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The long-awaited results of the ENHANCE trial have revealed that although Merck & Co/Schering-Plough's combination heart drug Vytorin significantly lowered cholesterol, it had little effect on the build up of fatty plaques in the arteries. Although Vytorin's prospects look bleak on the back of this study, the real indicator will be the results of larger mortality outcome studies
Datamonitor estimates the market for cholesterol lowering drugs to be worth in excess of $30 billion over the seven major markets. Single-pill combinations account for 6% of this market, and the majority of this share is attributed to Merck/Schering-Plough's ezetimibe/simvastatin combination, Vytorin. Vytorin has achieved blockbuster sales, despite a complete lack of outcome data to support its effects on lipid lowering, or overall cardiovascular morbidity and mortality.
The ENHANCE (ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression) trial is the first trial to evaluate Vytorin - ezetimibe and simvastatin in combination - against simvastatin (Zocor), alone, in reversing the atherosclerotic thickening of the carotid artery in patients with high cholesterol. It is not an outcomes trial, per se, but instead uses widely accepted surrogate end points as a measure of atherosclerotic plaque development. The trial endpoints assessed the mean change in arterial plaque thickness, at various points in the carotid artery, as well as the effect on blood cholesterol, and the incidence of major cardiovascular events.
After the two-year study period, Vytorin failed to demonstrate a significant effect on atherosclerotic plaque progression compared to simvastatin (Zocor) alone. However, it did reduce LDL, "bad", cholesterol by 58%, compared to 42% in the Zocor group.
In contrast, statins have been proven to reduce cardiovascular morbidity and mortality, whereas as Zetia (ezetimibe) and Vytorin (ezetimibe plus simvastatin) have not. The high prescription rates for both drugs are driven solely by physicians' belief that achieving LDL goals are of primary importance.
The fact that the reduction of LDL is not mirrored in reduced plaque progression raises some questions about the relevance of LDL measurement in the prediction of cardiac outcomes. This is the primary indicator used to promote the use of statins, although the 58% lowering of LDL seen with Vytorin is not a statistically significant improvement on that seen with high-doses of the most potent statins, Lipitor and Crestor. However, it is possible that ezetimibe counteracts simvastatin's positive effect in halting plaque progression; it is important to note that atherosclerotic plaques have countless other attributes that are relevant to their implication in cardiovascular events - including lipid density, inflammatory cell concentration and endothelial characteristics - and none of these are measured in ENHANCE.
The ENHANCE trial has been in the public eye since last November when publication of trial results was delayed. Next it emerged that the primary end-point had been changed, and Merck and Schering-Plough subsequently attempted to obscure results that demonstrate ezetimibe and simvastatin have hepatic side effects when used in combination. Initially, an FDA pharmacology reviewer recommended against the approval of Vytorin, warning that the earliest tests had showed serious toxicity in laboratory animals, even at very small doses.
The trial was completed in April 2006, but by November 2007 no trial data had been published or presented in their entirety and 18 months after its completion, the trial had not been registered at ClinicalTrials.gov. Additionally, Schering-Plough attempted to switch the primary and secondary endpoints while the trial was in progress, presumably to enable more favorable effects on atherosclerosis progression to be demonstrated.
Eventually, the lack of results aroused such suspicion that the US House of Representatives Energy and Commerce Committee felt compelled to write to the companies and the clinical trial investigators, saying: "We are concerned with the delay in releasing the results of the study, the timing of the ENHANCE trial registration, and the apparent manipulation of the trial data." This prompted Schering-Plough to return to its original endpoints, and the final data are expected to be reported at the 2008 American College of Cardiology (ACC) Scientific Sessions in March.
Despite the bleak future ENHANCE predicts for Vytorin and Zetia, investigation into Merck and Schering-Plough's apparent attempts to withhold data, and divert the course of the trial, are far from over. At face value, the evidence seems to support the fact that the companies are aware that their work is nothing beyond an attempt to "evergreen" Zetia (ezetimibe), and that adding an expensive drug (ezetimibe) to a cheap, established generic (simvastatin) will benefit none other than their profit margins.
Merck and Schering-Plough will be hoping for more positive results from their large (20,000 patient) mortality and morbidity outcome studies. The most important of these is the IMPROVE-IT study, which is the largest trial, and includes the broadest patient population. The results of this should provide physicians with the solid evidence they current lack in making the decision to prescribe Zetia or Vytorin.
One further question remaining is the effect of the results on prescription trends, as the competing statins use the outcomes to disparage Vytorin. In the past, this market has not shown particular sensitivity to either positive or negative trial results. For example, when the results of the METEOR Study were published in March 2007, they demonstrated Crestor's addition benefit in terms of halting atherosclerotic plaque progression but Crestor's market share immediately fell, presumably as a function of other market pressures.
There are two possible physicians reactions; one is piloted by Dr Steve Nissen, director of cardiovascular medicine at the Cleveland Clinic, who called for the use of both ezetimibe (Zetia) and ezetimibe/simvastatin (Vytorin) to be suspended on the basis that, "if it doesn't work in [heterozygous familial hypercholesterolemia], why use it?".
But Dr Robert Harrington, who is leading the IMPROVE-IT trial, does not believe the ENHANCE study should provoke such a strong reaction. "Dr Nissen's suggestion about a moratorium on ezetimibe is rather alarmist, given that this was just an imaging study, and an imaging study should not change clinical practice. So for me, whatever way it went, I would not have been blown away by results from this trial," he told MedPage Today.
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