In what may be an anticlimatic end to a controversy that has hovered over the Vytorin cholesterol pill, an FDA medical reviewer is endorsing the largely positive findings of a study that indicates the drug could be used safetly to treat patients with chronic kidney disease. An FDA advisory committee is scheduled to meet this Wednesday to review the data.
The clinical trial, known as Sharp, found that Vytorin - which combines Zetia and simvastatin, otherwise known as Zocor - reduced the risk of “major vascular events” among adult subjects with CKD, or chronic kidney disease, who did not have a history of myocardial infarction or coronary revascularization by 16 percent compared with a placebo. Merck sells all three meds.
The drugmaker claims by “lowering low density lipoprotein-cholesterol (LDL-C) level, Vytorin is effective in reducing cardiovascular risk in CKD patients. My review of the statistical evidence suggests support for the claim,” writes James Smith, of the Division of Metabolism and Endocrinology Products in the FDA Center for Drug Evaluation and Research, in briefing documents posted on the FDA web site. “However, the treatment effect appears to be heterogeneous among patients with different renal function status…Whether it could be claimed that Vytorin is effective in reducing cardiovascular risk in all patients with CKD is a question up for discussion at the advisory committee meeting.”
There were also no safety issues, particularly regarding cancer, which had been an issue surrounding Vytorin a couple of years ago, when an earlier study suggested a link. Two years ago, the FDA stated an interim finding did not indicate a link existed (read this) and the latest agency review found the incidence rate was 9.4 percent compared with 9.5 percent among those on a placebo (see Table 52 on page 99 of the briefing document). However, there were 18 more deaths resulting from the incidence of cancer in those randomized to Vytorin compared with placebo (see page 100).
Not surprisingly, the FDA review was interpreted as a plus by one Wall Street analyst. In an investor note this morning, Leerink Swann analyst Seamus Fernandez noted that the key question the agency panel will review is the extent to which Vytorin at 10 to 20 mg is effective in patients before dialysis -where the pill showed a 22 percent drop in major vascular and atherosclerotic events - compared with dialysis patients - where Vytorin showed a 6 percent drop in MVE and 10 percent drop in MAE.
“We believe these data should help lay to rest investor concerns about Vytorin/Zetia’s safety,” he wrote. “We also believe the efficacy data from SHARP strongly suggest that reducing LDL with Vytorin/Zetia is consistent with the efficacy demonstrated with statins over time.” The next key test for Vytorin will be the results of yet another trial called Improve-It that compared the pill with simvastatin. He expects interim results early next year.
The findings, by the way, were published last June (read here), but the FDA endorsement potentially removes a cloud over Merck, which has struggled to overcome the lingering effects of a scandal that have plagued Vytorin research, as well as the competitive threat of generic statins. So far this year, Vytorin sales are down 3 percent compared with a year ago, according to recently released Merck sales data (look here).
Last year, University of Oxford researchers, who were running the Sharp trial, attempted to change the composite endpoint, which would make it easier to show positive results. Merck, however, resisted and both later issued press releases about the favorable results. However, the Oxford researchers caused a flap by trumpeting findings that were skewed - they never mentioned the primary endpoint and compared Vytorin favorably with simvastatin alone, when the trial compared the drug only to a placebo. The ruckus was yet another stain on Vytorin (see this).
You may recall that Merck was at the center of a huge scandal involving a trial called Enhance, which found the costly combination of Zocor and Zetia - which was sold by Schering-Plough, now part of Merck - failed to show a benefit over the much cheaper Zocor in reducing plaque in the carotid artery, and even showed a statistically insignificant buildup, although it did a better job of lowering LDL in patients with an inherited form of high cholesterol. However, the drugmakers delayed releasing the study for nearly two years; never appointed an independent board, and briefly changed the primary endpoint without consulting the key investigator (read here).