April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Topical Administration of SAR397769, a Novel Multikinase Inhibitor, Decreases Laser-Induced Choroidal Neovascularization
Author Affiliations & Notes
  • Katarzyna Trzaska-Accurso
    Aging Therapeutic Strategic Unit,
    Sanofi-Aventis U.S., Bridgewater, New Jersey
  • Rama Shmeis
    Pharmaceutical Sciences,
    Sanofi-Aventis U.S., Bridgewater, New Jersey
  • Fei Liu
    Drug Disposition/Pharmacokinetics,
    Sanofi-Aventis U.S., Bridgewater, New Jersey
  • Preethi A. Sundaram
    Aging Therapeutic Strategic Unit,
    Sanofi-Aventis U.S., Bridgewater, New Jersey
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 980. doi:
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      Katarzyna Trzaska-Accurso, Rama Shmeis, Fei Liu, Preethi A. Sundaram; Topical Administration of SAR397769, a Novel Multikinase Inhibitor, Decreases Laser-Induced Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2011;52(14):980.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : SAR397769 is a competitive and reversible multikinase inhibitor showing activity on a number of kinases involved in angiogenesis and inflammation. Target kinases include Yes and c-Raf (IC50=30nM), which are downstream mediators of pathways coupled to angiogenesis and leakage. This study aimed at investigating the anti-angiogenic efficacy of an eye drop formulation of SAR397769, on laser-induced choroidal neovascularization (CNV) in the rat. Distribution of topical SAR397769 into plasma, ocular anterior and posterior segments were also analyzed.

Methods: : CNV was induced in 50 Brown Norway rats (n=10 per group) using a green argon laser (514 nm wavelength). Three-four laser spots (100 µM size, 0.5 sec, 200 mW power) were placed close to the optic nerve. SAR397769 was formulated in proprietary vehicle at a 0.1% concentration (1mg/ml) and administered topically to each eye in a volume of 30µL/eye (30µg/eye). SAR397769 was also formulated for oral dosing at 10mg/kg as a positive control/comparator. Rats were treated for 1 week with SAR397769 via oral BID dosing, or QD, BID and TID eye drops, initiated the day before laser treatment. Rats were perfused via tail vein with fluorescein-dextran and sacrificed 30 min, 1 h or 4 h later. Eyes were immediately harvested, retina-choroid was flat mounted, and 3D microscopy was used to measure volume of CNV. The contralateral eye from each animal and blood samples were collected for compound level exposure by LC-MS analysis.

Results: : SAR397769 eye drops were well tolerated, based on clinical observations. SAR397769 significantly reduced the development of CNV in the rat model. The QD, BID and TID doses reduced CNV by 56.7% (p=0.0039), 68.3% (p<0.0001), and 63.7% (p<0.0001), respectively. Orally dosed SAR397769 reduced CNV by 66.3% (p<0.0001). Parallel PK analysis indicated exposure in the posterior eyecup after multi-day dosing with minimal systemic exposure. The maximal concentration in the posterior eyecup for topical dosing was at 30 min; QD, 520±121; BID, 320±18; and TID, 1001±532, whereas for the orally dosed group, maximal level was observed at 1 h, 1160±58 (ng/g, SEM).

Conclusions: : SAR397769 inhibits a wide spectrum of tyrosine kinases including c-Raf and Yes. In the rat CNV model, topical dosing was well tolerated and significantly reduced CNV volume. This study provides the first preclinical proof of principle for future studies to evaluate SAR397769 as eye drops in other animal models and subsequently humans.

Keywords: age-related macular degeneration • choroid: neovascularization • drug toxicity/drug effects 
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