Pegaptanib (Macugen) is an effective treatment for neovascular age-related macular degeneration

Dec 30 2004

Results from two concurrent, prospective, double-blind, multi-center clinical trials show that pegaptanib (Macugen), an anti-vascular endothelial growth factor therapy, is an effective treatment for neovascular age-related macular degeneration (AMD), according to a paper in the Dec. 30 issue of the New England Journal of Medicine. Macugen was approved by the Food and Drug Administration on Dec. 17.

AMD is the leading cause of irreversible, severe loss of vision in people 50 years and older in the developed world and remains an area of unmet medical need. The neovascular or wet form of the disease represents about 10 percent of the overall disease prevalence, but is responsible for 90 percent of the severe vision loss. In wet AMD, abnormal blood vessels grow under the central retina and cause a progressive loss of central vision, interfering with driving, reading and other everyday tasks. As the population ages, almost 1 million people over the age of 55 years in the United States are expected to develop AMD in the next five years, making it a major public health issue in an increasing population of older persons.

The paper in the New England Journal of Medicine details two clinical trials that were held at 117 sites in the Unites States, Canada, Europe, Israel, Australia and South America. Patients were eligible for inclusion if they were 50 years of age or older and had subfoveal choroidal neovascularization caused by AMD and a range of best corrected visual acuity of 20/40 to 20/320 in the study eye and of 20/8000 or better in the other eye. Of the 1,208 patients randomly assigned to treatment in the two studies, (297 patients were assigned to receive 0.3 mg of pegaptanib; 305 patients, 1.0 mg of pegaptanib; 302 patients, 3.0 mg of pegaptanib; and 304 patients, sham injections), 1,190 received at least one study treatment. Treatments were given by injection into the eye.

According to lead author, Evangelos Gragoudas, M.D., Director of Retina Services at the Massachusetts Eye and Infirmary and Professor of Ophthalmology at Harvard Medical School, pegaptanib produced a statistically significant and clinically meaningful benefit in the treatment of wet AMD.

"Overall, a reduced risk of visual-acuity loss was observed with all doses as early as six weeks after treatment was begun, with evidence of an increasing benefit over time up to week 54," the authors write. "Pegaptanib reduced the chance of not only the loss of 15 letters or more of visual acuity (considered a moderate loss) but also a loss of 30 letters or more (six lines on the eye chart, which is considered a severe loss.) In addition, treatment with pegaptanib reduced the risk of progression to legal blindness in the study eye, promoted stability of vision, and in a small percentage of patients, resulted in more visual improvement at week 54 than among those receiving sham injections."

The authors conclude that treatment with pegaptanib provide a statistically significant and clinically meaningful benefit in a broad spectrum of patients with neovascular AMD, regardless of the size or angiographic subtype of the lesion or the baseline visual acuity. The rate of injection-related adverse events represents a potentially modifiable risk but necessitates vigilance, the authors caution.

The Massachusetts Eye and Ear Infirmary (MEEI) in Boston participated in these clinical trials. In addition, researchers and physicians at MEEI -- Drs. Anthony P. Adamis (formerly of MEEI), Evangelos Gragoudas (MEEI) and Joan Miller (MEEI) -- were among the first to study the role of vascular endothelial growth factor (VEGF), which causes abnormal blood vessel growth in eye disease. Their experimental studies showed that levels of VEGF protein were increased in eyes that developed abnormal new blood vessels, and that VEGF-blocking drugs were able to prevent the growth of these abnormal blood vessels. Others, including Harvard's Dr. Lloyd Paul Aiello of the Joslin Diabetes Center, Dr. Patricia D'Amore of the Schepens Eye Research Institute and Dr. Lois Smith of Children's Hospital, corroborated the importance of VEGF in neovascular eye disease. These studies formed the basis for the drug development and clinical trials of anti-VEGF therapies, including pegaptanib, and demonstrate the importance of translational research, in order to transform scientific discoveries into new therapies for patients.

Pegaptanib differs from current treatments, which are directed at the results of the disease. Current treatments, which employ a drug and laser, are able to slow vision loss, but have not been widely applicable to all patients. Pegaptanib is the first treatment designed to target the source of the disease and blocks the pathological form of a chemical called VEGF, which is produced in the eye of patients with wet AMD.

The results of the two studies provide validation of the aptamer-based therapy in the treatment of human disease and support ongoing investigations into the use of VEGF antagonists in patients with diabetic retinopathy and retinal-vein occlusion, which are other disorders associated with elevated levels of intraocular VEGF.