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Phase III clinical trial demonstrated that ruboxistaurin (RBX) may reduce the
risk of moderate vision loss especially in cases with diabetic macular edema.
BOSTON ? July 14, 2005 ? A multicenter
international study chaired by a Joslin Diabetes Center
investigator and reported in the July issue of the American
Diabetes Association?s journal Diabetes brings hopeful news
to the 18 million people in the United States ? and millions
more worldwide ? with type 1 or type 2 diabetes. Initial
results of the Phase III clinical trial demonstrated that 32
milligrams per day of ruboxistaurin (RBX) was well tolerated
and may reduce the risk of moderate vision loss, especially
in patients with diabetic macular edema.
Loss of vision is a common complication of diabetes and results
from two primary conditions: diabetic retinopathy and diabetic
macular edema. In diabetic retinopathy, tiny blood vessels in the
retina become damaged. While early in the disease (the
nonproliferative stage) there are often no symptoms, over time new,
abnormal blood vessels proliferate and bleed easily. If 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 severe vision loss, but because the laser destroys areas of
the retina, side effects of treatment may include reduction in
peripheral vision or night vision.
The purpose of the PKC-Diabetic Retinopathy Study (DRS) was to
evaluate the safety and effect of an oral treatment, RBX, on
retinopathy progression or visual loss in patients with moderately
severe to very severe nonproliferative diabetic retinopathy. In the
double-masked, randomized multiple-dose study, 252 patients with
type 1 or type 2 diabetes received either RBX or a placebo over a
period of 3-4 years. The study measured the effect of three orally
administered doses of RBX (8, 16, or 32 mg/day) on progression of
diabetic retinopathy, moderate visual loss and sustained moderate
visual loss. The study was conducted at Joslin Diabetes Center,
medical centers across the United States as well as in Canada,
Denmark, the Netherlands and United Kingdom.
The oral treatment RBX inhibits, or blocks, the activity of an
enzyme called protein kinase C. PKC is essential to the normal
production of energy in the body, but a 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, according to the researchers.
?Our results demonstrate that although RBX did not prevent
progression to proliferative diabetic retinopathy, it may reduce the
risk of moderate vision loss caused by macular edema,? said study
chairman Lloyd Paul Aiello, M.D., Ph.D., Head of Joslin?s Section on
Eye Research, Director of Joslin?s Beetham Eye Institute and
Associate Professor of Ophthalmology at Harvard Medical School. ?If
these findings hold true in a currently ongoing larger clinical
trial, then RBX may eventually offer a new treatment option for
patients with diabetes, especially in light of the lack of serious
side effects reported to date.? Other members of the writing
committee and study executive committee included Matthew D. Davis,
M.D., of Madison, WI; Roy C. Milton, M.D., of Rockville, MD; and
Matthew J. Sheetz, M.D., Ph.D., Vipin Arora, and Louis Vignati,
M.D., of Indianapolis, IN.
?Joslin has a long history of PKC research which has made
significant contributions toward the work which ultimately made
evaluation of this inhibitor possible,? said Dr. Aiello. 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-DRS study was funded by Eli Lilly and conducted by the
PKC-DRS Study Group.
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