ENHANCE Results Do Little To Enhance Merck’s Statin Product Outlook

The Merck/Schering-Plough combination cholesterol therapy Vytorin 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 (ezetimibe/simvastatin) 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 piqued the interest of Congress. The House Energy and Commerce Committee in December requested details of the trial from Merck and Schering-Plough.

Following the release of the ENHANCE results, Energy and Commerce said they were concerned the companies failed to release the data while running Vytorin direct-to-consumer ads.

Oversight and Investigations Subcommittee Chairman Bart Stupak, D-Mich., says because the results "were released nearly two years after" the trial ended, "it is easy to conclude that Merck and Schering-Plough intentionally sought to delay the release of this data."

In a release, Stupak says it is "unclear whether these companies knew that adding a new expensive drug accomplished nothing more than an established, cheaper, generic. But it is clear that our investigation is far from over."

Additionally, the Hagens Berman Sobol Shapiro law firm announced Jan. 16 it is investigating Merck/Schering-Plough's marketing practices for Vytorin. Seattle-based HBSS says it is looking into whether the firms violated state consumer protection laws and whether to pursue action to enable patients to get money back from their purchases of Vytorin and Zetia (ezetimibe).

However, Merck and Schering-Plough attribute the delay to the rigorous design and analytical process for the ENHANCE (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) trial.

The companies planned to release the 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, according to Schering-Plough.

The release of the ENHANCE results comes a month after FDA advisory committees, for the third time, in December recommended against approving Merck's application to switch lovastatin 20 mg Mevacor Daily to OTC (Also see "FDA Advisors Say Greater Insight Needed On Self-Selection Of OTC Statins" - Pink Sheet, 17 Dec, 2007.), p. 3).

The committees also voted that Merck's consumer behavior study did not demonstrate consumers can make an appropriate self-selection decision on their own. Some members of the panel suggested Merck should have conducted another actual use study following its unsuccessful 2005 application in addition to modifying the proposed label and performing new label comprehension studies.

The ENHANCE 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 levels of low-density lipoprotein 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) compared with 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.

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 after 24 months in the trial, compared with a 41 percent decrease in the simvastatin group.

Vytorin gained FDA approval for the treatment of primary hypercholesterolemia and for heterozygous familial hypercholesterolemia in 2004 ( (Also see "Interview With Schering-Plough CEO Fred Hassan" - Pink Sheet, 1 Jan, 2005.), p. 18).

- Cathy Kelly ([email protected])