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The End Of Obesity As We Know It


Ever wonder why marijuana smokers get the munchies? So did a team of scientists at Sanofi Recherche lab in Montpelier, France. Fifteen years ago they began investigating marijuana's effects on the brain, including the well-known fact that cannabis makes users hungry. "We set out to try and create an anti-marijuana," a drug that could suppress appetite by blocking the same switch in the brain activated by cannabis, says Gérard Le Fur, senior executive vice-president and board member at newly merged French pharmaceutical giant Sanofi-Aventis (SNY).

They succeeded beyond their wildest dreams, discovering a medicine that not only helps people lose weight but also shrinks abdominal fat, helps people stop smoking, improves cholesterol levels, and helps patients better regulate blood sugar.

Talk about a potential blockbuster. Initially, though, Sanofi will take it slow. It will seek approval of the drug, Acomplia, in Europe and the U.S. by the second quarter of 2005 as a treatment for just two of the conditions: obesity and tobacco addiction. Because patients in Acomplia trials regained weight after stopping treatment, the company hopes regulators will approve it for long-term use.

Researchers say side effects such as nausea and depression are relatively minor and short-lived. But as the first in an entirely new class of drugs that affect a pleasure center in the brain, even the slightest hint of psychiatric side effects may lead regulators to demand more long-term safety data, potentially delaying Acomplia's launch beyond 2006 as planned. Still, Sanofi-Aventis is confident that the drug's impressive efficacy will assuage any such worries. "It's a product that takes aim at two of the great maladies of the century," says Sanofi-Aventis CEO Jean-François Dehecq.

DEPRESSION QUESTION

Acomplia is the first in a new class of compounds under development to block receptors found in the brain and in fat tissue known as cannabinoid type 1 (CB1). These receptors control hunger and tobacco addiction. Chronic overeating and smoking sends them into overdrive. Blocking the CB1 receptors dramatically reduces such cravings. Results of a two-year clinical trial in the U.S. showed patients given Acomplia lost an average of 19 pounds, compared with five pounds for patients given a placebo. Those on Acomplia also reported higher levels of HDL, the good cholesterol, lower levels of triglycerides, and improved sensitivity to insulin. All are important in keeping heart disease at bay. "This could be a paradigm-shifting drug," says Dr. Louis J. Aronne, president of the North American Society for the Study of Obesity.

The market potential is huge. More than a third of Americans are clinically obese, or 30% above their ideal body weight. And it's not just an American phenomenon. Dr. Gbola Amusa, senior research analyst for Sanford C. Bernstein & Co. in London, estimates that as much as 10% of health-care costs in other industrialized countries are related to being overweight. The two leading obesity drugs, Xenical and Meridia, have unpleasant side effects such as diarrhea or high blood pressure, so analysts think Acomplia will quickly win market share if approved. Amusa estimates sales will reach $5.6 billion a year by the end of the decade.

Accomplia's real potential may go well beyond eating and smoking. The company hopes it will also become the first drug approved for the treatment of metabolic syndrome, a combination of abdominal fat, high blood pressure, high blood-fat levels, low levels of HDL cholesterol, and high blood-sugar levels, all of which contribute to cardiovascular disease. "This is not just a diet drug but a significant advancement in cardiovascular treatment," says Amusa.

Still, there is reason for caution. There was a noticeable rate of withdrawal in Acomplia's clinical trials due to depression. Researchers involved in the trials say that might be because people taking the drug went in with unrealistic weight-loss expectations or were more susceptible to depression to begin with.

Either way, there are no long-term studies yet of the effects of interfering with this part of the brain. And given the increased regulatory scrutiny on new drugs after the Vioxx and antidepressant controversies, the company may find it needs to submit more data than anticipated to secure approval. Is Acomplia too good to be true? "There has never been a diet drug approved that has had more benefits than risks," says Dr. Larry D. Sasich of Public Citizen's health research group in Washington. Dehecq and Le Fur are determined to prove doubters like him wrong.

By Kerry Capell in London, with Carol Matlack in Paris


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