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Andy Whitlock, Rafal Farjo, Geoffrey P Lewis, Steven K Fisher, Gabriel Luna, Takenao Odagami, Tetsushi Inada, Hiroyuki Kouji; PRI-724 Significantly Reduces Retinal Fibrosis in Models of CNV and PVR. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1203.
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Fibrosis is a component of a number of ophthalmic diseases such as late-stage wet AMD, diabetic retinopathy, proliferative vitreo-retinopathy (PVR), and bleb closure/failure following trabeculectomy surgery. While fibrosis is a multi-factorial process, the Wnt signaling pathway is certainly implicated during the initiation of this process. PRI-724 is a potent anti-fibrotic agent that has been shown to inhibit both liver and pulmonary fibrosis in pre-clinical disease models. PRI-724 also possesses significant anti-proliferative properties, and is currently in human clinical trials for the treatment of both solid and liquid tumors. PRI-724 acts by binding specifically to CREB Binding Protein (CBP) and antagonizing β-catenin/CBP-mediated transcription. This inhibition results in the down-regulation of many genes required for cell proliferation. The purpose of this study was to determine the efficacy and potential utility of this novel anti-fibrotic drug in several models of retinal disease.
The appropriate dosing level and route of administration (systemic/subcutaneous, intravitreal (IVT), or topical) was determined in preliminary rabbit and rat pharmokinetic (PK) studies. The anti-angiogenic effect of PRI-724 and its active metabolite, C-82, were explored in a laser-induced CNV model in rats in comparison to an anti-VEGF control. The direct anti-fibrotic effect of PRI-724 was examined in a retinal detachment model of PVR. Fibrosis was measured in this model by quantifying both the number of anti-phosphohistone labeled proliferating Muller cells, and the size and number of subretinal glial scars.
The most efficient route for retinal exposure was IVT administration, which demonstrated measureable levels of compound out to 7 days following a single injection of PRI-724 or C-82. In the laser-induced CNV model, treatment with PRI-724, C-82, and the anti-VEGF clinical comparator significantly reduced lesion size compared to vehicle control. Treatment with PRI-724 in the rat PVR significantly reduced Muller cell proliferation and glial scar formation when compared to the vehicle control.
Given the favorable PK profile of this small molecule and the effects on both vascular lesion size and sub-retinal fibrosis, PRI-724 may possess clinical utility for the treatment of several retinal fibro-vascular diseases. This would provide an added improvement to the current anti-VEGF treatment paradigm.
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