In-Vivo Studies with Trans-Scleral Anecortave Acetate Delivery Device Designed to Treat Choroidal Neovascularization in AMD

Abstract

Abstract: : Pupose: Three in-vivo studies were conducted with a trans-scleral drug delivery device (TS/DDD) to determine the surgeon's ability to accurately and reproducibly place the device on the rabbit's hypothetical macula, to assess the drug's pharmacokinetic distribution, and to evaluate its biocompatibility. Methods: Rabbit TS/DDD was fabricated from medical-grade silicone, having a curved flat shape with a circular cavity at its distal end, in which a 25 mg anecortave acetate (AA) tablet was inserted. Under general anesthesia, the device was inserted in a surgically created sub-Tenon tunnel, at the supero-temporal quadrant, and advanced toward the scleral area correspondent to the hypothetical macula with the tablet facing the scleral surface. Animals were euthanized and their eyes evaluated. Results: Placement: In all cases (n=49, 12-week study), device implantation was uneventful. Statistical analysis showed 97.5% accuracy in targeting the hypothetical macular area of the rabbit retina. Pharmacokinetics: At 1,6,12,18,24,36,52, and 104 weeks post-implantation, tissue distribution of AA and its active metabolite, AL-4940, showed the rank order of drug concentration to be: sclera>choroid> retina>>>vitreous (n=40). Choroidal and retinal levels were both 1.3µM at 1 week, and declined to ca. 0.2µM and 0.1µM, respectively, by 6 weeks; remaining at approximately these levels through 2 years. In contrast, scleral concentration, after an initial decline, steadily increased to the highest level at 2 years (ca. 3.0µM), indicative of accumulation. During the 2-year long study, about 60% of the tablet was depleted, mainly by surface erosion. Biocompatibility: In a 1-year biocompatibility/safety study (n=72) indirect ophthalmoscopy showed the fundus to be within normal limits for all animals at nearly all observation intervals. Device implantation did not affect corneal thickness or endothelial integrity, intraocular pressure, or clinical pathology parameters. Necropsy did not show any test article (experimental and controls)-related observations. In general, The AA-TS/DDD did not produce signs of ocular toxicity. Histologically, a fibrous capsule and minimal inflammation, due to the AA-TS/DDD, were expected as a normal response. Conclusion: The TS/DDD introduces a new, unique, and versatile means to safely treat disorders of the posterior segment of the eye (e.g., age-related macular degeneration) continuously for years.

Keywords: age-related macular degeneration • retina • sclera