Vioxx Successor Faces FDA Hurdles
Merck Pushes Replacement
For Disgraced Painkiller,
But Safety Issues Linger
By SARAH RUBENSTEIN and ANNA WILDE MATHEWS
April 4, 2007; Page D1
More than two years after the painkiller Vioxx was taken off the market because it was found to increase the risk of heart attack and stroke, its maker is asking the Food and Drug Administration to approve a Vioxx successor.
Next week, an FDA advisory committee will hold a public meeting on Merck & Co.'s Arcoxia, a new medication which is part of the same class of drugs as Vioxx, called Cox-2 inhibitors. The agency is expected to rule by the end of April on whether to approve Arcoxia.
Merck says it is forging ahead with Arcoxia because there's still an unmet medical need for painkillers for arthritis. "There are obviously a variety of drug treatments for it, but there is an immense amount of patients out there who are not satisfied with those therapies," says Sean Curtis, head of Merck's clinical development program for Arcoxia, who will be speaking at the advisory meeting. The drug would provide "an additional treatment option for those patients," he says.
Dr. Curtis says there are a lot more data on Cox-2 drugs than there were around the time of the withdrawal of Vioxx. Merck pulled the drug from the market in September 2004 after a study linked it to an increased risk of heart attacks and strokes compared with placebo. Critics, however, complain that Merck's major study of Arcoxia's cardiovascular safety doesn't do enough to prove that the medication is safe, since it compared Arcoxia to a drug that itself has an increased cardiovascular risk. Vioxx was a blockbuster drug, used by millions of patients during its five years on the U.S. market. The drug had $2.5 billion in global sales in 2003, its last full year on the market.
The purported benefit of Cox-2 inhibitors is that they relieve pain while going easy on the stomach. Older painkillers such as ibuprofen and Aleve, known generically as naproxen, block two enzymes, called Cox-1 and Cox-2. These medicines, known as nonsteroidal anti-inflammatory drugs, or NSAIDs, can damage the stomach and intestines. Arcoxia, Vioxx and Pfizer Inc.'s Celebrex are a subset of the NSAIDs that aim to reduce the gastrointestinal problems by only blocking Cox-2.
Some former Vioxx users say they would welcome a new Cox-2 inhibitor. Cynthia Daube, an arthritis patient from Rochester, Minn., says she had taken Vioxx for several months until it was withdrawn. Now she's taking an aspirin product, which she says is "adequate." But Vioxx did work better for her, she says, and she might give Arcoxia a try once it has been on the market in the U.S. for a year or so. "I did like Vioxx, it did make me comfortable, I think more so than what I'm taking now," she says. "I might be interested in [Arcoxia], but I would be cautious after all of the publicity from Vioxx."
Indeed, many former Vioxx patients complain that the drug was the only thing that worked for them. Merck says it hasn't decided whether to bring Vioxx back to the market.
Eric Matteson, chair of the rheumatology division at the Mayo Clinic in Rochester, Minn., says some patients have chronic, long-term pain and inflammation, and Arcoxia "can offer us at least another alternative."
Merck tested Arcoxia in a massive study, called Medal, that included 34,701 patients enrolled in three trials. The study showed a similar cardiovascular risk for Arcoxia and an older drug, diclofenac. But FDA committee members may question the use of diclofenac as the comparator, because while diclofenac is not categorized as a Cox-2 drug, experts including the American Heart Association view it as closer to the Cox-2s than other painkillers in its class. "What they did is say, our Cox-2 is similar to another Cox-2," says Bruce Psaty, a professor at the University of Washington who wrote about the issue in a recent New England Journal of Medicine commentary. "That's not terribly reassuring."
Steven Nissen, immediate past president of the American College of Cardiology, also pointed out that more patients on certain Arcoxia doses dropped out of the study due to high blood pressure. "I do not believe that [Arcoxia] should be approved," he said.
Merck's Dr. Curtis defends the company's use of diclofenac. He says Merck chose diclofenac because it is not a Cox-2 inhibitor and because when the company was designing the study in 2002, there was evidence emerging that certain drugs other than diclofenac might block the heart-protective effects of aspirin, which the company expected many patients in the trial would take. Dr. Curtis also emphasized that diclofenac is prescribed very widely world-wide. "To judge yourself against a clinical standard like that is very valuable," he says.
There also may be debate over Arcoxia's benefits for the stomach. The Medal study showed that Arcoxia was no better than diclofenac at reducing the risk of serious gastrointestinal problems such as ulcers with significant bleeding, but Arcoxia did have a comparatively lower risk of "uncomplicated" gastrointestinal problems such as less-serious ulcers.
But a recent commentary in the medical journal Lancet said Arcoxia's gastrointestinal benefit "is certainly not large and might not be clinically relevant."
Wall Street analysts are skeptical that the FDA will approve Arcoxia. Even if it is approved in the U.S., they're not optimistic about its sales potential. "We sort of view Arcoxia as dead and we don't have any estimates for it," says Barbara Ryan, a drug analyst at Deutsche Bank. If it is approved, "it will probably have a very nasty label, and they probably won't be able to advertise it to consumers."
Arcoxia is currently being sold in 63 countries in Europe, Latin America, Asia and the Middle East. Outside of the U.S., Arcoxia drew $265 million in sales in 2006. That makes it currently a minor player for a company as large as Merck. But while the market for these types of drugs has shrunk, it is still significant. Pfizer's Celebrex, the only Cox-2 inhibitor currently on the U.S. market, rang up more than $2 billion in global sales in 2006, and the company this week began a new direct-to-consumer marketing campaign.
Arcoxia's road to the U.S. market has been bumpy. In March 2002, Merck withdrew its FDA application for the drug in order to "better position the product to compete successfully," the company said at the time. Later that year, Merck said it would gather more data for regulators on Arcoxia's effect on the heart. It didn't resubmit its application until December 2003.
Then, about a month after Vioxx's withdrawal in fall 2004, the FDA asked for additional safety and efficacy data on Arcoxia. Late last year, Merck submitted new data and also scaled back its FDA application for the drug, reducing the dosages for which it is seeking approval and limiting its use to osteoarthritis alone -- not other uses it had previously sought, such as rheumatoid arthritis or acute and chronic pain. The company says it plans to seek approval for expanded uses later.
Next week's advisory committee meeting will force the FDA to publicly revisit the politically sensitive issue of the Cox-2 drugs for the first time since 2005, when it won strong "black box" warnings on all the nonsteroidal painkillers and got Pfizer to agree to pull its Cox-2 Bextra off the market. The agency, as well as its advisers, are under pressure to show they are paying attention to any signal of risk. The FDA is drawing close scrutiny from Congress, which is weighing drug-safety legislation, and Vioxx has been a lightning rod for critics who have faulted the FDA's handling of safety issues.
The FDA said in written answers to questions that it doesn't believe that Cox-2 painkillers are necessarily more risky for the heart than other nonsteroidal painkillers. For the agency to consider approval, a new drug's safety profile has to be "convincingly shown to be comparable to what is known for the class and it does not pose any demonstrated, unacceptable risks" beyond the cardiovascular danger of all the painkillers, the FDA said. That means studies big and long enough to provide "reasonable characterization of safety -- including comparative cardiovascular safety," the FDA said.
Write to Sarah Rubenstein at sarah.rubenstein@wsj.com and Anna Wilde Mathews at anna.mathews@wsj.com |
