April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
PRI-724 Significantly Reduces Retinal Fibrosis in Models of CNV and PVR
Author Affiliations & Notes
  • Andy Whitlock
    Pre-Clinical, Ora, Andover, MA
  • Rafal Farjo
    EyeCRO LLC, Oklahoma City, OK
  • Geoffrey P Lewis
    Neuroscience Institute, University of California, Santa Barbara, CA
  • Steven K Fisher
    Neuroscience Institute, University of California, Santa Barbara, CA
  • Gabriel Luna
    Neuroscience Institute, University of California, Santa Barbara, CA
  • Takenao Odagami
    Prism Pharma, Ltd, King of Prussia, PA
  • Tetsushi Inada
    Prism Pharma, Ltd, King of Prussia, PA
  • Hiroyuki Kouji
    Prism Pharma, Ltd, King of Prussia, PA
  • Footnotes
    Commercial Relationships Andy Whitlock, Ora, Inc (E); Rafal Farjo, EyeCRO (E); Geoffrey Lewis, UCSB (F); Steven Fisher, UCSB (F); Gabriel Luna, UCSB (F); Takenao Odagami, Prism Pharma (E); Tetsushi Inada, Prism Pharma (C); Hiroyuki Kouji, Prism Pharma (E), Prism Pharma (P)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 1203. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: 695 retinal degenerations: cell biology • 700 retinal neovascularization  
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