Ruboxistaurin tested in nonproliferative diabetic retinopathy

Boston-Ruboxistaurin mesylate (Arxxant, Eli Lilly), an investigational drug that is an oral protein kinase C (PKC) beta inhibitor, reduced the occurrence of sustained moderate vision loss by 40% in patients with moderately severe to very severe nonproliferative diabetic retinopathy, reported Lloyd P. Aiello, MD, PhD.

Ruboxistaurin is the first of a new class of drugs being evaluated for diabetic retinopathy and diabetic nephropathy. Dr. Aiello reported retinopathy results on behalf of the PKC-DRS2 Study Group. He is associate director, Beetham Eye Institute, Joslin Diabetes Center, and associate professor of ophthalmology, Harvard Medical School, Boston.

"We are well aware that the hyperglycemia of diabetes frequently leads to cellular dysfunction and damage. Although this occurs through a variety of diverse mechanisms, activation of PKC is involved in many of these pathways. Thus, inhibiting PKC may ameliorate diabetes-induced microvascular complications," Dr. Aiello said in explaining the rationale for use of a PKC inhibitor.

Two randomized, multicenter, double-masked, placebo-controlled, multi-dose studies of PKC beta inhibitor in diabetic retinopathy have been undertaken thus far: the PKC Diabetic Retinopathy Study (PKC-DRS) and the Diabetic Macular Edema Study (PKC-DMES). The PKC-DRS trial evaluated progression of retinopathy as the primary endpoint, which was not met, Dr. Aiello said. A secondary analysis of data suggested that there was a reduction of visual loss and of progression of diabetic macular edema.

In the original PKC-DRS, ruboxistaurin reduced sustained moderate visual loss by more than 40% compared with placebo. The study enrolled only about 60 patients per group and the result did not reach significance.

Regarding the effect of the PKC inhibitor ruboxistaurin in diabetic retinopathy, Dr. Aiello presented the results of a new phase III study, the PKC beta inhibitor DRS2, the primary endpoint of which was sustained moderate visual loss. Visual loss was defined as a 15-letter or more decrease of best-corrected visual acuity (BCVA) that was present for at least the last 6 months of participation in the 3-year study, Dr. Aiello explained, and pointed out that this endpoint is more stringent than the endpoint of moderate visual loss alone.

The PKC-DRS2 was also a randomized, multicenter, double-masked, placebo-controlled, multi-dose, phase III trial. Patients, all of whom were adults with either type 1 or type 2 diabetes, received either placebo or 32 mg of ruboxistaurin administered as a pill once daily. Patients were followed for at least 36 months.

Every 3 months, the patients underwent safety laboratory analysis and ophthalmic examinations, and every 6 months lens grading was performed and stereofundus photographs were taken. Sustained moderate visual loss was the primary endpoint; the secondary endpoints were subgroup analysis of visual loss, progression of diabetic macular edema to within 100 μm of the center of the macula, and progression of diabetic retinopathy.

At least one eye of each patient had a best-corrected visual acuity (BCVA) of 20/125 or worse and diabetic retinopathy that was classified as moderately severe to very severe nonproliferative retinopathy. To participate in the study, patients could not have undergone previous panretinal photocoagulation.

Seventy clinical sites participated and 685 patients were randomly assigned to either active treatment or placebo. A total of 258 patients (599 eyes) and 256 patients (584 eyes), respectively, completed the study in the ruboxistaurin and placebo groups. The mean patient age was 59 years; 12% of the patients had type 1 diabetes; and the mean duration of diabetes was 16 years.

Reduced vision loss

"Treatment with ruboxistaurin reduced sustained moderate vision loss after 3 years by 40%," he reported. "Patients treated with ruboxistaurin had less sustained vision loss at each visit throughout the study, especially after 18 months of therapy when the treatment and placebo curves began to diverge more strongly. Regarding the secondary outcomes, there was a consistent decline in visual acuity in the placebo group, a decline that was not observed in the patients treated with ruboxistaurin.