Glaxo's Avandia Should Be Pulled, U.S. Scientist Says
July 30, 2007
By Justin Blum and Michelle Fay Cortez

GlaxoSmithKline Plc's diabetes pill Avandia should be removed from the market because of heart risks, said the U.S. drug safety scientist who spurred the withdrawal of the painkiller Vioxx.

Avandia may have caused 30,000 to 140,000 heart attacks or deaths since it was introduced in the U.S. in 1999, said David Graham, the Food and Drug Administration scientist, at a meeting of agency advisers in Gaithersburg, Maryland today. There's no proof Avandia provides ``major'' health benefits, Graham said.

Dr. Steven Nissen speaks out on Avandia and the increased risk of heart attack

Graham's position was backed by his boss, Gerald Dal Pan, head of the FDA's Office of Surveillance and Epidemiology, which monitors side effects of marketed drugs. Robert Meyer, director of the Office of Drug Evaluation II, said there is "fundamental disagreement'' within the agency on the drug, which is also known as rosiglitazone. The advisers are weighing whether Avandia should be removed from the market, and Graham's presentation may increase that likelihood.

"If rosiglitazone increases the cardiovascular risks, a wrong decision will cost thousands of lives,'' Graham said at the meeting.

Glaxo's shares fell 10 pence, or 0.8 percent, to 1,215 pence in London to close at the lowest level since April 2005. They have declined 9.6 percent this year. The company's American depositary receipts dropped 20 cents, or less than 1 percent, to $49.43 at 4:02 p.m. in New York Stock Exchange composite trading. One depositary receipt equals two ordinary shares.

Critic of Vioxx

Graham questioned Avandia's health benefits compared with other treatments. The scientist became well-known after calling for Merck & Co.'s Vioxx to be pulled from the market long before it was withdrawn in 2004 because of heart risks.

"Patients have been scared enough by a lot of snippets of information here and there,'' said Chris Viehbacher, president of U.S. pharmaceuticals at Glaxo, in an interview today. "The advisory committee's going to hear a lot of people, including Dr. David Graham, and I think what you're going to find is that the weight of scientific evidence continues to support the safety of Avandia.''

Glaxo stock has fallen 17 percent since a May 21 report in the New England Journal of Medicine tied Avandia to a 43 percent increased risk of heart attacks. In February, drug-safety scientists at the FDA concluded Avandia shouldn't be used with insulin or by patients with heart disease, according to documents posted on the agency's Web Site July 26.

The FDA often follows the advice of its advisory panels, though the agency isn't required to do so.

Graham's recommendation doesn't mean the FDA will pull the drug from the market, said Navid Malik, an analyst at Collins Stewart in London, in a telephone interview today.

'Against the Grain'

"He obviously made a good call about Vioxx, but these guys, they're very vocal, they sometimes go against the grain of what the evidence is saying,'' Malik said. "I'm not sure the reasons he cited for the withdrawal correlate with the evidence. He cites cardiovascular risks, but there are data which are contradictory.''

Glaxo's Chief Executive Officer, Jean-Pierre Garnier, has repeatedly said Avandia doesn't raise the risk of heart attacks and heart disease and is as safe as competing medications.

"We stand firmly behind the safety profile of Avandia,'' he said on a conference call with reporters last week. "Avandia is a very important drug for millions of diabetic patients.''

Numerous Studies

Numerous studies involving more than 1.3 million patients show no clear risk of heart attacks with Avandia and indicate it doesn't increase deaths, said Ronald Krall, Glaxo's chief medical officer. Patients taking Avandia had fewer strokes, which generally rise in tandem with heart attacks, underscoring the uncertainty of the analyses that do show a risk, he said.

Glaxo proposed continuing studies of Avandia to determine the heart risks and adding information to the drug's package insert in the meantime.

"We have five ongoing trials, four of which are large, long-term outcome trials, three in high-risk populations, that will read out in the next 18 to 24 months and will undoubtedly alone or as a group help us resolve any current uncertainty'' about the heart attack risk of Avandia, Krall said.

Panel's Options

The FDA panel is considering more than 600 pages of data and dozens of studies on Avandia. The agency asked the advisers to vote on whether existing information ``supports the conclusion'' that Avandia increases cardiac risks like heart attacks and if such a risk is greater than that from other therapies.

If the panel recommends the drug should stay on the market, the agency wants to know what steps it can take, such as limitations on Avandia's use, to maximize its benefit while reducing its risk.

Graham said a similar drug called Actos from Osaka-based Takeda Pharmaceutical Co. doesn't have the same cardiovascular risks. The FDA's Meyer urged the advisers to consider side effects of Actos and other medicines used to treat diabetes.

An estimated 246 million people, nearly 6 percent of the world's adult population, suffer from diabetes and 3.8 million a year die from it, according to the International Diabetes Federation. The most common form is type 2, linked to a sedentary lifestyle and excess weight.

Progressive Disease

The cells of those patients don't properly produce and use insulin, the hormone that coverts blood sugar to energy. The disease is progressive, with patients needing more and more aggressive therapy to get their blood sugar under control. Persistently high levels eventually damage the nerves and blood vessels, leading to blindness, kidney failure and death.

Avandia and other treatments make the cells more sensitive to the insulin the body produces. Other therapies prompt the body to make more insulin. Eventually, most patients need insulin injections to control their blood sugar.

The advisory committee's position will help determine whether and to what extent Avandia will contribute to Glaxo's future earnings. It was the world's best-selling diabetes pill and London-based Glaxo's second-biggest drug last year, bringing in $3.3 billion for the company.

Avandia sales include revenue from two combination products. Avandamet, a combination with generic metformin used to control blood-sugar levels, had global sales of $400 million in 2006. Sales of Avandaryl, a combination with Sanofi-Aventis SA's Amaryl to stimulate production of pancreatic insulin, were $82 million.

Sales Fell

After the heart-attack risk was reported in May, Avandia sales fell 22 percent in the second quarter as doctors turned to Actos and newer medications from Merck & Co. and Eli Lilly & Co.

Before the controversy began, analysts were expecting Avandia to reach peak sales of about $6 billion (3 billion pounds) by 2011. Now many say the chances are slim.

"It will be very difficult to recover from this,'' Nick Turner, an analyst at Mirabaud Securities in London, said in a telephone interview earlier this month. "Even if the FDA doesn't can it, it is going to be hard to get patients to take the risk,'' he said. ``Every man and his dog is going to be looking at every trial for heart risk.''

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