Beyond the anti-VEGF inhibitors: New approaches to wet and dry AMD

June 28, 2008

New investigative drugs for age-related macular degeneration (AMD) may complement the vascular endothelial growth factor (VEGF) agents, improve the visual results, and require fewer injections. Various routes of administration are under investigation and combination treatments are likely to provide more favorable results, said Lawrence Singerman, MD, Case University School of Medicine, Cleveland, OH.

New investigative drugs for age-related macular degeneration (AMD) may complement the vascular endothelial growth factor (VEGF) agents, improve the visual results, and require fewer injections. Various routes of administration are under investigation and combination treatments are likely to provide more favorable results, said Lawrence Singerman, MD, Case University School of Medicine, Cleveland, OH.

Two drugs, bevasiranib (Opko) and E10030 (Ophthotech), are under investigation for wet AMD. Both are administered intravitreally. Bevasiranib prevents the production of VEGF by silencing mRNA. A phase II study showed the drug has an excellent safety profile, it inhibits growth of choroidal neovascularization (CNV), and there is the potential for longer duration of effect and fewer injections. A phase III study is evaluating bevasiranib and ranibizumab. E10030 is an anti-platelet-derived growth factor drug that may induce regression of CNV, he explained.

Combretastatin (Oxigene) destroys CNV by acting on the endothelial cells. The drug is being evaluated in a topical formulation; a primate study indicated that topical application results in therapeutic concentrations in the choroids and retina.

Rapamycin (MacuSight) is being administered subconjunctivally for AMD and diabetic macular edema in a phase II study.

"The drug has the advantages of being an anti-inflammatory, antiproliferative, antiangiogenic, and anti-VEGF [agent]. This drug may be very helpful in attacking CNV," Dr. Singerman said.

While anecortave acetate (Retaane, Alcon Laboratories) was not approved for use in patients with wet AMD, he is hopeful that it may have a place in preventing intermediate or advanced drusen from progressing to AMD.

"If the drug works in 20%, it will have a profound impact on the rate of blindness caused by AMD," he said.

Two drugs are under investigation for dry AMD: fenretinide (Sirion) and OT-551 (Othera). The former, given orally, may reduce accumulation of lipofuscin and slow progression of atrophy. A total of 245 patients are enrolled in a phase II study. The latter drug is a small-molecule antioxidant drop that may reduce the area of geographic atrophy. A phase II study is under way.

"An eye drop that reduces the complications by 10% or 20% as a supplement to other treatments would have a massive impact on AMD," Dr. Singerman said. "It suppresses photooxidative damage in RPE cells and photoreceptors."