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Periocular Injection of Microspheres Containing PKC412 Inhibits Choroidal Neovascularization in a Porcine Model

¹From the Departments of Ophthalmology and ²Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland; ³Pharmaceutical and Analytical Development, Novartis Pharma AG, Basel, Switzerland; and ⁴Novartis Ophthalmics, Duluth, Georgia.

PURPOSE. Oral administration of PKC412, a kinase inhibitor that blocks several isoforms of protein kinase C (PKC) and receptors for vascular endothelial growth factor (VEGF), platelet-derived growth factor, and stem cell factor, inhibits ocular neovascularization in a murine model. The purpose of this study was to determine whether sustained local delivery of PKC412 in a human-sized eye inhibits choroidal neovascularization (CNV).

METHODS. Laser photocoagulation was used to rupture Bruch’s membrane in young domestic pigs, and then a periocular injection of control microspheres or microspheres containing 25% or 50% PKC412 was given. After 10 days the integrated area of CNV at Bruch’s membrane rupture sites was measured by image analysis. The levels of PKC412 in choroid, retina, and vitreous were measured either 10 or 20 days after periocular injection of 50% PKC microspheres or at 20 days after injection of 25% PKC412 microspheres.

RESULTS. The areas of CNV at Bruch’s membrane rupture sites were significantly smaller in eyes that received a periocular injection of microspheres containing 25% (P = 0.0042) or 50% (P = 0.0012) PKC412 than those in eyes injected with control microspheres. Ten days after periocular injection of 50% PKC412 microspheres, PKC412 was detected in the choroid, but not in the retina or vitreous. Twenty days after periocular injection of 50% PKC412, high levels of PKC412 were measured in the choroid, vitreous, and retina. Levels were lower but still substantial in all three compartments 20 days after periocular injection of 25% microspheres.

CONCLUSIONS. Sustained local delivery of PKC412 provides a promising approach for treatment of CNV.

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