October 31st, 2011
FDA Gives Favorable Review to SHARP Ahead of Vytorin Advisory Panel
In preparation for Wednesday’s meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, an FDA reviewer has generally endorsed the positive interpretation of the SHARP trial of Vytorin (ezetimibe and simvastatin) in chronic kidney disease (CKD).
Based on the results of SHARP (Study of Heart and Renal Protection), Merck is seeking an expansion of its indication for Vytorin to include the reduction of major cardiovascular events in patients with CKD. The proposed label from Merck would include a statement noting that any added benefit for the combination of ezetimibe and simvastatin over simvastatin alone “has not been definitively established.”
Currently there are no drugs specifically available to CKD patients that reduce the high risk of CV events in CKD, although statins sometimes have been used. Previous studies have shown that statins are not beneficial in patients with end-stage renal disease, but the potential benefits in patients at earlier stages in the disease – including two thirds of patients in SHARP – had not been tested until now.
SHARP was the subject of discussion and controversy when it was first presented last November.
The analysis of SHARP by the FDA reviewer found that the combination of ezetimibe and simvastatin reduced the rate of major vascular events by 16% (p=0.001) compared with placebo. This result appeared robust, holding up to a number of different secondary and exploratory analyses.
The beneficial effect was much larger in the subgroup of 6,247 patients who were not on dialysis at the time of randomization (22% risk reduction) than in the subgroup of 3,023 patients on dialysis at randomization (6% risk reduction). The test for heterogeneity did not find a significant difference in treatment effect based on dialysis status, however (p=0.08).
The reviewer raised no red flags about safety. Cancer, which had been a subject of intense concern in the past, was not an issue. The rate of incident cancer was 9.4% with ezetimibe-simvastatin group versus 9.5% with placebo, although there were 18 more cancer deaths in the intervention group than in the placebo group (132 [2.8%] versus 114 [2.5%]).