Topical therapy to treat posterior segment disease is possible despite the limitations of the blood-retinal barrier.
Topical therapy to treat posterior segment disease is possible despite the limitations of the blood-retinal barrier. The effective route of drug penetrance of topical therapy is either by the transcorneal route or by the transscleral/conjunctival route, said Baruch Kuppermann, MD, PhD, at Retina Subspecialty Day. He is chief of the Retina Service, Department of Ophthalmology, University of California, Irvine.
A few such drugs are currently under development, and the hope is that they will eliminate the complications associated with intravitreal injections of drugs, he said.
801 kinase inhibitor (TargeGen) has activity against vascular endothelial growth factor (VEGF) receptor/PDGF receptor/Src family kinases and stops leakage, angiogenesis, and inflammation. In animal studies, the drug has been shown to have high concentrations in the anterior segment, lower effective concentrations in the posterior segment, very low concentrations in the aqueous and vitreous, and extremely low concentrations in the plasma.
ATG2 (mecamylamine) (CoMentis) is a powerful nonselective nAChR antagonist that has reduced angiogenesis in animal models and inhibits VEGF synthesis/release and responses. Topical mecamylamine was seen to penetrate the retina-choroid in mice, probably by the transscleral-conjunctival route.
OC-10X (Ocucure) is a nontoxic vascular targeting agent with selective tubulin inhibition. The agent is lipid soluble and crosses the human cornea; it achieves therapeutic concentrations at the retina-choroid. In rats, the drug, when given once every hour for 4 hours, achieved a corneal level of 100%, a lens/vitreous level of 11%, and a retina-choroid-sclera level of 83%.
OT-551 (Othera) catalytic antioxidant has multiple modes of action, i.e., antioxidant, antiangiogenic, and anti-inflammatory. The agent penetrates the cornea and sclera and reaches the retina. It also suppresses photo-oxidative damage in the retinal pigment epithelium and photoreceptors. A phase II study is ongoing for geographic atrophy, neovascular age-related macular degeneration, and cataract.
Pazopanib (GlaxoSmithKline) has completed a phase I trial with 38 healthy volunteers. This compound has been in development to treat solid tumors, according to Dr. Kuppermann.
"Historically, we have never contemplated the use of topical therapy for posterior segment disease because of poor ocular penetrance," he said. "The small molecule drugs are being developed to meet this challenge. They have shown good posterior segment penetrance, safety, and efficacy."