July 1 (Bloomberg) -- Sanofi-Aventis SA’s three-day stock decline last week prompted the European Association for the Study of Diabetes to publish research on the French drugmaker’s Lantus insulin a week ahead of schedule.

Lantus was linked to an increased risk of cancer in analyses of patient databases in Germany and Sweden, the association said. Edwin Gale, editor in chief of the group’s medical journal Diabetologia, said he told European regulators of the results in early June so they could be prepared for a reaction when the report was announced.

Speculation about negative study results for Lantus fueled a 14 percent drop in Sanofi shares from June 24-26, knocking 8.8 billion euros ($12.3 billion) off the Paris-based company’s market value. The studies were released on June 26 after the close of Paris trading, and the shares have gained 5.6 percent since then.

“The market was falling and there were rumors about papers that we assumed were ours,” Gale, 64, a professor at the University of Bristol in England, said in an interview. “Because we were aware there were leaks, we felt there would be an alarmist, uncontrolled statement coming out in the press, so we did a rush job on it, coming out a week earlier than expected. We’ve never had to do that before.”

The stock rose 1.28 euros, or 3.1 percent, to 43.15 euros today in Paris trading. Sanofi shares have fallen 5 percent this year, compared with a 6.4 percent decline in the 18-member Bloomberg Europe Pharmaceutical Index.

Sanofi Strikes Back

Sanofi Chief Executive Officer Chris Viehbacher said June 29 after the close of Paris trading that the research published in Diabetologia, which included two other studies, was of poor quality and had “significant limitations.” The company will convene a panel of experts for advice on how to proceed with a study to address concerns about Lantus, Viehbacher said. Sanofi said its own data show that the drug is safe.

“We’ve had extensive consultations with world opinion leaders in diabetes, in oncology, in epidemiology,” Viehbacher said on a conference call. “There have been major scientific questions posed for over two decades as to the role of insulin and diabetes and obesity and cancer. All of these experts would agree, and have said very clearly, that these four studies published in Diabetologia do not even begin to answer these questions and point out significant limitations of these studies.”

FDA Questions

The U.S. Food and Drug Administration questioned whether a link between Sanofi-Aventis SA’s Lantus and cancer exists. The four studies examined one to three years of therapy, less than what is generally necessary to evaluate a link between cancer and drug exposure, the agency said in a statement posted today on its Web site. Differences among the patients, such as weight and the dose of Lantus, also may have contributed to the finding of increased cancer risk, the FDA said.

“Inconsistencies in findings within and across individual studies raise concerns as to whether an association between the use of insulin glargine and cancer truly exists,” the agency said, using the chemical name for Sanofi’s Lantus. The FDA is reviewing the new studies and data from other completed trials “to better understand the risk, if any, for cancer associated with use of Lantus.”

Modified Insulin

More than 200 million people worldwide have diabetes, according to the European Association for the Study of Diabetes. Lantus is a modified form of insulin that is used to control blood-sugar levels in diabetics who have difficulty producing the hormone naturally. The injectable therapy, approved for sale in the U.S. in 2000, was the first once-a-day form of insulin.

The German research was submitted to Diabetologia last year, Gale and Ulf Smith, the president of association, wrote in an editorial.

The study examined the medical records of more than 127,000 patients covered by Germany’s largest health insurance fund, with researchers tracking their medical history for an average of 1.6 years. The incidence of cancer rose in tandem with the amount of insulin given, regardless of the type of insulin.

While patients getting Lantus initially had fewer cancers, they were also given lower doses of the drug. When the researchers adjusted their data to take into account the lower doses, they found a 9 percent increased risk of cancer for patients getting the smallest amount of Lantus and a 31 percent increased risk for those given five times as much.

‘Notorious’ Studies

“It’s notorious of big observational studies that they are difficult to interpret,” Gale said. “At the end of the day, you have to make statistical corrections. Concerns were there was a short period of follow-up: one-and-a-half years is an incredibly short time for a cancer study. Normally cancer studies take 5 to 10 years so it’s astonishing that there should be a signal within such a short time.”

The journal’s reviewers questioned other aspects of the study, including why researchers didn’t adjust for body mass index, a gauge of obesity that is linked to cancer risk independent of insulin, Gale said.

“You will find very few observational studies which do not have serious flaws,” he said. “It’s the nature of the game.”

A special advisory group convened by the association decided that it would be premature to publish the results without first replicating the studies in other countries. They commissioned further research in Sweden, Scotland and the U.K.

German Study

“The Germany study was putting out the alarm call and we thought the other studies would provide a correction,” Gale said. “Instead of rushing into print, we got it as good as we could. We were asking these guys to do it voluntarily and confidentially. They worked very hard to get these data out as fast as they could as it’s a public health issue.”

An analysis of a Swedish patient database found a link, with those taking Lantus alone having double the risk of breast cancer. A review of a registry of diabetics in Scotland found a statistically insignificant increased risk of breast cancer, while a study of U.K. patient records found no link.

“The studies don’t prove a causal link but they do enough to suggest a causal link and proved there were more studies to be done,” Gale said. “We were worried about the story getting out in a form that would be unnecessarily alarmist so we rushed to print.”

Chasing Rumors

Sanofi’s Viehbacher said the company had been trying to chase down rumors about the research.

“We’ve certainly had a busy time here at the headquarters in Paris since really late Friday evening, when we received around one hour before publication four articles that were published in Diabetologia,” he said on the call.

Gale said he and Smith flew to Paris on June 22 to present their data to senior executives at Sanofi, allowing them time to post safety data on the journal’s Web site on June 26. The company didn’t see final copies of the studies until the afternoon of June 26, he said.

“We regretted that we could not give them longer to look at the detailed data, but the papers were only ready to go out at that time, our hand was forced by the leaks of information, and our timing gave them the whole weekend to formulate their response,” Gale said.

Ralph DeFronzo, a diabetes researcher at the University of Texas Health Science Center, raised concern that Lantus would face questions about its safety on a June 11 conference call sponsored by Credit Suisse. DeFronzo predicted an “earthquake” event that might prompt doctors to not “feel so comfortable with” the drug, according to a transcript of the call. He didn’t provide details.

DeFronzo’s Comments

DeFronzo is unavailable for comment, a spokeswoman at his office in San Antonio told Bloomberg News.

“We are in the process of reviewing the facts of this particular situation,” Mary DeLay, the chief communications officer for the University of Texas Health Science Center at San Antonio, wrote in an e-mail. “The University has a comprehensive policy regarding conflict of interest and employees are required to abide by these policies.”

DeFronzo was an investigator on a company-sponsored study of Byetta, marketed by Eli Lilly & Co. of Indianapolis and San Diego-based Amylin Pharmaceuticals Inc. Byetta, a competing diabetes treatment, stimulates the body to produce more insulin.

“This is not at all the earthquake he seemed to be talking about,” Gale said in the interview. “I suspect it was unconnected with our paper. I don’t believe he could have seen our data. The only way you find out info like that is word of mouth, he might have heard a rumor or he might have seen a paper in review, in which case he should not be talking about it.”

To contact the reporter on this story: Trista Kelley in London at tkelley2@bloomberg.net

Last Updated: July 1, 2009 11:50 EDT