Full results of a controversial artery-imaging study are due to be presented March 30 at the annual meeting of the American College of Cardiology (ACC), following an unusual 18-month delay in releasing the negative results of the study by drug makers Schering-Plough (nyse: SGP - news - people ) and Merck (nyse: MRK - news - people ). The resulting controversy drew a congressional investigation and caused prescriptions for both drugs to slump 17%.
Shares of Schering and Merck plunged as investors fretted over the threat to a $5.2 billion cholesterol franchise. Zetia is a unique drug for lowering cholesterol; Vytorin combines it in one pill with the generic drug Zocor.
The problem: The delayed study couldn't prove that Vytorin prevents artery disease that leads to heart attacks and strokes any better than Zocor does, although it costs four times as much. A trial actually measuring whether the Vytorin combo prevents heart attacks better than Zocor won't be out until 2011. In the meantime, the lack of clear data could leave the companies in a long, slow battle to hold on to their sales.
They argue the controversy is "media-driven," and Wall Street analysts have expressed hopes that a scientific discussion of data will convince doctors, quiet doubters and stabilize sales of Zetia and Vytorin. But critics will be on hand, including Harlan Krumholz of Yale University, who will be among the top cardiologists discussing the data at the ACC meeting.
Cardiologists are torn about what to think of the imaging study, called ENHANCE. Prediman K. Shah, at Cedars Sinai Medical Center, says the results are "inconclusive." But he cautions, "It's not an unimportant study. It certainly raises questions, but doesn't answer them."
If it turns out that Zetia doesn't prevent heart attacks in the 2011 study, Merck and Schering are conducting, "we have some explaining to do," Shah says.
William Boden, a top cardiologist at the University of Buffalo, still uses the Zetia in rare cases and expects the big trial due in 2011 may vindicate it. But he warns his patients, "We don't really know if putting you on this additional drug will do anything more than make your numbers look better." He says the companies have "gotten a long-overdue pass on marketing a drug where there was no outcomes data."
Zetia, approved in 2002, works completely differently from drugs like Lipitor, Zocor and Crestor. The other medicines, called statins, work in the liver to lower blood levels of LDL, the "bad cholesterol." They also seem to have other benefits. Zetia works by preventing the absorption of cholesterol in food. Adding it to the other pills gives them an added LDL-lowering wallop with few side effects.
But some prominent doctors have questioned whether they can be sure that Zetia confers the same benefit as statins. Now, the ENHANCE study has given doubters ammunition.
Mounting Evidence
The first real convincing trial came in 1984, a test of the cholesterol-lowering drug Questran. It took seven years to prove a benefit from lowering LDL 12%. Sales of cholesterol drugs remained pretty low. Lopid, a cholesterol drug from Warner-Lambert, generated only $200 million in 1988. Merck introduced the first statin, Mevacor, in mid-1987; it generated $260 million in its first full year on the market.
"People regarded cholesterol as a major risk factor," says Boden. "But we didn't have very good treatments to lower it."
It was giant studies of the statins that finally convinced many doctors that lowering cholesterol saved lives. Mevacor and other statins were developed from genetic insights gleaned from patients with familial hypercholesterolemia. In 1994 and 1995, studies of Merck's Zocor, a Mevacor replacement, and Bristol-Myers Squibb's (nyse: BMY - news - people ) new Pravachol showed a striking 30% reduction in the risk of death for patients with established heart disease.
In 1998, cholesterol drugs were reportedly a $5 billion market. By 2000, that had tripled, according to drug data company IMS Health (nyse: RX - news - people ), and by 2002 they were the best-selling drug class in the world. The top dog was Pfizer's (nyse: PFE - news - people ) Lipitor. It was approved in 1996, getting a fast review because of its unprecedented ability to lower cholesterol in patients with the FH disorder that causes cholesterol levels of 300 or more. Within two years, Pfizer already had presented data showing that Lipitor prevented heart attacks and strokes.
But big studies to prove a statin reduces heart attacks and deaths are expensive and can take half a decade. So drug companies also pursued the approach of using ultrasound to measure the thickness of the wall of the carotid artery in the neck. Mevacor, Pravachol and Novartis' (nyse: NVS - news - people ) Lescol all have such ultrasound data in their product labels. A 2005 analysis in Current Controlled Trials in Cardiovascular Medicine concluded these imaging studies predicted how well the drugs would prevent heart attacks, strokes and deaths.
"No Valid Evidence"
When Zetia was approved in October 2002, cardiologists were starting to think that the lower they could get cholesterol with statins, the better. The refrain in studies, in company press releases and at medical meetings was that lower cholesterol is better. Some cardiologists argued that LDL levels should be brought down to levels seen most often in rural China. But many doctors were statin-shy because patients didn't like the muscle achiness and liver testsrequired with Lipitor, Zocor, and Pravachol.
Zetia seemed to represent a solution. Added to a low dose of a statin, Zetia lowers LDL as much as the top dose, with fewer side effects. Vytorin, approved in 2004, provided such a combo in a single pill, allowing patients to get it for one insurance co-payment. Sales ramped up fast. Zetia had annual sales of $900 million in 2004; Vytorin hit the same mark in 2005.
But that year, Rodney Hayward, a clinical researcher at the University of Michigan's School of Public Health, wrote that cardiologists may have gone too far in assuming lower is actually better. Patients at high risk of heart attacks do better on high doses of statins, he wrote in a 2005 issue of Annals of Internal Medicine, but it hasn't been proved that how low their LDL goes predicts their risk of heart attacks or strokes.
He also warned, "There is no valid clinical evidence to suggest that using treatments other than statins to pursue proposed LDL cholesterol goals is safe or effective."
Pfizer conducted 12 big studies to prove Lipitor's benefit, and AstraZeneca (nyse: AZN - news - people ) started three imaging trials and three trials measuring hard outcomes like heart attack and stroke. Merck and Schering started only one imaging study and three outcomes trials. A second imaging trial, with Steven Nissen of the Cleveland Clinic, was planned but never begun.
The most important study, due in 2011, is a 12,500-person trial to show whether adding Zetia to Zocor predicts heart attacks, strokes and heart procedures. The study was announced two years after Zetia was approved and started one year after that.
The Problem With ENHANCE
ENHANCE, involving 720 patients, began immediately in June 2002 and was modeled on an imaging study that had worked for Pfizer, called ASAP, conducted by John Kastelein of the University of the Netherlands. The patients in ASAP had FH, the genetic cholesterol disease. LDL, the bad cholesterol, was cut 50% on Lipitor, compared with 41% on Zocor. But while artery thickness increased by 0.036 millimeters on Zocor, it actually decreased by 0.031 millimeters on Lipitor.
ENHANCE was supposed to repeat that success, this time comparing Zocor and Vytorin. But it didn't. After delaying the release of the results for more than 18 months, the companies finally revealed data showing no statistically significant benefit in using the more expensive Vytorin. One explanation is that the patients in ENHANCE had been better treated and had less atherosclerosis, making it harder to prevent plaque buildup. Another is that lowering cholesterol with Zetia in addition to Zocor didn't provide a benefit in terms of slowing atherosclerosis.
"The full data will hopefully put in full perspective that there weren't any harmful effects at all," says A. Michael Davidson, executive medical director at Radiant Research. "This was a population that was so well treated that there wasn't really any opportunity to see any difference."
He says that FH patients are no longer a good population to use in these studies. He points out that LDL lowering is a main driver of the benefit of these drugs.
The danger to Merck and Schering this week isn't simply that the full data from the study will cause doctors to decide Zetia doesn't work. More doctors may decide they don't have enough data and use other drugs instead while they wait for the big trial the companies are conducting. Zetia and Vytorin will remain blockbusters, almost certainly. But if a significant minority of doctors find the ENHANCE results unconvincing, the drug makers will face strong headwinds, and a fast-growing brand could not only stagnate but also shrink.
This is what was happening to Vioxx, because of safety concerns, before Merck yanked it. And it's what happened with the schizophrenia drug Zyprexa, from Eli Lilly (nyse: LLY - news - people ), as prescriptions in the U.S. dropped because of concerns about weight gain and high blood sugar. And the companies spent a lot of their time defending these franchises when they needed to look for new opportunities for growth.
One person who won't be convinced by ENHANCE: Eric Topol, the noted chief of translational medicine at Scripps Health in La Jolla, Calif. He still wants to see clear data on how Zetia affects heart attacks, strokes and deaths, and doesn't understand why it took so long to embark on a big study to prove it.
Doctors have been "hanging in suspense for years, unnecessarily," Topol says. "It's still conceivable there would be improvement in outcomes. Until we have that data, the jury is out."
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