Purpose:
To investigate whether topical (eye drop) administration of ATG003, an ophthalmic solution containing mecamylamine (MEC), a non-selective nicotinic acetylcholine (nACh) receptor antagonist with anti-angiogenic properties results in significant distribution to the retina-choroid and other ocular tissues in non-human primates.
Methods:
8 male Cynomolgus monkeys were divided into 4 groups and given topical 1% MEC ophthalmic solution (ATG003) (50uL) 3 times a day for 3 days into both eyes. Group 1 was terminated 3hrs post first dose on day 1 and Groups 2, 3 and 4 at 1, 3 and 6 hrs post-final dose on day 3. Tissues and fluids from the anterior and posterior segment of the eye and plasma were separated, snap frozen and analyzed for MEC concentration using a standard LC/MS/MS method.
Results:
These results show that MEC penetrates to the posterior segment of the eye, in particular the retina-choroid, following topical administration. MEC was undetectable in plasma suggesting that systemic effects of MEC are likely to be minimized following topical administration. The high concentration of MEC found in the sclera compared to the vitreous suggests that the agent reaches the posterior segment via a peri-scleral route. High levels found in retina-choroid after multiple topical administration suggests that the dosing interval may be increased to once or twice daily.
Conclusions:
Topical administration of MEC, a non-selective nACh receptor antagonist with anti-angiogenic properties, penetrates to the retina-choroid in Cynomolgus monkeys. These data, together with data showing that MEC has anti-angiogenic properties and reduces laser-induced choroidal neovascularization (CNV) in a mouse model, suggest that topical MEC is an attractive non-invasive anti-angiogenic treatment for neovascular AMD.
Keywords: age-related macular degeneration • choroid: neovascularization • acetylcholine