Presentation Abstract

Program#/Poster#: 2779/D817
Abstract Title: OC-10X, a Novel Tubulin Inhibitor, Inhibits Neovasclarization in a Nonhuman Primate Model of AMD
Presentation Start/End Time: Tuesday, May 04, 2010, 8:30 AM -10:15 AM
Session Number: 320
Session Title: AMD Preclinical and Translational Studies
Location: Hall B/C
Reviewing Code: 117 age-related macular degeneration: translational research – RE
Author Block: P.B. Williams1, F.A. Lattanzio, Jr.1, C.M. Grevem2, A. Hosseini1, S. Samudre1. 1TRLee Center for Ocular Pharmacology, Eastern Virginia Medical School, Norfolk, VA; 2Wake Forest University Eye Center, Wake Forest University School of Medicine, Winstson-Salem, NC.
Keywords: 412 age-related macular degeneration, 453 choroid: neovascularization, 697 retinal neovascularization
Abstract Body: Purpose: Exudative age-related macular degeneration (AMD) is characterized by growth of abnormal blood vessels under the retina, e.g. choroidal neovascularization (CNV). These studies examined the antiangiogenic efficacy of OC-10X in a nonhuman primate (NHP) model of CNV. Absorption and distribution of topical 14C-OC-10X into ocular tissues was also analyzed.
Methods: CNV was induced in 8 cynomolgus NHP by bilateral laser photocoagulation (75 μm, 100 msec, 440 mW) followed by intravitreal injection of 1% OC-10X (50 µL) in the right eye (OD); the left eye (OS) was the untreated control. A repeat injection followed 2 wk later. 4 wk after the laser NHP were injected IV with FITC-dextran, euthanized and the retina prepared as a flatmount. The area of CNV was quantitated by digital planimetry. Other NHP (n=10) received 3 bilateral topical doses of 1% or 2% 14C-OC-10X administered 30 min apart and were euthanized 1 to 4 hr later. 14C-OC-10X in the ocular tissues, major organs, plasma and urine was determined by liquid scintillation.
Results: Intravitreal injection of OC-10X was well tolerated; primates exhibited normal behavior. Flatmount histology of retinas following injection with FITC-dextran showed less CNV in OC-10X treated eyes ( 230170±117941 µm2 ) versus untreated eyes (406277±157399 µm2; p=0.025). No signs of ocular irritation were noted after multiple topical applications of 1% or 2% 14C-OC-10X. Within 1 hr after 1% 14C-OC-10X, the amount peaked in ocular tissues and plasma. After 4 hr, the amount (µg/g) in the retina = 0.023±0.035, 0.137±0.130 in the choroid, and 0.178±0.167 in the vitreous but plasma = 0.0016±0.0011 µg/mL. Topical application of 2% 14C-OC-10X did not increase concentrations in these tissues.
Conclusion: CNV in the OC-10X treated group was 43.0% less than in the untreated control group. Intravitreal injection or topical application of OC-10X was well tolerated. In the pharmacokinetic model, after topical application 14C-OC-10X penetrated to the back of the eye with 10 fold less in plasma. Between 1 and 4 hr, concentrations in retina and choroid, target organs for the AMD therapy, were 0.16 -1.48 µM, a therapeutically relevant amount. Increasing to 2% 14OC-10X did not increase absorption or distribution. This study provides evidence for antiangiogenic effects of OC-10X in a nonhuman primate model of CNV and supports the safety of OC-10X in the eye.
CommercialRelationships:   P.B. Williams: F; OcuCure. C; OcuCure. R; OcuCure. F.A. Lattanzio, Jr.: F; OcuCure. C; OcuCure. R; Ocu. C.M. Grevem: C; OcuCure. R; OcuCure, Regeron, GlaxoSmithKline, Genentech. A. Hosseini: None. S. Samudre: None.
Support: OcuCure Therapeutics, Inc.




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