Off-label bevacizumab shows promise for treating AMD

The results in patients who received intravitreal bevacizumab as salvage therapy showed stabilization and improvement in vision much like early results observed with ranibizumab (Lucentis, Genentech).

Philip Rosenfeld, MD, PhD, discussed systemic and intravitreal use of bevacizu-mab during the retina subspecialty day at the American Academy of Ophthalmology.

"Bevacizumab binds all biologically active forms of VEGF, as ranibizumab does. This is not surprising because ranibizumab and bevacizumab are derived from the same mouse monoclonal antibody against VEGF," Dr. Rosenfeld said. He is associate professor of ophthalmology at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami.

"The results that were achieved with ranibizumab in the phase I/II clinical trials made us interested in using bevacizumab systemically for the treatment of neovascular AMD," he added.

Systemic disadvantages

The disadvantages in cancer patients of the systemic route of administration are hypertension and doubling of the risk of thromboembolic events. Dr. Rosenfeld said the increased risk of thromboembolic events was not observed in patients being treated for neovascular AMD.

In contrast, the patients treated for cancer were receiving the drug in high doses every 2 weeks, over months, for up to a year or longer, and in combination with chemotherapy, which also increased the risk of thromboembolic events.

"In patients treated for neovascular AMD, we observed a slight increase in the systolic and diastolic blood pressure by 3 weeks, which then subsided by the 6-month end point of the SANA (Systemic Avastin for Neovascular AMD) Study, a study of intravenous bevacizumab conducted at the Bascom Palmer Eye Institute," Dr. Rosenfeld noted. No other adverse events were observed with the high-dose systemic therapy.

"It seemed reasonable to us that if we delivered 400- to 500-fold less drug directly into the eye, less drug would likely result in lower systemic risk," Dr. Rosenfeld said.

Thus far, more than 250 patients have been treated with intravitreal bevacizu-mab salvage therapy, and Dr. Rosenfeld reported on the first 40 patients with 3-month follow-up.

In this population, the average visual acuity was 20/125. Most patients had a gain of at least one line of vision, but 40% had a three-line improvement in visual acuity, and optical coherence tomography showed that the average retinal thickness decreased from 332 to 228 μm. The patients received an average of 1.8 injections over 3 months.

Case studies

Dr. Rosenfeld showed bevacizumab's clinical effect in the first patient treated with the drug. In this patient, treatment with photodynamic therapy, plus triamcino-lone acetonide (Kenalog, Bristol-Myers Squibb), had failed. The patient was continuing to lose vision while being treated with pegaptanib sodium (Macugen, OSI Pharmaceuticals/Eyetech Pharmaceuticals). The patient had a large, predominantly classic lesion that was leaking and received one injection of bevacizumab (1 mg).

"A dramatic response to bevacizumab was seen within 1 week of the injection," Dr. Rosenfeld said. "While the patient's vision has remained stable at 20/125 for 5 months after the single injection, there has been a marked resolution of the fluid as measured by OCT and the distorted vision resolved. Fluorescein angiography showed that the leaking had stopped by 1 month and this has continued through 4 months after the treatment."

A more typical response in patients with less chronic disease was shown by a patient with a lesion characterized as a retinal angiomatous proliferation. The patient had been treated with pegaptanib sodium, the leaking increased, and the vision decreased.