Effect of Ruboxistaurin on Visual Loss in Patients with Diabetic Retinopathy

PKC-DRS2 Group. Ophthalmology. 2006. Epub ahead of print.

Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults in the developed world and is present in nearly 40% of the diabetic population. Diabetic macular edema (DME), an accumulation of fluid within the retina due to vascular leakage, is a common complication of DR and can also cause visual loss. There is strong evidence suggesting that protein kinase C β (PKC β) plays a central role in the development of ocular complications of diabetes. Activation of PKC β during diabetes increases retinal vascular permeability and neovascularization and mediates changes in retinal blood flow in patients with diabetes. Ruboxistaurin, an orally administered PKC β inhibitor, alleviates the effects of high blood glucose and diabetes on retinal blood flow. In a previous phase 3 clinical trial (PKC-DRS), ruboxistaurin had no effect on the primary study endpoint of retinopathy progression, but demonstrated a beneficial effect on sustained moderate visual loss (SMVL) in patients with moderate to very severe nonproliferative diabetic retinopathy (NPDR). The present study (PKC-DRS2) is a new, 3-year, phase 3 study that reports the effect of orally administered ruboxistaurin (32 mg/day) versus placebo for the primary endpoint of reduced SMVL.

The PKC-DRS2 was a multicenter, double-masked, parallel, placebo-controlled study in which 685 patients were randomized to either ruboxistaurin or placebo treatment groups. Eligibility was based on 2 screening tests, after which visits occurred every 3 months until each patient had completed 36 months of follow-up. Eligible patients had at least 1 eye that met ocular entry criteria: (1) Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy levels of ≥47A and ≤53 E, (2) best-corrected visual acuity (BCVA) of ≥45 letters as measured by the ETDRS visual acuity (VA) protocol, (3) no history of panretinal photocoagulation (PRP) for DR, (4) no evidence of glaucoma, and (5) no history of conditions affecting DR progression. Earlier treatment for macular edema in study eyes was allowed. Exclusion criteria included unstable angina, systolic BP ≥190 mmHg or diastolic BP ≥105 mm HG, corrected QT interval of >500 msec, major surgery within 3 months, or malignancy within 6 months. Slit-lamp biomicroscopy, intraocular pressure measurement, and ophthalmoscopy were performed at screening and each visit. Retinopathy status was tested every 6 months using ETDRS 7-standard field 30° color stereoscopic fundus photography, and the ETDRS retinopathy severity scale was employed to categorize DR. Severity of DME was categorized using the ETDRS DME severity scale, and progression from >100 µm to ≤100 µm of the center of the macula was assessed. The primary objective of the study was to test the hypothesis that ruboxistaurin would reduce the occurrence of SMVL, defined as continuous moderate vision loss from month 30 to month 36, relative to placebo. The major secondary objectives were: (1) DME progression to within 100 µm of the center of the macula, (2) definitive and continuous measurements of VA, (3) application of focal or grid photocoagulation, and (4) progression of DR by 3 steps on the ETDRS eye scale or the use of PRP. Additionally, adverse events were collected at each visit and statistical analyses were performed with an intent-to-treat population.

At baseline, all patients either had type 1 diabetes or type 2 diabetes with an HbA1c ≤13%. The mean age was 59±11 years, and the mean diabetes duration was 16±8 years. Over 50% of eyes had clinically significant macular edema (CSME) and over one-third had center-involved macular edema. Close to 50% of patients received prior photocoagulation, and mean BCVA was 77 in both eyes. Study results demonstrated a 40% risk reduction for incidence of SMVL between the ruboxistaurin and placebo groups (5.5% vs 9.1%; P = .034). The probability for modified SMVL, defined as ≥15-letter loss of VA for any 6-month period, was less in patients treated with ruboxistaurin than placebo, although the difference was not markedly different until after 18 months of treatment. Notably, the incidence of SMVL was reduced regardless of baseline NPDR or DME. Improvement by ≥15 letters in VA from baseline was doubled in the treatment group compared to placebo (4.9% vs 2.4%; P = .027) and the probability of ≥15-letter loss was one-third less (9.9% vs 6.7%; P = .044). Ruboxistaurin treatment also resulted in significant reduction of CSME progression from >100 µm to ≤100 µm of the center of the macula (placebo 68%, ruboxistaurin 50%; P = .003), improved DME severity, and less frequent worsening. Eyes without a history of photocoagulation showed a ruboxistaurin-induced reduction in initial focal/grid photocoagulation from 37.9% to 28%. Logistic regression analysis revealed that ruboxistaurin treatment was correlated with 55% risk reduction of SMVL. Discontinuation due to adverse events was not significantly different between the 2 groups: ruboxistaurin 4.6% (n = 16), placebo 2.6% (n = 9). A total of 36 deaths occurred, none of which were drug-related; the major cause of death was cardiovascular events. The difference in death rates was not significantly different between the treatment groups. No patients on placebo developed diabetic nephropathy, whereas 7 of 345 patients (2.0%) on ruboxistaurin treatment reported this event. However, there was no difference between treatment groups from baseline to the study endpoint change in glomerular filtration rate or in the incidence of other renal- or diabetic-related complications.

The data from this trial demonstrate that over a 3-year period the orally administered drug ruboxistaurin reduces the risk of SMVL by 40%. As in the first trial, ruboxistaurin did not affect the progression of DR. The authors mention several factors that may explain this lack of effect, including too-short follow-up, too-severe DR pathology at baseline, inadequate dose, activation of compensatory mechanisms, or a limited role of PKC β activation in this process. Ruboxistaurin is the first oral drug to show a significant reduction in vision loss due to diabetes over a prolonged period, and represents a novel therapeutic with the potential to reduce the risk of vision loss due to diabetic retinopathy.