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Fort Lauderdale, FL-Treatment with ruboxistaurin mesylate (RBX, Eli Lilly Co.) reduced the risk of sustained moderate vision loss by 41% in patients with moderately severe to very severe nonproliferative diabetic retinopathy compared with placebo, according to a combined analysis of two studies.
RBX therapy also reduced the need for initial laser photocoagulation and increased the chance of visual gain in these patients, said Lloyd Paul Aiello, MD, PhD, at the annual meeting of the Association for Research in Vision and Ophthalmology.
RBX is a specific protein kinase C-beta (PKC-beta) inhibitor being investigated for the treatment of diabetic neuropathy, nephropathy, and retinopathy. It is currently under review by the FDA for preventing visual loss. RBX blocks increased activation of PKC-beta, which causes microvascular complications of diabetes such as eye and nerve disease.
Both studies enrolled patients with moderately severe to very severe nonproliferative diabetic retinopathy. Patients had similar demographic characteristics and underwent treatment for at least 36 months.
The PKC-Diabetic Retinopathy Study (PKC-DRS) enrolled 252 patients who were randomly assigned to placebo (n = 61) or 8 mg/day (n = 60), 16 mg/day (n = 64), or 32 mg/day (n = 67) RBX given orally. The primary endpoint was diabetic retinopathy progression on the ETDRS retinopathy severity scale or application of panretinal photocoagulation. Progression by three steps was required for patients with two study eyes, and progression by two steps was required for patients with only one study eye.
This study, conducted between 1998 and 2002, demonstrated that 32 mg/day of RBX was well tolerated and might reduce the risk of moderate vision loss. However, there was no statistically significant impact on retinopathy progression or application of laser photocoagulation at any dose level.
The second study, the PKC-DRS2, was conducted from 2001 to 2005 to determine whether once-a-day dosing with RBX would reduce the amount of vision loss. The study enrolled 685 patients; 340 were randomly assigned to placebo and 345 to 32 mg/day RBX. The primary endpoint was sustained moderate visual loss (SMVL), defined as a ≥15-letter loss in ETDRS best-corrected visual acuity in a study eye, sustained between months 30 and 36 or for the last 6 months of study participation for those who discontinued early.
Although the first study was not designed to evaluate visual acuity, that information had been collected, so investigators were able to combine data from the two studies.
"The take-home message was very much the same," Dr. Aiello said. "Patients who were taking ruboxistaurin had about a 41% reduction in the risk of having SMVL at the end of the study as compared with those patients who were taking placebo. That result was statistically significant (p = 0.016)."
Analysis of the sustained loss over 3 years in the PKC-DRS2 showed that treatment with 32 mg/day RBX led to a 40% risk reduction; the reduction was 45% in the PKC-DRS at that dose level.
Statistically significant differences in visual acuity loss between the treatment and placebo group were evident at all levels. Integrated data from 401 patients in the placebo group and 412 in the group receiving 32 mg/day RBX demonstrated that sustained losses in visual activity of ≤5 ETDRS letters occurred in 29.4% of the placebo group and 20.9% of patients receiving RBX (p = 0.002); a loss of ≥10 letters occurred in 15.7% of the placebo group and 10.9% of the RBX group (p = 0.020); and a loss of ≥15 letters occurred in 10.2% of the placebo group and 6.1% of patients receiving RBX.