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      Reduction of diabetic macular edema by oral administration of the kinase inhibitor PKC412.

      Investigative ophthalmology & visual science
      Administration, Oral, Adult, Aged, Aged, 80 and over, Diabetic Retinopathy, diagnosis, drug therapy, Double-Blind Method, Female, Fluorescein Angiography, Humans, Macular Edema, Male, Middle Aged, Protein Kinase C, antagonists & inhibitors, Retina, drug effects, pathology, Safety, Staurosporine, administration & dosage, adverse effects, analogs & derivatives, Tomography, Optical Coherence, Visual Acuity

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          To evaluate the efficacy and safety of PKC412, an orally administered kinase inhibitor, in subjects with diabetic macular edema. This was a randomized (1:1:1:1), multicenter, double-masked, parallel-group study in which subjects (n = 141) received placebo or PKC412 (50, 100, or 150 mg/d) for up to 3 months. Subjects were 18 to 85 years of age and had retinal thickening that met predefined criteria and best corrected visual acuity of 55 letters or more. Efficacy was based on changes in retinal thickening measured by grading of fundus photographs and optical coherence tomography (OCT) and changes in visual acuity. Grading of fundus photographs showed a statistically significant decrease in the area of greatest retinal thickening in patients receiving 150 mg/d of PKC412 (P = 0.032). OCT demonstrated that the two higher doses of PKC412 caused a significant decrease in thickening in the region of greatest thickening and in the fovea (P < or = 039), with response in the high-dose group significantly different from that in the placebo group (difference = -66.69 micro m [95.2% CI: -128.57 to -4.81]; P = 0.030). Retinal volume for all locations also showed a significant decrease from baseline in the 100- and 150-mg/d PKC412 groups (P < or = 004), and the 150-mg/kg group showed significantly less retinal volume than the placebo group at 3 months (difference = -0.46 mm(3) [95.2% CI: -0.86-0.06]; P = 0.019). There was a small (4.36 letters), but significant (P = 0.007), improvement in visual acuity at 3 months compared with baseline in the 100-mg/d PKC412 group. Gastrointestinal side effects (diarrhea, nausea, and vomiting) were the most common adverse events attributed to the drug. Dose-related effects were observed for tolerability, glycemic control, and liver toxicity. Orally administered PKC412 at doses of 100 mg/d or higher may significantly reduce macular edema and improve visual acuity in diabetic subjects. However, concern regarding liver toxicity with systemic therapy makes local delivery an appealing approach.

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