The Merck/Schering-Plough combination cholesterol therapy Vytorin (ezetimibe/simvastatin) has failed to demonstrate significant benefit over simvastatin alone in preventing formation of arterial plaque in the ENHANCE trial.

Release of the results Jan. 14 follows months of speculation that the trial would fail to show an edge for the combination therapy over simvastatin. The speculation was fueled by repeated delays in reporting the data.

The holdup in the public release of the study, completed in April 2006, also piqued the interest of Congress. In December, a letter to the chief executives of Merck and Schering-Plough from the House Energy & Commerce Committee requested details of the trial and implied that the delay may be linked to data manipulation (¹ Also see "Lack Of Data Released From Merck/Schering-Plough Vytorin Trial Spurs House Inquiry" - Pink Sheet, 12 December, 2007.).

Merck and Schering-Plough, however, attributed the delay to the rigorous trial design and analytical process (² Also see "Vytorin Outcomes Comparison To Zocor Anticipated In 2008, Merck/Schering-Plough Say" - Pink Sheet, 20 November, 2007.).

The companies had planned to release results at the American College of Cardiology meeting in late March but decided to disclose the findings earlier in the interest of transparency and in response to intense interest in the trial, Schering-Plough told "The Pink Sheet" DAILY. However, the firms still expect a discussion of the results at ACC.

The ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial enrolled 720 patients with heterozygous familial hypercholesterolemia, a rare condition that affects approximately 0.2 percent of the population and leads to extremely high LDL cholesterol.

Investigators determined the primary endpoint, mean change in the intima-media thickness, through ultrasound measurements of the carotid arteries. ENHANCE evaluated the highest dose of Vytorin (10 mg ezetimibe plus 80 mg simvastatin) versus 80 mg simvastatin.

The study found "no statistically significant differences between treatment groups" in either the primary endpoint or in key secondary imaging endpoints. Overall incidence of treatment-related adverse events was generally similar between the two groups.

The announcement could impact sales of Vytorin, which has continued to gain market share despite the availability of generic simvastatin. Vytorin share stands at 12.2 percent of the U.S. statin market, Credit Suisse analyst Catherine J. Arnold said in a Jan. 14 research note.

Arnold projected that ex-U.S. sales of Vytorin should more than double in 2007 over 2006 levels. While acknowledging the controversy the ENHANCE study has stirred up, she noted, "Plaque studies have had no impact on the category if you consider prescription trends for Lipitor and Crestor post positive plaque studies."

During recent presentations to the investment community executives at Merck and Schering-Plough downplayed the relevance of ENHANCE to the value of Vytorin.

ENHANCE is a surrogate endpoint trial and should not be considered an outcomes study, according to the firms. Results of the ongoing 10,000-patient IMPROVE-IT trial, evaluating Vytorin in acute coronary syndromes, are expected to be more definitive in determining outcomes, they claim.

The firms also emphasized what they consider Vytorin's key attribute: superiority over simvastatin in reducing LDL cholesterol. Vytorin reduced LDL levels by 58 percent in the ENHANCE trial, compared with a 41 percent decrease in the simvastatin group after 24 months.

Vytorin gained FDA approval for the treatment of primary hypercholesterolemia and for heterozygous familial hypercholesterolemia in 2004.

- Cathy Kelly (c.kelly@elsevier.com)

Vytorin Fails To Show ENHANCEd Benefit Over Simvastatin In Plaque Reduction

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