Ruboxistaurin Reduced Vision Loss in
Moderate-to-Severe Nonproliferative DR

The once-daily, oral investigational therapy reduced sustained
moderate vision loss over 3-year period.

Ruboxistaurin mesylate (proposed brand name Arxxant; Eli Lilly and Company; Indianapolis) reduced the risk of sustained moderate vision loss by 40% when compared to placebo in patients with moderate-to-severe nonproliferative diabetic retinopathy (DR).

The 3-year phase 3 clinical trial study findings were published online in Ophthalmology. Vision loss, measured in the study as sustained moderate vision loss, occurred in only 5.5% of patients treated with ruboxistaurin versus 9.1% of patients treated with placebo, equaling a 40% relative risk reduction (P=.034) over 3 years. Vision loss was defined as a three-line loss on a standard eye chart that was sustained for at least 6 months.

This multicenter, 36-month, placebo-controlled, double-masked, phase 3 clinical trial, labeled protein kinase C-diabetic retinopathy study 2 (PKC-DRS2), involved 685 patients randomized at 70 clinical sites to either placebo (n=340) or 32 mg/day of ruboxistaurin (n=340). PKC-DRS2 examined whether ruboxistaurin could reduce the risk of long-term or sustained moderate vision loss caused by nonproliferative DR. Patients had moderate-to-severe nonproliferative diabetic retinopathy at the start of the study (Figure 1). Mean visual acuity was better in the ruboxistaurin- treated patients after 12 months. Baseline-to-endpoint visual improvement of ≥15 letters was more frequent (4.9% vs 2.4%) and ≥15-letter worsening was less frequent (6.7% vs 9.9%) in ruboxistaurin-treated patients compared with placebo (P=.005). The beneficial effect of ruboxistaurin was not accompanied by a reduction in the progression of study patients from nonproliferative to proliferative DR.

Patient discontinuations due to adverse events were not statistically different between treatment groups (n=9, 2.6% placebo; n=16, 4.6% ruboxistaurin), according to a news release. There were 36 patient deaths (n=22, 6.5% placebo; n=14, 4.1% ruboxistaurin), none of which was considered by the investigator or sponsor to be related to study drug. There was no consistent pattern of adverse events to suggest a causal relationship between ruboxistaurin and any spontaneously reported adverse event.

Ruboxistaurin is an investigational therapy for the treatment of moderate-to-severe nonproliferative DR. It works by limiting the overactivation of protein kinase C beta, a naturally occurring enzyme that has been linked to the development of DR. It is the first of a new class of compounds being investigated for the treatment of moderate-to-severe nonproliferative DR.

Lilly submitted a new drug application to the US Food and Drug Administration (FDA) for approval of ruboxistaurin for the treatment of moderate-to-severe nonproliferative DR in February 2006. Lilly received an approvable letter from the FDA in August 2006. The FDA has indicated it will require efficacy data from an additional phase 3 study before it will consider approving the molecule. Lilly has decided to appeal the FDA’s decision and has recently begun discussions with the agency.

Lloyd P. Aiello, MD, PhD is director of the Beetham Eye Institute, Joslin Diabetes Center, Boston. Dr. Aiello is a consultant/advisor for Eli Lilly and he receives lecture fees, travel fees or reimbursement. He can be reached at LloydPaul.Aiello@joslin.harvard.edu.

Aiello LP et al for the PKC-DRS2 Group. Effect of ruboxistaurin on visual loss in patients with diabetic retinopathy: ruboxistaurin treatment of diabetic visual loss. Ophthalmology. Available online before print, at: www.ophsource.org/periodicals/ophtha/article/
PIIS0161642006010335. Accessed on: Dec. 1, 2006.
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