Glaxo’s Avandia to Be Pulled in EU, Restricted in U.S.

GlaxoSmithKline Plc (GSK)’s Avandia, once the world’s best-selling diabetes drug, will be withdrawn in Europe and restricted in the U.S. after a three-year review of the medicine’s heart risks.

Glaxo said it will stop promoting the drug in all countries after the decisions announced today by the European Medicines Agency and the U.S. Food and Drug Administration. Regulators disagreed on the reliability of the data and whether potential risks could be contained. Glaxo’s American depository receipts fell the most in a month in New York trading.

Avandia’s sales have fallen by two-thirds since an analysis released in May 2007 tied it to a 43 percent increased risk in heart attacks. Glaxo said sales will be minimal after this year. The financial impact on Glaxo will also be limited because Avandia’s patent expires in 2012, said Eric Le Berrigaud, an analyst at Raymond James in Paris.

“We struggled with it, and colleagues in other jurisdictions struggled as well,” Hans-Georg Eichler, the EMA’s senior medical officer, said on a conference call with reporters. “There’s no single perfect tool to study this risk.”

In the U.S., the medicine will carry new warnings after a three-year battle that divided staff at the FDA. London-based Glaxo must add new cautions to Avandia’s prescribing information, the agency said today. The decision to allow continued sales of the treatment follows the recommendations of an FDA advisory panel in July.

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GlaxoSmithKline's Avandia diabetes drug. Close

GlaxoSmithKline's Avandia diabetes drug.

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Photographer: JB Reed/Bloomberg

GlaxoSmithKline's Avandia diabetes drug.

Heart Attack Risk

The FDA advisers called for stronger warnings on the label after re-examining a 2007 decision to keep the medicine on the market. Glaxo has said “extensive clinical data” have shown the treatment to be safe.

“Ninety-nine percent of drug use should go away,” Steven Nissen, chairman of the Cleveland Clinic’s department of cardiovascular medicine and author of the 2007 analysis, said in a telephone interview. “The drug will essentially disappear from use in the U.S. and will disappear in Europe.”

Glaxo’s ADRs fell 72 cents, or 1.8 percent, to $39.43 at 4:01 p.m. in New York Stock Exchange composite trading, their biggest percentage decline since Aug. 24. Each receipt represents two ordinary shares.

‘Important Treatment’

“The company continues to believe that Avandia is an important treatment for patients with Type 2 diabetes and is now working with the FDA and EMA to implement the required actions,” according to Glaxo’s statement.

“Our primary concern continues to be patients with Type 2 diabetes and we are making every effort to ensure that physicians in Europe and the U.S. have all the information they need to help them understand how these regulatory decisions affect them and their patients,” Ellen Strahlman, Glaxo’s chief medical officer, said in an e-mailed statement.

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London-based Glaxo must add new cautions to Avandia’s prescribing information, the agency said today. Close

London-based Glaxo must add new cautions to Avandia’s prescribing information, the agency said today.

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Photographer: JB Reed/Bloomberg

London-based Glaxo must add new cautions to Avandia’s prescribing information, the agency said today.

Avandia and Avandamet, which both contain the active ingredient rosiglitazone, last year garnered revenue of 771 million pounds ($1.2 billion), down from 1.6 billion pounds in 2006. Actos, from Takeda Pharmaceutical Co. (4502), is the world’s best-selling diabetes medicine, generating 387 billion yen ($4.6 billion) in the year ended March 31, according to the Osaka, Japan-based company’s annual report.

‘Minimal’ Revenue Ahead

Glaxo said it expects Avandia sales of 100 million pounds to 150 million pounds in the second half, and “minimal” revenue from the drug after that. The drugmaker said it will have one-time costs of 100 million pounds this year to write off Avandia and inventories of the medicine.

Le Berrigaud, the analyst at Raymond James, will cut his revenue estimates by 300 million pounds to 400 million pounds for the next couple of years, he said.

“That’s not very meaningful when you have annual sales of 30 billion pounds and as the drug will go off patent in 2012 anyway,” Le Berrigaud said.

Avandia already had restrictions in Europe, limiting use to patients that had failed to respond to another treatment, the EMA said. The regulators said they couldn’t identify another way to limit the risk to patients other than suspending sales. The drug will stop being available in Europe in a few months, the agency said.

“I am not happy with this decision,” said Gregor M. Hess, a physician from Worms, Germany, who specializes in diabetes. Pulling the medicine from the market doesn’t make sense “because it could always be an option for some patients,” he said in Stockholm, where he was attending the European Association for the Study of Diabetes annual meeting.

A Decade to Decide

The EMA’s Eichler said it took the agency a decade to be sure that the heart risk seen in studies was linked to the drug and not merely a result of diabetes.

“Are we happy with the fact it took 10 years? Of course not,” Eichler said on the conference call. “Could there have been a better way to handle this? I don’t think there would have been many other opportunities to handle this faster.”

Glaxo conducted a study of Avandia, dubbed Record, at the request of European regulators. The 4,447-person, five-year trial found that Avandia more than doubled the risk of heart failure without increasing the rate of hospitalization or death from cardiovascular causes, compared with older diabetes medicines. The data, presented in June 2009, are limited because more people in the group receiving Avandia were taking cholesterol medications and patients and doctors knew which diabetes drug was prescribed.

Increased Danger

“Data from clinical trials, observational studies and meta-analyses of existing studies that have become available over the last three years have suggested a possibly increased risk of ischaemic heart disease associated with the use of rosiglitazone,” the EMA said today.

A study published last month found that Actos, which is the same type of treatment as Avandia, causes as many heart problems as the Glaxo medicine. Takeda says the drug is safe. Eric Abadie, the chairman of the EMA’s Committee for Medicinal Products for Human Use, said on a conference call that Actos doesn’t appear to have the same risks as Avandia.

FDA reviewers were divided about the Record study, according to documents released on July 9. Thomas A. Marciniak, a medical team leader at the agency, said Record “was inadequately designed and conducted,” while Ellis Unger, deputy director of the FDA’s Office of Drug Evaluation, called the results of the study “reassuring.”

Considerable Uncertainty

“We are not withdrawing the drug at this time because there is considerable uncertainty about this signal and whether it is valid,” said Janet Woodcock, head of the FDA’s Center for Drug Evaluation and Research, on a conference call today with reporters. The next step is for independent doctors to review Glaxo’s Record study.

The FDA ordered Glaxo to develop a program where doctors will register patients who are prescribed Avandia and document why they need the drug. Patients will have to review statements describing the cardiovascular safety findings and acknowledge that they understand the risks. Physicians will have to prove that people prescribed Avandia for the first time haven’t been helped by other diabetes drugs and choose not to take Actos because of medical reasons.

The new risk-management program will take “several months” to implement, the FDA said.

Warring Factions

“This is clearly a compromise between warring factions in the FDA,” said Diana Zuckerman, director of the National Research Center for Women & Families in Washington, whose father had taken Avandia. “For FDA to say they can manage this restriction seems overly optimistic, not evidence-based.”

European regulators may reconsider their decision if new data emerges on Avandia, said FDA Commissioner Margaret Hamburg. The agencies came to different conclusions on how best to protect patients because the U.S. is comfortable relying on restricted access programs to manage risks, Hamburg said.

Patients should consult their doctors before they stop taking any treatment for diabetes, said Ulf Smith, president of the European diabetes group.

“Physicians have an array of drugs that they can replace rosiglitazone with,” Smith said in an interview in Stockholm.

Earlier this year, Glaxo agreed to settle about 10,000 lawsuits alleging the drugmaker hid Avandia’s heart-attack risk for about $460 million, or an average of $46,000 a case, people familiar with the settlements said. Those people sought anonymity because the accords are private.

The company still faces about 3,000 suits over Avandia, analysts say. Those cases are consolidated in federal and state courts in Pennsylvania.

To contact the reporter on this story: Kristen Hallam in London at khallam@bloomberg.net; Catherine Larkin in Washington at clarkin4@bloomberg.net.

To contact the editors responsible for this story: Phil Serafino at pserafino@bloomberg.net; Reg Gale at rgale5@bloomberg.net.

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