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Aug 18, 2008
 |  BioCentury  |  Product Development

Surrogate uncertainty

Partners Merck & Co. Inc. and Schering-Plough Corp. took a beating in January after releasing data from the ENHANCE trial showing that their cholesterol drug Vytorin ezetimibe/simvastatin missed the primary endpoint of reduced progression in carotid intima-media thickness vs. simvastatin alone. Since then, two more trials have raised doubts about the trial designs and endpoints without doing anything to allay concerns about Vytorin’s efficacy.

In one of the trials, similar results from Pfizer Inc.’s Lipitor atorvastatin suggested that intima-media thickness (IMT) may not be a good endpoint.

In March, Pfizer posted data on ClinicalStudyResults.org in which 80 mg of Lipitor missed the primary endpoint of slowed progression of carotid IMT from baseline to 12 months vs. placebo in the CASHMERE trial in 399 post-menopausal women with moderate hypercholesterolemia.

Those results conflicted with the product’s already documented positive cardiovascular outcomes data.

Indeed, using clinical endpoints, Lipitor has been shown to reduce the rate of coronary events, as well as the risk of revascularization procedures. Its label includes data from the ASCOT study in 10,305 patients showing 10 mg Lipitor produced a 36% reduction in the incidence of non-fatal myocardial infarction (MI) and fatal coronary heart disease (CHD).

In July, Merck and Schering-Plough released new Vytorin data that also appear to clash with the ENHANCE IMT data. Preliminary results from the SEAS trial showed Vytorin missed the composite primary endpoint of reducing major cardiovascular events (MCEs) in patients with aortic stenosis, but met the secondary endpoint of reduced atherosclerotic disease events.

The secondary endpoint included non-fatal MI, coronary artery bypass surgery or percutaneous coronary intervention, hospitalization because of unstable angina, non-hemorrhagic stroke and cardiovascular death.

Nevertheless, because the placebo-controlled SEAS trial did not include an active control like ENHANCE, cardiologists remain uncertain about whether Vytorin provides any better efficacy than statins alone. It also raised new safety questions for Vytorin, because of a higher rate of cancer in patients who received the drug than in those given placebo.

While subsequent analysis showed the increase in cancer is unlikely to be attributable to the drug, cardiologists must wait for outcomes data comparing the efficacy of Vytorin to statins alone. The first such data are expected in 2011.

While clinicians will remain focused on the efficacy and safety of Vytorin, the apparently contradictory outcomes to the ASCOT, CASHMERE, ENHANCE and SEAS studies raise questions about the use of carotid IMT as a surrogate endpoint for cardiovascular outcomes.

Thus, Pfizer’s Global medical team leader, Halit Bander, said she is not too...

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