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Experimental Drug Helps People Lose Weight, Quit Smoking
By RON WINSLOW
Staff Reporter of THE WALL STREET JOURNAL
NEW ORLEANS -- It sounds too good to be true. A drug developed from research into how marijuana affects the brain shows remarkable promise as a potential magic bullet against many of the major risks for heart disease.
Researchers at the annual science meeting of the American College of Cardiology here presented two large studies of an experimental drug called rimonabant, being developed by France's Sanofi-Synthelabo SA, demonstrating its ability to help people to both lose weight and quit smoking.
The drug generated the meeting's principal buzz: "It's exercise in a pill," one cardiologist quipped. The findings showed that study patients who lost weight also had significant improvement in such measures as HDL ("good cholesterol"), blood sugar and other factors that at abnormal levels are precursors to both diabetes and cardiovascular disease. The drug's primary benefit may result from its ability to reduce abdominal fat.
Rimonabant appears to "improve a whole set of cardiovascular risk factors by targeting the expanded waist line," said Jean-Pierre Despres, one of the two scientists presenting results of rimonabant studies. Dr. Despres is an expert in blood lipids at Laval University, Laval, Montreal.
Smoking and risk factors linked to obesity are the two most preventable causes of cardiovascular disease. An estimated 40 million U.S. adults smoke cigarettes. And obesity is rising at epidemic proportions in many countries.
Effective treatments against high blood pressure and LDL -- "bad cholesterol" -- are widely available. However, doctors lack medicines that offer a comprehensive approach to a cluster of factors -- including low levels of HDL cholesterol and high levels of abdominal fat -- that are known as the metabolic syndrome and predispose people to diabetes and heart disease.
Rimonabant, which is likely at least two years away from being approved for marketing, blocks targets called endocannabinoid receptors in the brain and in fat cells that are stimulated by cannabis, the active ingredient in marijuana.
As a result, the drug is already being referred to as the "munchies" pill, reflecting the widely reported observation that smoking marijuana makes you hungry. But if the results from these two studies hold up, the drug could become a major weapon against heart disease and help change thinking about weight loss.
"It's mind-boggling how this one receptor seems to be tied into all of these risk factors for cardiovascular disease," says Christopher Cannon, a cardiologist at Harvard Medical School and Brigham and Women's Hospital, Boston, who isn't involved in the study.
Sidney Smith, director of the center for cardiovascular science and medicine at University of North Carolina, Chapel Hill, said the drug could be "a very helpful development" against metabolic syndrome. But he added that "it would be a mistake for us to neglect lifestyle changes and just change to a pill."
What's more, the pill faces challenges. Both smoking and obesity are notoriously difficult to fight, and weight-loss pills have a checkered history. The fen-phen diet-pill combination was a hugely popular medicine that had to be withdrawn after heart-related side effects emerged.
Sanofi officials said they are determined to develop the medicine as a treatment for important medical conditions and not as a lifestyle drug. "This drug takes time to work," said Douglas Greene, vice president, corporate medical affairs at Sanofi. "It's not something you can take on Thursday because you're going to the beach on Saturday."
In addition, while researchers are still learning about how rimonabant works, if it targets receptors in various areas of the body, the risk increases that some of its activity will be harmful. So far, says Dr. Despres, the main side effects are relatively mild -- nausea and dizziness.
Sanofi is sponsoring seven large trials -- four in obese patients and three for smoking -- involving a total of 13,000 patients as part of its research program aimed at gaining marketing approval for the drug. If all goes well, Sanofi plans to file an application with the Food and Drug Administration and European regulators early next year, with the best-case scenario leading to approval in 2006. Sanofi's American depositary shares rose 47 cents to $34.53 in 4 p.m. composite trading Tuesday on the New York Stock Exchange.
Dr. Despres said the drug appears to target the waistline, the so-called visceral fat that accumulates in the abdomen. An emerging body of research indicates this fat is much worse for heart risk than fat that accumulates, say, in the thighs or buttocks.
"This is the form of obesity that is a time bomb for diabetes and heart disease," Dr. Despres said.
The study he headed involved 1,036 patient with body-mass indexes ranging from 27 to 40 -- people with BMIs between 30 and 40 are considered obese -- and with low-HDL cholesterol and/or high levels of blood fats called triglycerides. The patients were randomly assigned to take either a placebo or rimonabant -- the latter in doses of five or 20 milligrams -- and put on a reduced-calorie diet.
People who stayed on the high dose of the drug for the full year lost an average of nearly 20 pounds, Dr. Despres said, compared with about five pounds for those on a placebo. The five-milligram dose wasn't much better than a placebo. The weight-loss achieved with the high-dose corresponded with a 3.5-inch reduction in waistline measurement.
Nearly 75% of 20 milligram patients who completed the study lost at least 5% of their body weight, compared with 42% of those on the placebo. The 20 milligram dose was associated with a 23% increase in HDL, a 15% drop in triglycerides and improvements in other metabolic measures.
"This is not the solution to the obesity epidemic," Dr. Despres said. "That would be naive." But he said the results suggest it would be an effective strategy for helping to reduce heart risk among people who are obese.
The study on smoking enrolled 787 patients in the U.S. Robert Anthenelli, a psychiatrist at University of Cincinnati College of Medicine and leader of the trial, said 36% of those who completed the 10-week study on 20 milligrams successfully quit smoking, compared with nearly 21% of those on placebo.
Smokers who were obese lost weight while on the drug, a benefit since many people who quit smoking go back to cigarettes because they gain weight. Smokers who weren't obese didn't lose any weight, prompting researchers to suggest that people who aren't overweight but just want to lose a few pounds may not benefit.
Write to Ron Winslow at ron.winslow@wsj.com
Updated March 10, 2004
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