June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Aflibercept Action in a Rabbit Model of Chronic Retinal Neovascularization: Extended, Reversible Inhibition of Pathological Leak with Dose-dependent Duration
Author Affiliations & Notes
  • Jingtai Cao
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Thomas Clayton MacPherson
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Bibiana Iglesias
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Yang Liu
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Natasha Tirko
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Stanley J Wiegand
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • George Yancopoulos
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Carl Romano
    Ophthalmology, Regeneron Pharmaceuticals Inc, Tarrytown, New York, United States
  • Footnotes
    Commercial Relationships   Jingtai Cao, Regenton Pharmaceuticals, Inc. (E); Thomas MacPherson, Regeneron Pharmaceuticals, Inc. (E); Bibiana Iglesias, Regeneron Pharmaceuticals, Inc (E); Yang Liu, Regeneron Pharmaceuticals, Inc (E); Natasha Tirko, Regeneron Pharmaceuticals, Inc (E); Stanley Wiegand, Regeneron Pharmaceuticals, Inc (E); George Yancopoulos, Regeneron Pharmaceuticals, Inc (E); Carl Romano, Regeneron Pharmaceuticals, Inc (E)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4068. doi:
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      Jingtai Cao, Thomas Clayton MacPherson, Bibiana Iglesias, Yang Liu, Natasha Tirko, Stanley J Wiegand, George Yancopoulos, Carl Romano; Aflibercept Action in a Rabbit Model of Chronic Retinal Neovascularization: Extended, Reversible Inhibition of Pathological Leak with Dose-dependent Duration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4068.

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

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Abstract

Purpose : Intravitreal Aflibercept (Eylea) is approved for the treatment of neovascular Age-related Macular Degeneration (AMD), macular edema following retinal vein occlusion (RVO), Diabetic macular edema (DME) and Diabetic Retinopathy (DR) in patients with DME. The purpose of this study was to evaluate the effects of Aflibercept in an animal model of chronic retinal neovascularization (RNV) in rabbit, induced by intravitreal injection of a gliotoxin, DL-alpha-aminoadipic acid (AAA).

Methods : Adult male New Zealand White rabbits (2.0-2.5kg) received AAA intravitreally (IVT), with follow-up examinations by fluorescein angiography (FA) and optical coherence tomography (OCT). After 10 weeks of follow-up, rabbits were divided into treatment or control groups with an equal distribution of RNV. Intravitreal Aflibercept was given at 25 mcg, 125mcg, or 500 mcg/50 mcl/eye, and control group received buffer or human Fc 167 mcg/50mcl IVT. FA and OCT were performed at baseline and weekly (weeks 1 to 20) post IVT treatment. RNV leak was quantified by image analysis with ImageJ and Photoshop Extended CS6 software. At some time-points, the eyes were collected for histological analysis.

Results : Within a few days after IVT injection, AAA produced retinal degeneration over a large but incomplete fraction of the neural retina, usually the 50% on the side of the injection. RNV formed in the damaged area over 6-8 weeks, and by 10 weeks the RNV had a stable morphology and amount of leak. The vascular pathology and leak were qualitatively and quantitatively stable for at least 65 weeks. Treatment with buffer or human Fc did not affect RNV leak, but intravitreal aflibercept at doses above 10 mcg completely blocked RNV leak. The inhibition was reversible, and the leak returned as the drug cleared. The duration of anti-leak effects with 500 mcg aflibercept was about 8 weeks and with 125 mcg dose, about 3-4 weeks.

Conclusions : Most other models of RNV involve vascular pathologies that resolve spontaneously in several weeks when untreated. This model mimics a chronic human disease in its stability and persistence, and the anti-leak action of aflibercept is fully reversible with a dose-dependent duration. This large eye model is therefore uniquely suitable for investigations into novel pharmacotherapies and formulations for retinal angiogenic diseases.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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