PKC-? inhibitor may reduce risk of vision loss in DME

Indianapolis-The investigational compound ruboxistaurin (Eli Lilly and Co.) may reduce the risk of vision loss associated with diabetic macular edema (DME), according to post hoc analysis of previously reported data. The new analysis also showed that the proximity of DME to the center of the macula was associated with visual acuity and that the severity of central macular involvement was associated with the severity of vision loss, according to Matthew J. Sheetz, MD, PhD, a clinical research physician at Eli Lilly.

"In patients with retinal thickening greater than 500 µm from the center of the macula, there was a trend toward lower eventual center involvement in patients receiving ruboxistaurin. In eyes with retinal thickening at the center of the macula, ruboxistaurin treatment was associated with a higher average visual acuity," Dr. Sheetz said.

Dr. Sheetz presented the analysis of data from two phase III, placebo-controlled studies of ruboxistaurin in patients with diabetic retinopathy and varying degrees of severity of DME. The studies were completed in 2002, and primary data previously had been presented at the 2003 International Diabetes Federation meeting and at the 2003 AAO retina subspecialty day meeting.

"The PKC-DRS showed that there was no effect of ruboxistaurin on the progression of retinopathy to proliferative retinopathy," Dr. Sheetz said. "However, we did find that there was an effect of ruboxistaurin on sustained moderate vision loss, defined as 15 letters or more of vision loss (3 lines) that occurs for at least 6 months."

The new analysis of PKC-DRS data, treating each visit with both visual acuity and retinal thickening observations as a separate data point, showed that eyes of patients who received 32 mg/day of ruboxistaurin had better average visual acuity than eyes of patients in the placebo group when the center of the macula was involved (71 versus 60 letters correct, p < 0.0001).

Dr. Sheetz also presented new information from the Protein Kinase C Beta Inhibitor-Diabetic Macular Edema Study (PKC-DMES), which enrolled a total of 686 patients equally into each of four dose arms for a treatment period between 30 and 48 months.

The primary endpoint in the PKC-DMES was progression of macular edema from outside of 300 µm to within 100 µm of the center of the macula, or the application of photocoagulation.

"Again, ruboxistaurin did not show a statistically significant effect on this primary endpoint," Dr. Sheetz said.

However, when patients with baseline hemoglobin A1c levels from the top quartile were excluded (HbA1c> 10%), researchers observed an effect of ruboxistaurin on reducing the progression of macular edema to within 100 µm of the center of the macula.

In the follow-up analysis of the PKC-DMES trial, eyes were categorized by baseline levels of macular edema. About two-thirds of the eyes had macular edema >500 µm from the center at baseline, while the other third had macular edema between 500 and 300 µm from the center of the macula.

Eyes of patients taking 32 mg/day of ruboxistaurin whose baseline macular edema was within 500 µm of the center did not experience less progression of DME to the center of the macula, while there was a trend toward less progression ( p =0.083) in eyes with DME >500 µm from the center at baseline, Dr. Sheetz said.

In the group with DME > 500 µm from the center of the macula at baseline, progression of DME to the center of the macula occurred in 20% of the eyes of patients taking ruboxistaurin (n=119) versus 31% of the patients treated with placebo (n = 137). The difference was apparent only at the 32-mg/day dose of ruboxistaurin, the highest dose given in the trial.

Phase III clinical trials are underway to investigate the findings from the earlier studies and subsequent analysis further.

A PKC-β inhibitor might be expected to have a benefit on DME and its associated visual loss because PKC activation by diabetes can increase the permeability of retinal vessels and contribute to DME, Dr. Sheetz said.