VEGF Inhibitors for Age-Related Macular Degeneration

Public disclosure of payments made by Medicare to individual physicians has generated widespread interest in the use of expensive VEGF (vascular endothelial growth factor) inhibitors by ophthalmologists to treat exudative (“wet”) age-related macular degeneration. Reimbursement for the cost of these agents appears to be responsible for some of the headline-generating amounts paid to ophthalmologists. The availability, although not in an ophthalmic formulation, of a relatively inexpensive VEGF inhibitor, which is widely used for this indication outside the US, has sharpened the tone of the discussion. We reviewed this subject in the November 2012 issue of Treatment Guidelines from The Medical Letter on Drugs for Some Common Eye Disorders.

The principal mediator of neovascularization in wet AMD is thought to be vascular endothelial growth factor (VEGF), which induces angiogenesis and increases vascular permeability and inflammation. Treatment of wet AMD with VEGF inhibitors has reduced vision loss in many patients and has led to the recovery of lost vision in patients whose treatment began soon after the onset of the leakage causing the vision loss. These drugs are given as periodic intravitreal injections with topical anesthesia. They can rarely cause serious complications such as retinal detachment and endophthalmitis, leading to loss of vision.

Ranibizumab (Lucentis) is a VEGF inhibitor approved for intravitreal injection in patients with wet AMD; it is also approved for treatment of diabetic macular edema (DME). A recombinant, humanized monoclonal antibody fragment (Fab) derived from the same antibody as bevacizumab, it causes regression of the abnormal vessels and reduction of leakage from these vessels in wet AMD, improves visual acuity, and decreases swelling of the retina.

Bevacizumab (Avastin) is a systemic VEGF inhibitor FDA-approved only for treatment of colon cancer and non-small cell lung cancer, but it has also been used off-label as an intravitreal injection for treatment of wet AMD. Divided into aliquots, it costs much less than ranibizumab, but repackaging of the drug without proper aseptic technique has led to endophthalmitis in a small number of patients. An NIH-sponsored trial (CATT) comparing monthly or as needed injections of bevacizumab with ranibizumab found that they had equivalent effects on visual acuity (8 letters gained with bevacizumab vs. 8.5 letters gained with ranibizumab) after 1 year. Among the patients who continued treatment for an additional year and were randomized to monthly or as needed treatment with the same drug, ranibizumab and bevacizumab had similar effects on visual acuity in the second year. Patients who received bevacizumab had more systemic adverse events, but most of these had not previously been associated with VEGF treatment.

Aflibercept (Eylea) is a fusion protein FDA-approved for treatment of wet AMD. It acts as a decoy VEGF receptor, competing for binding of VEGF. In 2 controlled trials, it appeared to be similar to ranibizumab in effectiveness. Aflibercept has not been compared directly to bevacizumab.

The adverse effects of all of these agents have been largely related to the injection procedure rather than the drug itself; they include conjunctival hemorrhage, acute intraocular pressure rise after injection, traumatic cataract, uveitis, and retinal detachment, all occurring in less than 2% of patients. Intravitreal injection of VEGF inhibitors carries a risk of intraocular infection or endophthalmitis. In one study, endophthalmitis developed after 2 of 5449 injections (0.04%) with ranibizumab and after 4 of 5508 injections (0.07%) with bevacizumab; the risk increases with each additional injection. Whether less frequent injections would be equally effective and safer remains to be established.

Bevacizumab may cost as little as $50 for a single injection, while ranubizumab may cost as much as $2000. Both are manufactured by Genentech, which therefore has no economic incentive to develop an ophthalmic formulation of bevacizumab. Hopefully, when bevacizumab becomes available generically, another company will seek FDA approval for its ophthalmic use, the prices of the other VEGF inhibitors will come down, and Medicare can use all those millions for something else.

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  1. Barry S Gloger, MD says:

    Everything you say is true, but Bevacizumab (Avastin) has to be prepared by a compounding pharmacy, such as New England CP. If an adverse event happens after a Bevacizumab (Avastin) injection, you can be sure you’ll be sued for malpractice for using an off label drug compounded by a criminal or unregulated enterprise. So why should an Ophthalmologist risk his entire life’s work just to save the government money?

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