2 Sources of Trouble for Vytorin

You know that a drug study has gone very, very bad when you can't find out its results without a congressional inquiry.

Last month the House Committee on Energy and Commerce demanded information about the Enhance clinical trial. Some data was released on Jan. 14, and it's been a popular topic on television news since then.

Merck (NYSE: MRK  ) and Schering-Plough (NYSE: SGP  ) jointly market and share the profits of Zetia and Vytorin. Zetia blocks the uptake of food-borne cholesterol from the digestive tract and thus lowers LDL (the lousy or lethal) cholesterol. Vytorin is a combination of Zetia and Zocor. Zocor is now available as a generic, simvastatin.

Simvastatin is a well-studied medication, and like other statins, such as Pfizer's (NYSE: PFE) Lipitor and AstraZeneca's (NYSE: AZN) Crestor, works on receptors in the liver to lower cholesterol levels.

Because Vytorin lowers cholesterol levels more effectively than other cholesterol drugs, and because heart patients with lower cholesterol levels tend to do better in clinical trials, many cardiologists felt that Vytorin was an excellent medication to prescribe to patients with heart disease.

It is certainly well marketed. Surely you've heard the commercial: "There are two sources of cholesterol: food and family. Vytorin treats both." Sales of Zetia, approved in 2002, and Vytorin, approved in 2004, are around $5 billion annually, making it one of the world's best-selling drugs.

Although multiple studies prove that Zocor not only lowered cholesterol levels but also lowered the risk of heart attacks, there are no similar studies for Zetia or Vytorin that demonstrate clinical benefits. If adding Zetia to Zocor (to make Vytorin) does not improve patients' clinical outcomes more than just Zocor, then why take the more expensive medication?

The Enhance study was designed to show a benefit among patients taking Vytorin, primarily by documenting less buildup of plaque in the carotid arteries, a surrogate for the progression of coronary artery disease.

In the trial, 720 patients with a genetic abnormality that caused extremely high levels of LDL cholesterol were randomized into two groups. One received Vytorin (Zocor plus Zetia), and the other group received Zocor. The Vytorin group had a statistically lower level of LDL cholesterol, as expected; the incidence of serious side effects was low and similar in both groups. So far, so good.

While not statistically significant, there was evidence of more thickening of carotid arteries in patients in the Vytorin group than in the Zocor group. The Vytorin group also had a minuscule, statistically non-significant, higher number of deaths, heart attacks, and angioplasty or bypass surgeries. Although the number of patients studied is small, and the type of patients studied is different from those usually prescribed the medication, the outcome trends went in the wrong direction.

The American College of Cardiology released a statement recommending that major clinical decisions not be made on the Enhance study results alone. Leading cardiologists had differing opinions.

Dr. Robert Califf, noted Duke University cardiologist, stated that he plans to continue to take Zetia. "I don't see any signal of toxicity from this trial, so that is reassuring. There's no indication that it's working, either, but that was also the case before Enhance came out. For me, the fact it lowers LDL and does not appear to have side effects is enough until definitive outcome data become available."

Dr. Steven Nissen, Cleveland Clinic cardiologist -- of anti-GlaxoSmithKline's (NYSE: GSK  ) Avandia fame -- expressed a different sentiment: "The main problem is that after six years on the market, there are no data for ezetimibe demonstrating any health outcome benefit. Statins do much more than lower LDL. They increase HDL, lower triglycerides, and reduce inflammation. In the absence of any demonstrable effect beyond LDL lowering, nearly 1 million prescriptions per week are written for ezetimibe. Is this rational?"

Adding salt to the wound, the biggest headache might come from Congress as it begins to investigate why it took so long for the Enhance results to be made public. Congress is also investigating those ubiquitous Vytorin ads.

In an election year, hearings about who knew what details of the study, and when, can only be bad news for prescription sales.

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