Source: New York Times
Date: 7 September 2004

Diet Pill Was a Driving Force
in French Drug Merger


packet of rimonabant /Acomplia
FRANKFURT, Sept. 6 - The year's big drug-industry merger may turn out to be about using marketing muscle to fight fat.

In April, when the French drug company Sanofi-Synthélabo vanquished all other players with a long-shot takeover bid for a much larger French-German rival, Aventis, many commentators focused on the role of politicians in Paris.

The French government, determined to create a national champion in pharmaceuticals, all but stage-managed the deal, which created the world's third-largest drug company, after Pfizer of the United States and GlaxoSmithKline of Britain.

But last week, with Sanofi's release of promising test results for a new drug that fights both obesity and smoking, it became clear that the $65 billion merger was about more than Gaullist bragging rights.

The drug, which is known as rimonabant and will be marketed as Acomplia, was in Sanofi's pipeline long before the merger, and the company - now called Sanofi-Aventis - says that it could become one of the industry's once-in-a-decade blockbusters. Many doctors and analysts agree. While doubters note that other promising obesity drugs have proved disappointing and that the company has not completed some crucial tests, Sanofi plans to file for regulatory approval early next year in the United States and Europe. If regulators sign off, the company hopes to put the drug on the market in 2006.

With obesity affecting 100 million people in the United States and Europe, analysts say such a drug could generate up to $6 billion a year in sales by the end of the decade. That would put Acomplia on the top shelf of the medicine cabinet, with the likes of Pfizer's Lipitor and Merck's Zocor cholesterol treatments.

"We Europeans, whenever we came to America, we always noticed the enormous number of obese people on the streets," said Jean-Pierre Bassand, a cardiologist who chaired the meeting of the European Society of Cardiology in Munich last week, where the results were presented.

"But now obesity is spreading all over the world, like wildfire," Dr. Bassand said. "Fifteen percent of French adolescents are obese. This is potentially a major breakthrough in treating this condition."

The data presented in Munich last week were based on interim results from a planned two-year study that is not yet complete. But the figures were striking - and in keeping with the outcome of an earlier trial in the United States. More than 1,500 patients treated daily for one year with a 20-milligram dose of Acomplia lost an average of 8.6 kilograms (19 pounds) and reduced their waistlines by an average of 8.5 centimeters (3.5 inches). The drug also increased levels in the blood of HDL cholesterol - the so-called good cholesterol - by an average of 27 percent.

Doctors taking part in the trial say they are particularly excited by the drug's shrinking effect on waistlines.

"We know that the deep abdominal weight in your belly is the dangerous fat that leads to heart disease and diabetes," said Luc van Gaal, a professor of medicine at the Antwerp University Hospital in Belgium.

What makes Acomplia even more tantalizing is a clinical trial in the United States indicating that the drug, taken in daily 20 milligram doses, can nearly double a patient's odds of stopping smoking. Moreover, those who did quit gained little weight afterward - avoiding a common aftereffect that has been a disincentive for smokers to give up cigarettes.

"It gives us another bullet in the gun," said Robert M. Anthenelli, an addiction psychiatrist at the University of Cincinnati and an investigator in the smoking trial. "It is totally unlike other medicines."

But if Acomplia's early promise eventually translates to a marketable drug, then selling it - especially in the huge American market - will demand a much larger sales force than Sanofi could have fielded before the takeover. Currently, for example, the company relies on Bristol-Myers Squibb to market two of Sanofi's best-selling drugs in the United States - the blood-thinner Plavix and the blood pressure pill Avapro. But the alliance has a steep price: Bristol-Myers reportedly pockets about half the drugs' American profits.

Through the merger with Aventis, with its large stateside sales force, Sanofi will be able to market Acomplia by itself, retaining all its sales and profits. Although the market motive was scarcely mentioned by Sanofi's executives when they announced the bid, it turns out to have been a driving force behind the takeover.

"We needed more muscle to sell such a product," Gérard Le Fur, the company's chief scientist and No. 2 executive, said in a telephone interview from Paris. "We knew the first results of the trials back in January. Knowing that, it was more or less linked to the deal."

To be sure, Dr. Le Fur said, this was not the only reason to acquire Aventis. In a rapidly consolidating industry, Sanofi needed to become bigger - a need underscored by the potential loss of its patent on Plavix, which is being challenged in North America by generic-drug makers in a legal case likely to be decided next year. And nobody is revising the judgment that Sanofi benefited from old-fashioned industrial policy on the part of the French government, which maneuvered to stop the Swiss drug maker Novartis from bidding for Aventis.

But the tremendous promise of Acomplia, especially in the United States, adds a twist to the story. France's newest champion, it appears, will stake its claim to industry leadership in no small part by helping bulging Americans to reduce their waistlines and quit smoking.

The obesity trials in Europe and the United States turned up some evidence of side effects, including nausea and diarrhea. But doctors involved in the tests said the effects were generally mild and transient.

The two main anti-obesity drugs already on the market in the United States, Meridia from Abbott Laboratories and Xenical from Roche Laboratories, have been hampered by more troublesome side effects: high blood pressure in the case of Meridia, and soiling oneself in the case of Xenical.

Obesity experts describe the medications and a third one on the market, the generic drug phentermine, as only moderately useful. People on Meridia tend to lose 10 to 14 pounds in six months, and those on Xenical, 13 pounds in a year. Phentermine is approved only for short-term use - a few weeks at a time - and most people lose less than a pound a week.

People often regain weight quickly once they stop taking the drugs. That is why some skeptics say that only longer-term studies can determine whether the preliminary results of Sanofi's Acomplia trials will translate into lasting weight loss.

Rimonabant works by blocking a certain kind of receptor, or trigger, that governs food intake and tobacco dependency. The receptors are in the brain, but also throughout the body, notably in fat cells. Among other things, they account for the sudden surge of appetite felt by people who smoke marijuana.

Doctors say that this system of receptors is disrupted by tobacco and by chronic overeating. The drug restores the balance in the system, reducing dependence on tobacco and suppressing appetite. Since many smokers are also overweight, Acomplia could end up doing double duty.

"Smoking and obesity are the No. 1 and No. 2 killers in the Western world," Dr. Anthenelli, the addiction specialist, said. "This one medication has the power to combat both conditions, and that explains the excitement."

He cautioned, though, that the smoking trial, involving 787 patients, lasted only 10 weeks. Results from a six-month trial are not yet available. For that matter, Sanofi must still analyze the second year of data from the obesity trial that was presented in Munich last week. The results will probably be presented at the meeting of the American Heart Association in November. In the meantime, some doctors are skeptical.

"I want to know what happens after the patients stop taking the drug," said Kevin Wei, a cardiologist at the University of Virginia. "Do they have a massive rebound in weight, or do they manage to keep it off? To counteract the effects of obesity, you need to keep the weight off for years or even decades."

Sanofi said it was confident that its two-year trials would show that the drug's effects were lasting.

Even if Acomplia is eventually approved for sale, other variables could determine how profitable the drug will be. In the United States, the Food and Drug Administration treats existing anti-obesity medications as lifestyle drugs, which typically makes them ineligible for reimbursement under health-insurance policies. That financial consideration has helped limit their sales.

Dr. Bassand, however, said Acomplia would probably be prescribed only to patients whose weight put them at risk of cardiovascular disease or other illness. "This will not be a Thursday pill for the Sunday beach," he said, alluding to the array of over-the-counter medications for quick weight loss.

Noting that obesity was "more than an epidemic" in the United States, Dr. Le Fur of Sanofi said he was confident that the drug would be approved by the F.D.A., and that it would be reimbursed under many health insurance plans.

Sanofi will not estimate the sales potential of Acomplia at these early stages, or predict how the sales may be distributed globally. But analysts figure the drug would derive 60 percent of its sales in the United States and 40 percent in Europe.

Marc Booty, a pharmaceutical analyst at Commerzbank Securities in London, said that if Sanofi could sell Acomplia to 5 percent of the obese population in 2010, at a price equal to that of standard anticholesterol drugs - which can range from about $2 to $4 a pill - it would generate 5 billion euros, or $6 billion, a year.

To avoid giving away a chunk of those sales, however, Sanofi would have to market the drug without any partners, which could prove challenging for its existing United States sales force of 2,500. Once its merger with Aventis is complete by year's end, however, Sanofi will pick up 4,500 additional sales representatives in the United States - giving it a force similar in size to those of Merck, Novartis and AstraZeneca.

"They've been very good at developing drugs, but they haven't had the clout to market the drugs," Mr. Booty said. "This would give them a very credible voice in the United States."

Dr. Le Fur agrees that a muscular American presence is critical to the drug's future. But for reasons perhaps having to do as much with politics as with profits, he is careful not to dwell too much on overweight Americans. "We have big bottoms in Europe, too," he said.

Denise Grady contributed reporting for this article.

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