Intravitreal drugs promising to treat diabetic retinopathy, but dosing still suboptimal

New Orleans-The off-label use of intravitreal drugs may have a promising future for treating patients with diabetic retinopathy, but currently the dosing of these drugs is suboptimal. There is no solid track record for the drugs because controlled clinical trials are lacking and all follow-up periods have been too short to reach any definitive conclusions about safety and efficacy, according to George A. Williams, MD, who spoke at the annual meeting of the American Academy of Ophthalmology.

"The Diabetic Retinopathy Study and the Early Treatment Diabetic Retinopathy Study clearly established laser photocoagulation as the standard of care for most patients with diabetic retinopathy. However, we recognize that there are substantial limitations to laser photocoagulation in that it is best applied in the early stages of the disease, and it is a destructive therapy. The use of intravitreal drugs to treat diabetic retinopathy is driven by the elucidation of the molecular mechanisms of diabetic retinopathy and the variable efficacy of laser treatment in some patients. In addition, multiple mechanisms can be targeted with drug therapy," Dr. Williams commented.

Intravitreal drugs currently are prescribed for patients with diabetic macular edema, diabetic retinopathy, and neovascular glaucoma. However, few randomized controlled studies have been performed.

Steroids

Triamcinolone acetonide resolves edema following injection, but serious side effects include glaucoma and cataract development and sterile and infectious inflammation. Triamcinolone acetonide has been administered at doses of 2 and 25 mg, and a randomized trial, the Diabetic Retinopathy Clinical Research Study, is ongoing. Typically, Dr. Williams pointed out, macular edema resolves after intravitreal injection of the drug.

Because of the serious complications associated with intravitreal injection of triamcinolone, drug delivery systems have been developed. The Posturdex delivery system (Allergan) allows implantation of dexamethasone in a PLGA copolymer with a significant increase in vision at 90 and 180 days after surgery in patients with persistent macular edema, Dr. Williams reported. This implant is not associated with the development of glaucoma, but increases in IOP have occurred. This delivery system is presently being evaluated in clinical trials using an in-office injection device.

The fluocinolone delivery device has been implanted in 180 patients with diabetic macular edema who had undergone laser treatment previously, he said. Three years after surgery, there was a significant improvement in visual acuity compared with laser, but there was also the associated complication of increased IOP, with 30% of patients undergoing filtration surgery. In this study, cataracts developed in all phakic eyes.

"The implant seems to provide improvement over time, but lens clarity and IOP elevations are substantial problems," he said.

VEGF inhibitors

The anti-VEGF drugs, pegaptanib sodium (Macugen, OSI (Eyetech)/Pfizer), bevacizumab (Avastin, Genentech), and ranibizumab (Lucentis, Genentech) are being used in patients with diabetes.

Pegaptanib induces regression of neovascularization, increases visual acuity, and decreases retinal edema 3 weeks after injection every 6 weeks. However, the results are complicated by rebounding neovascularization after discontinuation of treatment. A phase II randomized trial indicated that the drug improved vision and decreased retinal edema at 3 weeks after injections every 6 weeks.

"This study was also the first to report regression of neovascularization with an anti-VEGF agent and return of the neovascularization after the treatment was stopped," Dr. Williams said.

In a number of reports, administration of bevacizumab has resulted in a short-term increase in visual acuity and decreased edema at 3 weeks but not later, and the results were not as good as with laser. The most recent phase II, randomized, controlled pilot study of bevacizumab by the Diabetic Retinopathy Clinical Research Network results showed that compared with laser therapy, 1.25 mg and 2.5 mg of the drug decreased macular edema at 3 weeks after injection but not thereafter. Only 50% of eyes had a response at 3 or 6 weeks after treatment and no difference was seen between the two doses.

"The results suggested that dosing at 6-week intervals may be too long. There was no advantage to combining bevacizumab with laser therapy," he explained.

"The preliminary experience with dosing of intravitreal drugs for diabetic retinopathy is suboptimal but promising. Improved drug delivery systems for steroids and anti-VEGF drugs are needed. Longer follow-up is needed to determine the efficacy and safety of treatment," Dr. Williams concluded.