Study cites safety questions about GlaxoSmithKline's diabetes drug

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NEW YORK, May 21, 2007: An article released Monday by the New England Journal of Medicine raised safety questions about the widely used diabetes pill Avandia. An analysis of clinical trials concluded that the drug might significantly increase the risk of heart attacks.

The journal, a prestigious U.S. weekly, posted the paper on its Web site, ahead of its print publication June 14, a step that the editors take with matters they consider to have public health importance.

"We view this as the best publicly available data on a very important question," said the editor of the journal, Dr. Jeffrey Drazen. "It shows what we regard as a preliminary, but worrisome, signal about cardiovascular toxicity of this drug."

While noting possible weaknesses in data used in the analysis, an accompanying editorial calls for a review by the U.S. Food and Drug Administration. It also questions why physicians would prescribe Avandia, which is made by the British pharmaceutical company GlaxoSmithKline and is known generically as rosiglitazone.

The company's stock fell 74 pence, or 5.05 percent, to 1,390 pence on Monday.

In a statement, Glaxo said it strongly disagreed with the conclusions of the report, Reuters reported.

"GSK stands firmly behind the safety of Avandia when used appropriately, and we believe its significant benefits continue to outweigh any treatment risks," the company said.

FDA officials were not immediately available for comment.

Avandia, on the market since 1999, is used by an estimated two million people a year worldwide for the treatment of Type 2, or adult-onset, diabetes. With $3.2 billion in worldwide sales last year, it was Glaxo's second-biggest product, after the asthma drug Advair.

Drazen said patients concerned about the drug should meet with their doctors to decide whether to remain on it or switch to another drug.

"In view of the potential cardiovascular risks," the editorial said, "and in the absence of evidence of other related advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear." The editorial cautioned patients not to stop taking the medication without discussing it with their doctors.

The editorial, by Dr. Bruce Psaty of the University of Washington and Dr. Curt Furberg of Wake Forest University, said the accompanying study had once again spotlighted flaws in the U.S. drug approval and monitoring system. They asserted that those problems had not been fully addressed by recently passed legislation meant to strengthen the agency's powers.

Both Psaty and Furberg have been critical of the drug approval process in the past.

The finding - that Avandia raises the risk of heart attack by 43 percent - was based on a review of 44 studies of the drug. The review was conducted by Dr. Steven Nissen and Kathy Wolski of the Cleveland Clinic, where Nissen is the chief of cardiovascular medicine.

Nissen was among the first doctors to raise questions about the cardiovascular safety of Vioxx, the Merck painkiller that was withdrawn from the market in 2004. His concerns about Avandia were first publicly raised last December in a letter in the Lancet.

Nissen's letter noted increased cardiovascular problems in a 5,000-patient clinical study, called Dream. GlaxoSmithKline had sponsored the Dream trial in an effort to expand the product beyond a treatment for diabetes by using it to prevent the disease.

In the trial, patients taking Avandia had 66 percent more heart attacks, 39 percent more strokes and 20 percent more deaths from cardiovascular-related problems. That outcome, Nissen wrote, "virtually precludes the possibility of an overall benefit and suggest an unexpected mechanism for harm."

Results from another trial, Adopt, published in December, also indicated an elevated risk of heart problems compared to another diabetes drug.

Study cites safety questions about GlaxoSmithKline's diabetes drug

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MILWAUKEE, Wisconsin, May 21, 2007: The widely prescribed diabetes drug Avandia is linked to a greater risk of heart attack and possibly death, a new scientific analysis revealed, and the U.S. government issued a safety alert Monday.

The Food and Drug Administration urged diabetics taking the pill to talk to their doctors, but stopped short of forcing a sharper warning label on the drug sold by GlaxoSmithKline PLC of London.

More than 6 million people worldwide have taken the drug sold by London-based GlaxoSmithKline PLC since it came on the market eight years ago. Pooled results of dozens of studies revealed a 43 percent higher risk of heart attack, according to the review published by the New England Journal of Medicine.

Experts said the overall risk was small and cautioned people not to stop taking the drug on their own but to talk to their doctors.

The company downplayed the report of heart risks, saying the analysis by Dr. Steven Nissen and statistician Kathy Wolski at the Cleveland Clinic is not definitive scientific proof. In a conference call Monday, Dr. Lawson McCartney who leads Glaxo's diabetes drug development, said the company is not seeing "anything like" the problems reported in the medical journal.

"We remain very confident in the safety and of course in the efficacy of Avandia as an important diabetic medicine," McCartney said.

The government will take no immediate action on a label change or other measures regarding the drug, said Dr. Robert J. Meyer of the U.S. Food and Drug Administration's Center for Drug Evaluation and Research.

Some data suggests "that there is a potentially significant increase in the risk" but there also is risk if patients switch drugs or do not keep their blood-sugar under control, an FDA statement says.

FDA officials acknowledged that Glaxo submitted information last August indicating some increased risk from the drug but that other studies were contradictory. However, several members of Congress expressed alarm at the report and said they would hold hearings on the safety issues.

Avandia is used to treat Type 2 diabetes, the most common form of the disease, which is linked to obesity and afflicts 18 million Americans and 200 million people worldwide. This form of diabetes occurs when the body does not make enough insulin or cannot effectively use what it manages to produce.

Avandia helps sensitize the body to insulin and was considered a breakthrough medication for blood-sugar control.

Worried patients should not quit Avandia on their own and should discuss concerns with their doctors, wrote Drs. Bruce Psaty and Curt Furberg in an editorial in the New England Journal. Psaty is with the University of Washington in Seattle and Furberg is with Wake Forest University.

However, to the extent that the new analysis shows valid risks, the drug "represents a major failure of the drug-use and drug-approval processes in the United States," they said.

When the drug was approved, "evidence was at best mixed" on its benefit, wrote the two doctors. Both have been frequent critics of the FDA's failure to spot dangers in the drug approval process and its conduct in the case involving Vioxx. The popular arthritis medicine sold by Merck & Co. was taken off the market in 2004 when heart problems came to light after it had been taken by millions of people

Several experts said Avandia was another example of the FDA failing to detect a safety problem early enough.

Glaxo's shares trading in the United States fell $3.85, or 6.6 percent, to $53.89 in afternoon trading.

The report on the diabetes drug's risks follow Glaxo's $2.5 million settlement of a lawsuit filed by former New York Attorney General Eliot Spitzer over the release of data on the safety and effectiveness of its drugs. Spitzer, now New York governor, accused Glaxo of fraudulently withholding some results of studies that had examined the safety of prescribing the antidepressant Paxil to children.

GlaxoSmithKline disputed that it attempted to mislead anyone, and said it has always been in favor of widespread disclosure of clinical trial results.

The company's clinical trials registry (GlaxoSmithKline Clinical Trial Register) is available to the public, although the reports within it are highly technical and may appear incomprehensible to an untrained reader.

Diabetes drug Avandia raises risk of heart attacks, study finds

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What did Glaxo know?

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Avandia doubts

Doubts over the safety of GlaxoSmith-Kline's diabetes drug Avandia, could open up a black hole in the company's future profits of almost £1bn, analysts estimated yesterday.

The drugs company's shares slid by 19p to £13.71, bringing their two-day fall to 6.5% since doctors at an influential American cardiovascular hospital suggested Avandia could put patients at risk of heart attacks.

Citigroup forecast that sales of Avandia, which is Glaxo's second most lucrative drug, could be flat rather than rising for the next three years - wiping out £950m of the group's expected £9.9bn profit in 2010. At Deutsche Bank, the analyst Mark Purcell downgraded his advice on Glaxo shares from buy to hold. Both the US food and drug administration (FDA) and a Congressional oversight committee are investigating the issue.

The US is particularly sensitive to drug safety since a furore erupted last year over an arthritis drug, Vioxx, which was withdrawn by its maker Merck because of heart attacks. Critics said the drug should never have been approved by regulators.

Pharmaceuticals analysts at Morgan Stanley warned that the issue cast a cloud over the entire industry: "The melodramatic Senate and Congress reaction [to the Avandia study] indicates the phenomenal levels of distrust of industry and the FDA by Congress, posing a continued and significant negative dynamic for the industry."

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May 26, 2007 -- A large clinical study meant to test the heart safety of the diabetes treatment Avandia may be in jeopardy as a result of recent reports of the drug's risks, according to an executive for its maker, GlaxoSmithKline.

Dr. Ronald Krall, the medical director for GlaxoSmithKline, said in an interview Friday that some of the 4,450 patients enrolled in the drug trial dropped out in the past week because of safety concerns about Avandia.

Krall said that he did not know how many patients had withdrawn but that Glaxo was now worried about whether it could complete the drug trial, scheduled to run through next year. The company has been counting on a successful outcome from the study to dispel widespread concerns that Avandia carries a higher risk of heart attacks than other diabetes drugs.

Now, though, the independent research committees overseeing the study "are concerned about the ability of the study to continue" and are "considering what to do to prevent people from dropping out of the trial," Krall said.

The safety concerns were ignited by an analysis published Monday by The New England Journal of Medicine suggesting that Avandia, used to treat Type 2 diabetes, carries an increased risk of heart attack, estimated at 43 percent, compared with other diabetes drugs or placebos.

In response to the medical journal article, the U.S. Food and Drug Administration issued a safety alert for Avandia and advised patients who take it to consult their doctors.

Avandia, which was approved by the FDA in 1999, has been used by an estimated seven million people, six million of them in the United States.

On Friday, the FDA said its own recent analysis of more than 40 clinical studies of Avandia seemed to confirm the findings in The New England Journal of Medicine's study, whose lead author was the influential Cleveland Clinic heart specialist Steven Nissen.

But an agency spokeswoman urged caution in interpreting those results. "Dr. Nissen's meta-analysis and the FDA's meta-analysis both arrived at a similar figure of 40 percent" the spokeswoman, Julie Zawisza, said by e-mail. "But this alone is not conclusive of anything. What it does mean is that we need to try to reconcile the meta-analysis finding with clinical trial data that do not show this increased risk."

People with Type 2 diabetes are already at risk of heart attacks, facing a 20.2 percent chance of such an attack over seven years. One of the main reasons for controlling blood sugar in diabetic patients is to manage that risk.

But if Nissen's analysis is an accurate reflection of Avandia's increased risk, it appears the drug would do more cardiovascular harm than good. Diabetics taking Avandia would run a 28.9 percent chance of heart attack over the same seven-year period, according to his analysis.

GlaxoSmithKline's own meta-analysis, submitted to the FDA last August, showed a slightly lower 31 percent increased risk of heart attack.

A meta-analysis, which involves comparing the results of disparate clinical trials, is not considered as definitive as a uniform controlled patient study of the sort GlaxoSmithKline has been counting on with its trial. Both GlaxoSmithKline and the FDA have said that the meta-analyses indicating a heart risk with Avandia are contradicted by an interim look at the trial as well as data from an analysis of more than 20,000 patients enrolled in a UnitedHealthcare plan.

But neither GlaxoSmithKline nor the FDA has released results from that interim assessment, which was conducted within the last month.

The FDA received heavy criticism from members of Congress who suggested that Avandia was shaping up as another Vioxx. That drug, a painkiller that became a best seller despite periodic questions about its safety, was taken off the market in 2004 when its heart risks became irrefutable.

The FDA plans to ask an advisory panel to review the Avandia data. Such panels, if they find safety risks with a drug, can recommend that the agency require a stronger warning label or ban the drug altogether.

Avandia is Glaxo's second largest selling drug, with more than $3 billion in sales last year worldwide. The company's American depository receipts fell nearly $5 this week on news of safety concerns about the drug. The shares closed Friday at $52.43.

GlaxoSmithKline has urged regulators and the public not to rush to judgment based on the New England Journal of Medicine article and has said that the drug trial, which began in 2000, would be a more reliable way to estimate the cardiovascular risks.

In that study, half the 4,450 patients are being treated with Avandia in combination with another diabetes drug, while the others are being treated with two other drugs.

The trial is designed to determine whether patients taking Avandia are more likely to have a range of cardiovascular problems, including heart attack and stroke.

Test of diabetes drug is in jeopardy

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WASHINGTON, June 6, 2007: U.S. regulators said Wednesday that GlaxoSmithKline and Takeda Pharmaceutical should add the strictest warning about the risk of heart failure to their diabetes drugs after a recent study linked Glaxo's diabetes drug Avandia to potential heart risks.

Avandia and Actos, a rival diabetes drug made by Takeda, should carry warnings in their prescribing information set off by a black box, the strongest possible caution, Andrew von Eschenbach, the commissioner of the Food and Drug Administration, told lawmakers at a hearing. The drugs are being inappropriately prescribed for high-risk patients, he said.

U.S. lawmakers are examining whether to press for new U.S. drug-safety legislation after the study suggested Avandia increased the risk of heart attack. The study, released May 21, showed that Avandia, the world's best-selling diabetes pill, increased the risk of a heart attack by 43 percent.

The study has reignited complaints by Congress that the drug agency is too lax in monitoring drug complications after a product is on the market. The agency previously was criticized for failing to act on heart dangers linked to Merck's painkiller Vioxx before it was withdrawn in 2004.

Glaxo has said it gave regulators information in August 2006 that estimated a 30 percent higher heart-attack risk with Avandia. Some critics question why neither the agency nor Glaxo alerted patients sooner.

Millions of patients take Avandia, and sales topped $3 billion last year. But prescriptions have fallen 16 percent since the study, done by the Cleveland Clinic, as doctors switch patients to Actos.

"In looking at all the studies to date related to the potential contribution of rosiglitazone to increasing the risk of heart attack, the data are inconsistent and conclusions are not clear," von Eschenbach said in testimony submitted to the House Oversight and Government Reform Committee. "That means FDA is not at present justified in taking additional regulatory action or recommending that patients stop using it."

The hearing came after an analysis in The New England Journal of Medicine concluded that Avandia could raise heart attack risk by more than 40 percent.

Glaxo released two studies ahead of the hearing that it said backed Avandia's safety and paid for at least a dozen full-page newspaper ads. Moncef Slaoui, the company's research and development chairman, said in prepared testimony that data showed Avandia was as safe as other diabetes drugs and the company had shared data with regulators.

The food and drug agency is finishing its own analysis of whether Avandia contributes to heart risk. The agency has scheduled a July 30 public meeting to discuss risks with Avandia, as well as other oral diabetes drugs.

Von Eschenbach said the agency last month asked GlaxoSmithKline to place a stronger warning about the risk of congestive heart failure for some patients on the labels of Avandia and Actos. Both drugs already have a less-prominent warning about that risk.

U.S. urges strongest warning on 2 diabetes drugs

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June 13, 2007 -- The drug giant GlaxoSmithKline is seeking to move on from the furore surrounding its Avandia diabetes drug with the launch of an over-the-counter diet pill.

Alli, which is the first prescription weight-control drug to be switched to over-the-counter sales and the only one to have won Food and Drug Administration approval, will go on sale in the US next week.

The launch was overshadowed yesterday by the news that Glaxo faces a lawsuit from US investors who are claiming that the drug maker misled shareholders about the safety of Avandia.

Shares in Glaxo have been tumbling since a study published in May linked Avandia to an increased risk of heart attack. Although Glaxo disputes the findings, sales and prescriptions of the drug, which is the company's second-best seller, have been falling.

The law firm Kaplan Fox & Kilsheimer said it had filed a class action suit in the US District Court for the Southern District of New York against Glaxo, alleging the company had made false statements. The suit was made on behalf of anyone who purchased shares in the company between 27 October 2005 and 21 May this year, with plaintiffs given 60 days to act.

The complaint alleges that Glaxo "failed to adequately disclose the fact it had performed a meta-analysis - a pooled analysis of several clinical trials - of Avandia which showed an increased risk of heart attacks".

A spokesman for Glaxo said the company would vigorously defend its medicine. "GSK has acted responsibly, transparently and with the best interest of patients in mind," he said. "Any fair examination of the company's record will show that GSK has been transparent in its efforts to thoroughly study the safety and effectiveness of Avandia, and to widely communicate that information to governments, regulatory authorities, scientific peers, physicians and others in a variety of ways."

Despite the recent hit to the share price, analysts remain positive on the stock due to the potential of its other new products, including its breast cancer drug Tykerb, which was launched in the US in March.

Peter Cartwright at Evolution Securities, said the fall in the share price will "prove to be excessive when set against the longer-term hit to group earnings from the Avandia safety issue".

Glaxo said Alli, which it hopes will be on sale in Europe in 2008, will be one of the largest launches the company has ever undertaken. Analysts are expecting Glaxo to spend around $150m this year on marketing Alli, which is a half-dose version of Roche's prescription drug Xenical and works by reducing the amount of fat the body absorbs from food.

Glaxo is stressing that the drug must be taken in conjunction with a low-fat diet and is being marketed to serious dieters in the hope it will not be seen as a fad. It will retail at around $55 to $60 for a month's supply.

The company's new £50m Clinical Imaging Centre in west London, which will focus on the research of major diseases, including cancer and neurological diseases, is being opened today by the Trade and Industry Secretary Alistair Darling.

Lawsuit over Avandia overshadows Glaxo's launch of new diet pill