RBX AND PROGRESSION OF DIABETIC RETINOPATHY

Fig. 4. Effect of RBX on time to progression of DR or to application of PRP. (From Fig. 2 in (29). Reproduced with permission from The American Diabetes Association).

that RBX treatment had no demonstrable effect on DR progression to PDR or the application of scatter photocoagulation (31).

ONGOING TRIALS WITH RBX

There are currently three ongoing clinical trials assessing RBX as a treatment for diabetic ocular complications (33). One of these studies, entitled “The Effect of Ruboxistaurin on Clinically Significant Macular Edema”, is actively enrolling patients. This trial tests the hypothesis that treatment with RBX will reduce the baseline-to-endpoint change in retinal thickness as measured by OCT in patients with noncenter-involving CSME over the course of 18 months (34). Two other studies have finished patient recruitment and are in follow-up phase. Patients in the “Reduction in the Occurrence of Center-Threatening Diabetic Macular Edema Study” receive either placebo or 32 mg per day RBX for three years. The primary endpoint for this study is the development of center-threatening DME (i.e., DME that extends to within 100 m of the macular center) (35). The third ongoing trial is an extension of the previous PKC-DRS2 study, in which patients who completed participation and who might benefit from further treatment with RBX are receiving open-label RBX (32 mg per day) for up to two additional years (36). The primary study objective is to evaluate the effect of RBX on the occurrence of SMVL. Secondary objectives are to evaluate the long-term effect of RBX treatment on SMVL using Visit 1 of the PKC-DRS2 as baseline, and to examine effect of withdrawing RBX on vision loss during the time period that elapsed between the end of the PKC-DRS2 and the beginning of this study (approximately 18 months).

RBX AND OTHER, NONOCULAR COMPLICATIONS OF DIABETES

The role of RBX in preventing and/or treating diabetic microvascular complications other than DR has also been investigated. Several studies have evaluated the effect of PKC-β inhibition on nephropathy and neuropathy, but definitive conclusions regarding the role of PKC-β in these conditions are still pending.

Preclinical nephropathy studies in animal models of Type 1 and Type 2 diabetes have demonstrated efficacy of RBX in decreasing urinary albumin, normalizing the glomerular filtration rate (GFR), and preventing tubulointerstitial pathology, glomerulosclerosis, transforming growth factor-β overexpression, mesangial expansion, and osteopontin expression (22, 37, 38, 39). Human clinical trials have also shown trends consistent with amelioration of diabetic nephropathy by PKC-β inhibition. A randomized, double-masked, placebocontrolled clinical trial enrolled 123 subjects with Type 2 diabetes and baseline albuminuria (40). After one year of treatment of 32mg per day RBX, urinary albumin/creatinine ratio (ACR) was reduced in the RBX-treated group compared with the placebo group (fall in ACR of 24 vs. 9%, respectively). The estimated GFR did not decline as significantly in the RBX group compared with the placebo group (−2.5 ± 1.9mL min−1 per 1.73m2 vs. −4.8 ± 1.8mL min−1 per 1.73m2). However, this pilot trial was not powered sufficiently to demonstrate a significant difference between the two treatment arms.

Another Phase 2 trial examined the effect of RBX on symptomatic diabetic peripheral neuropathy (41). This was a double-masked, placebo-controlled trial that randomized 250 patients to 32 mg per day RBX, 64 mg per day RBX, or placebo for one year. No relationship was seen between RBX treatment and the primary endpoint of vibration detection threshold. However, in the 83 patients who had clinically significant neuropathic symptoms at baseline, a statistically significant reduction was found in the Neuropathy Total Symptom Score-6 (NTSS-6) in the 64 mg per day group as compared to the placebo group (p = 0.025). RBX treatment appeared to be of benefit for the subgroup of patients with less severe symptomatic diabetic peripheral neuropathy by relieving sensory symptoms and improving nerve fiber function (p = 0.006). In a recent study of 20 placebo and 20 RBX (32 mg d−1) treated patients with diabetic peripheral neuropathy, there was RBX benefit in NTSS-6 (p = 0.03) (42). To date, larger phase three trials have not been performed to replicate these findings.

SAFETY PROFILE OF RBX

Recently, safety data were reported from the combined outcome of 11 placebo-controlled, double-masked clinical trials with RBX (43). Overall, RBX appears well-tolerated with a favorable safety profile. Data evaluated 1,396 subjects treated with 32mg per day RBX as compared to data from 1,408 subjects given placebo. The cumulative proportions of patients who experienced one or more serious adverse events were 20.8% in RBX and 23.2% in the placebo group. No mortality event within the overall cohort was directly attributed to RBX. There were 21 deaths in the RBX-treated group and 30 in the placebo group. Common adverse drug reactions were dyspepsia (2.7% placebo, 4.3% RBX) and increased blood creatine phosphokinase (0.3% placebo, 1.0% RBX), although these levels did not exceed the normal range. The drug-discontinuation rate due to adverse events was equivalent between the treatment groups (4% placebo, 3% RBX).

CLINICAL STATUS OF RBX

RBX continues to be investigated in Phase 3 clinical trials. It is not currently commercially available for clinical use. In August, 2006, the US FDA issued an approvable letter regarding RBX, but required submission of further Phase 3 clinical data before proceeding with approval (44). An application by Eli Lilly and Company to the European Agency for the Evaluation of Medicinal Products (EMEA) for marketing authorization for RBX was withdrawn in March, 2007 (45). This withdrawal did not affect the status of ongoing clinical trials for the use of RBX in diabetic complications.

CONCLUSIONS

Clinical trials of PKC inhibition for DR have focused primarily on the oral PKC-β inhibitor, ruboxistaurin. Multiple multicenter, double-masked, randomized, placebocontrolled trials have demonstrated a tendency toward a modest benefit in preventing long-term visual loss, increasing rates of visual gain, reducing progression of DME, and less need for initial macular laser photocoagulation in patients with advanced NPDR. However, RBX clearly does not appear to halt the progression of DR. RBX is well-tolerated with a favorable safety profile. Additional phase clinical 3 trials will be required for regulatory approval of the drug in the United States. Phase 3 clinical studies of RBX are currently ongoing to help clarify its role in the treatment of DME and the prevention of vision loss in patients with diabetes.

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