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New COX-2 inhibitor drug called nonapprovable by FDA.

The Food and Drug Administration has issued a nonapprovable letter for the COX-2 inhibitor etoricoxib (Arcoxia), according to the drug's manufacturer, Merck & Co.

The decision followed a 20-1 vote against approval, largely based on safety concerns by the FDA's Arthritis Drugs Advisory Committee, which considered the drug on April 12.

Peter S. Kim, Ph.D., president of Merck Research Laboratories, expressed disappointment with the decision.

"We pursued FDA approval of Arcoxia because we strongly believe that new medicines are needed for patients whose osteoarthritis pain is inadequately managed with currently available therapies.

"In addition, there is more long-term safety data from controlled trials ... for Arcoxia than for any other NSAID, including traditional NSAIDs and COX-2 selective inhibitors," Dr. Kim said in a statement.

In presentations to the FDA and at scientific meetings in the last year, Merck has said that its large studies of etoricoxib showed no increased risk of cardiovascular events and demonstrated a decreased risk of uncomplicated gastrointestinal side effects.

At the advisory committee meeting, FDA advisers were not convinced, especially since they weren't overly impressed with the efficacy data. "It comes down to determining whether there is a clinical need," said Dr. Richard Cannon, a panel member and principal investigator at the National Heart, Lung, and Blood Institute's Cardiology Branch.

"We don't really have strong data there is a need for this drug in addition to what's available," Dr. Cannon said.

Other committee members agreed that Merck had not demonstrated that Arcoxia offered a particular benefit over other nonsteroidal anti-inflammatories (NSAIDs), including other COX-2 inhibitors. The panel also raised the specter of reexamining NSAIDs currently on the market.

Even though the entire class carries a black-box warning about cardiovascular events, panelists said there were still not enough data on whether traditional NSAIDs or the only other COX-2 inhibitor on the market, Celebrex (celecoxib, Pfizer), raises the risk of heart attack and stroke.

Dr. Cannon said he believed that all COX-2 inhibitors increased that risk.

Panelist Dr. David Felson suggested that Merck should shelve Arcoxia. He also said that other manufacturers should stop pursuing COX-2 development. "These drugs are modestly effective at best," said Dr. Felson, a professor of medicine and public health at Boston University.

"I don't see any reason to test this drug or any other drugs in this class any further," Dr. Felson said.

Novartis is continuing to develop its COX-2, Prexige (lu-miracoxib), which is approved in Europe.

In an interview after the advisory committee meeting, Dr. Roy Altman, a professor of medicine at University of California, Los Angeles, strongly disagreed with the panel's conclusion, stating that there was a pressing clinical need for more alternatives for arthritis patients.

At the meeting, Merck presented data from 11 studies on safety and efficacy at 30-mg and 60-mg once-daily doses in osteoarthritis patients, safety data from seven other studies in other patient populations, and more data on 34,000 patients in the Multinational Etoricoxib and Diclofenac Arthritis Long-Term (MEDAL) program.

The company said that at least 21 million Americans have arthritis and that many are not well served by current treatment options. Both the company and FDA agreed that Arcoxia is effective. At 30 mg, Arcoxia's efficacy is similar to 2,400 mg of ibuprofen or 200 mg of Celebrex; at 60 mg, it is comparable to 1,000 mg of naproxen, according to Merck.

For cardiovascular events, Arcoxia had a relative risk of 1.07 compared to placebo, 0.73 compared to NSAIDs, and 1.70 compared to naproxen.

Compared with diclofenac, Arcoxia had a relative risk of about 0.95 for per-protocol confirmed thrombotic events and per-protocol confirmed arterial events in the MEDAL trials.

Dr. Robert Shibuya, a medical officer with FDA's division of anesthesia, analgesia, and rheumatology products, estimated that if Arcoxia were prescribed to 1 million patients, there could be as many as 2,300 excess cardiovascular events per year, compared with diclofenac.

"We're talking about a potential public health disaster," Dr. David Graham of the FDA's Office of Surveillance and Epidemiology told the committee.

He also predicted an excess of heart attacks and strokes if Arcoxia were approved.

Dr. Graham is the FDA official who first sounded the alarm about Vioxx, which was withdrawn in 2004.

Dr. Sidney Wolfe, director of Public Citizen's Health Research Group, also warned of excess mortality with Arcoxia and said the drug should be removed from sales in the 63 countries where it is currently approved.


Associate Editor, Practice Trends
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Title Annotation:Across Specialties
Author:Ault, Alicia
Publication:Clinical Psychiatry News
Date:May 1, 2007
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