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 (Study of Heart and Renal Protection) trial of Vytorin (ezetimibe and simvastatin) in chronic kidney disease (CKD).

Based on the results of SHARP Merck is seeking an expansion of its indication for Vytorin to include the reduction of major cardiovascular events in patients with chronic kidney disease. The proposed label from Merck would include a statement noting that any added benefit for the combination of ezetimibe and simvastatin over simvastatin by itself “has not been determined.”

Currently there are no drugs specifically available to CKD patients that reduce the high risk of CV events in CKD, though 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– such as 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 and when it was published subsequently in the Lancet.

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 who were receiving dialysis at the time of 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 reviewers 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% in the ezetimibe/simvastatin group versus 9.5% in the placebo group, although there were 18 more cancer deaths in the combination group  than in the placebo group (132 [2.8%] versus 114 [2.5%]).

One additional note: the FDA usually posts meeting materials 48 hours prior to the scheduled start of the meeting. Documents for the SHARP meeting are expected to appear on Monday morning, October 31.  In this case, however, the URL for the PDF of the FDA review became available sometime over the weekend, prompting an article on Bloomberg news. At the time of this writing (Sunday afternoon) other documents associated with the meeting have not yet been posted, and there is no posted link to the FDA review, although the URL was still working.

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