Phase 2 Ziv-aflibercept in Ocular Disease Short and Long-term Study

Ascertain the long term safety and efficacy of ziv-aflibercept in a large variety of ocular diseases and over a long-term after its proven safety and efficacy in the laboratory, in phase one study and in isolated case report.

Background and Significance:

Anti-VEGF therapy is currently one of the mainstay of therapy in a great number of diseases of the eye with intravitreal injections of antiVEGF being the number one procedure done in the office of an ophthalmology practice. The ophthalmic community has currently 2 very expensive antiVEGF both approved by the FDA for ocular use: Ranibizumab and aflibercept. However because of the prohibitive cost of these medications in the third world and the need for repetitive use of these agents in the control of eye disease, the off-label use of bevacizumab is currently the most common anti-VEGF used worldwide because of its equivalent therapeutic efficacy and cost-effective superiority. Bevacizumab and ranibizumab have high affinity to VEGF, aflibercept possess additional properties. Aflibercept (Eylea; Regeneron, Tarrytown, New York, USA and Bayer Healthcare, Leverkusen, Germany) is a fusion protein consisting of the Fc portion of human immunoglobulin IgG1 and the extracellular domains of vascular endothelial growth factor receptors (VEGFR-2 and VEGFR-1), which binds to circulating vascular endothelial growth factor (VEGF), thus acting as a decoy receptor. Laboratory studies and clinical trials suggest that aflibercept's high binding affinity for VEGF may impart greater durability of activity and similar efficacy compared to ranibizumab1 or bevacizumab. Aflibercept is approved by Food and Drug Administration (FDA) for the therapy of wet age related macular degeneration (AMD) , macular edema from retinal vein occlusion or diabetes.3 Ranibizumab is given monthly, while aflibercept is given bimonthly after 3 monthly injections for eyes with wet AMD. Because of the high cost of ranibizumab and aflibercept, a majority of ophthalmologists worldwide tend to treat patients with bevacizumab at a major saving for the patient. Commercially, a much cheaper yet identical fusion protein to aflibercept is ziv-aflibercept. Ziv-aflibercept (Zaltrap, Sanofi-Aventis US, LLC, Bridgewater, NJ and Regeneron Pharmaceuticals, Inc, Tarrytown, NY) was approved by FDA in August 2012 for the treatment of metastatic colorectal carcinoma resistant to an oxiplatin-containing regimen. One may wonder if ziv-aflibercept can be used instead of aflibercept in ophthalmic disorders. Hence the need to answer some major safety concerns: first the difference in osmolarity, and second whether ziv-aflibercept could impair retinal function and alter morphology6. A preliminary study was conducted on the use of ziv-aflibercept in patients with exudative AMD or diabetic macular edema (DME) with poor vision. In addition, the investigators tested the stability of ziv-aflibercept over a period of 4 weeks and the economic implications of the use of compounded drug.

Ziv-aflibercept is supplied in single-use vials of 100 mg per 4 ml and 200 mg per 8 ml formulated as 25 mg/mL ziv-aflibercept in polysorbate 20 (0.1%), sodium chloride (100 mM), sodium citrate (5 mM), sodium phosphate (5 mM), and sucrose (20%), in Water for Injection USP, at a pH of 6.2. Eylea is supplied as a single-use, glass vial designed to deliver 0.05 mL (2mg) of aflibercept (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2).

Design and Procedures: