Compound Found To Reduce Vision Loss in People With Diabetes, Joslin-Chaired Study Shows
Findings published in the December issue of Ophthalmology
BOSTON — December 12, 2006 — The findings of a Joslin Diabetes Center-chaired multi-center clinical trial published in the December issue of the journal Ophthalmology are encouraging news for the 230 million people worldwide who have diabetes and are at risk for diabetic eye disease.
The study found that the experimental compound ruboxistaurin mesylate (RBX) reduced vision loss by 40 percent in patients with moderate to severe non-proliferative diabetic retinopathy.
The compound also was found to lessen the need for laser treatment and slow the progression of macular edema, while improving vision in patients with a particular type of diabetic retinopathy, according to study chairman Lloyd Paul Aiello, M.D., Ph.D., Director of Joslin’s Beetham Eye Institute, Head of Joslin’s Section on Eye Research, and Associate Professor of Ophthalmology at Harvard Medical School. (Data from this study were presented in part earlier this year at the American Diabetes Association and the American Academy of Ophthalmology scientific meetings. Earlier this year, Eli Lilly and Company, which is seeking to bring the compound to market, applied for U.S. Food and Drug Administration (FDA) approval. The FDA reviewed the data on RBX and considers the drug submission approvable; however, they desire at least one additional clinical trial before making the drug commercially available. Eli Lilly is currently in discussions with the FDA regarding what further information is needed.)
Vision loss is a common complication of diabetes, affecting an estimated 4 million Americans age 40 and older. Diabetic retinopathy and diabetic macular edema are the leading causes of vision loss and blindness in working-age adults across industrialized countries. In diabetic retinopathy, tiny blood vessels in the retina become damaged, and while early in the disease (the non-proliferative stage) there are often no symptoms, over time new, abnormal blood vessels proliferate and bleed easily. Left untreated, proliferative diabetic retinopathy can cause severe vision loss. In diabetic macular edema, leaky blood vessels cause swelling in the macula (the part of the retina responsible for sharp central vision). Current laser treatments for diabetic eye diseases may help prevent moderate and severe vision loss, but because the laser destroys areas of the retina, treatment side effects may include reduced peripheral vision or night vision.
The Phase III Protein Kinase C Beta Inhibitor-Diabetic Retinopathy Study 2 (PKC-DRS2) clinical trial reported on in the latest study involved 685 patients with type 1 or type 2 diabetes at 70 clinical sites across the nation. Patients in the three-year study took either a 32-milligram, once-a-day oral dose of RBX or a placebo (an inactive pill that has no treatment value.) The researchers found that sustained moderate vision loss occurred in 9.1 percent of the patients treated with the placebo compared to 5.5 percent of those treated with RBX, resulting in a 40 percent reduction in vision loss. After three years, the percent of individuals with significant visual improvement (three or more lines) was nearly double in the group treated with RBX (4.9 percent) compared to 2.4 percent in the control group. RBX proved beneficial for slowing the progression of moderate macular edema as well, with 26 percent less frequent use of laser treatment to treat the condition in the eyes of patients taking RBX. The researchers report RBX was well tolerated with few side effects.
“These findings continue to support the potential role of oral PKC beta inhibitors as a safe and convenient therapy for reducing visual loss and need for laser surgery in diabetic patients with moderate to severe nonproliferative diabetic retinopathy. Such a new tool in our fight against vision loss from diabetes would be good news for the 21 million Americans who have diabetes and are at risk for these eye complications,” said the study chair Dr. Lloyd Paul Aiello.
The oral treatment RBX inhibits, or blocks, the activity of a specific form of an enzyme called protein kinase C. This specific form of the enzyme, PKC-beta, has been linked to diabetic complications of the eye and other parts of the body. Thus RBX was designed to be selective for the single PKC-beta isoform, a fact that contributes to the inhibitor’s excellent safety profile, the researchers report.
Long History of PKC Research at Joslin
Joslin Diabetes Center has a long history of PKC research that has made significant contributions toward the work that ultimately made evaluation of this inhibitor possible. Indeed, the laboratory of George L. King, M.D., Joslin’s Director of Research and Head of the Section on Vascular Cell Biology, has studied PKC for two decades and was the first to hypothesize that activation of PKC – especially the beta isoform – is the major signaling pathway stimulated by hyperglycemia (high blood glucose associated with diabetes). In diabetic animal models, the lab also showed that abnormal activation of PKC is an important factor in decreasing blood flow to the retina. These seminal discoveries established the link between hyperglycemia, PKC and diabetic eye disease. Having established this link, Dr. King began working with scientists at Eli Lilly to design a chemical inhibitor for the PKC-beta isoform. It was from this collaboration that RBX emerged. Drs. King and Aiello also collaborated on a number of PKC retinal studies that provided further evidence of the link between PKC and blood vessel abnormalities of the eye, conditions that improved following treatment with the PKC-beta inhibitor.
The PKC-DRS2 study was funded by Eli Lilly and conducted by the PKC-DRS Study Group.