib (Sutent, Pfizer), a drug that is approved for the treatment of advanced renal cell carcinoma, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors. Compared with sunitinib, X-82 has a shorter half-life and accumulates less in tissues. X-82 inhibits VEGF and PDGF receptors without the toxicities associated with sunitinib. Both of these growth factors are implicated in the pathogenesis of wet AMD, and both are targets of existing and investigational intravitreal therapies. VEGF and PDGF play crucial roles in angiogenesis, inflammation, immune dysregulation, and fibrosis in eyes with wet AMD. VEGF facilitates new vessel growth. PDGF stabilizes maturing vessels through pericyte recruitment. X-82 blocks kinase activity associated with all receptor subtypes for VEGF and PDGF, and its potency against all receptor subtypes is thought to provide targeted inhibition at a relatively low dose with reduced risk of side effects.3 Preliminary studies of intravitreal injections of PDGF-blocking agents in conjunction with intravitreal anti-VEGF therapy have demonstrated the potential of this combination for the treatment of wet AMD.4 Oral X-82 provides dual inhibition of VEGF and PDGF via systemic distribution, which may allow it to efficiently target bilateral disease with fewer injections. in vitro and animal experiments In vitro and animal experiments showed that X-82 is a potent inhibitor of vessel proliferation and provided proof of concept of its potential in retinal disease. Experiments in human umbilical vein endothelial cells showed vessel growth inhibition at low concentrations (approximately 50 nM). X-82 was tested in a rat model of choroidal neovascularization (CNV), wherein a reconstituted basement membrane preparation (Corning Matrigel, Engelbreth-Holm-Swarm) was injected into the retina and the resulting area of induced CNV was measured over time. Daily oral dosing of X-82 at 10mg/kg prevented the growth of CNV and reduced its area by 80% compared with positive control in test animals. In a second di