Weight Loss CANNABINOID RECEPTOR-BLOCKING Agent Nearing FDA Approval

New Drug Helps Achieve Long-Term Weight Loss and helps with smoking cessation. Subjects taking the drug lost an average of 19 pounds. A novel drug that dampens the brain’s craving for flavorful foods and nicotine helps people lose weight—and keep it off over the long term.

Unlike other medications that often lose effectiveness after a few months of treatment, rimonabant (Acomplia, Sanofi-Aventis) helped patients maintain weight loss during a 2-year follow-up period, according to Xavier Pi-Sunyer, MD, chief of endocrinology at St. Luke’s-Roosevelt Medical Center in New York City and lead investigator of the Rimonabant in Obesity (RIO)-North America trial.

"This is a very interesting drug that works in a very different system," says Pi-Sunyer. "It’s very promising."
Rimonabant is the first of a novel category of drugs known as selective cannabinoid (CB) receptor blockers. The recently discovered endocannabinoids are a system of receptors and chemical messengers believed to play a role in weight regulation and lipid metabolism.

CB receptors in the brain stimulate the ingestion of palatable foods, a mechanism thought responsible for the "munchies." Activation of the CB system in peripheral tissues has been shown to stimulate fat accumulation.

RIO-North America is a multicenter trial of 3,040 subjects from throughout the U.S. and Canada. Participants were randomized to receive either 5 mg or 20 mg of the drug in a daily dose. For comparison, at the end of 1 year, subjects on rimonabant were re-randomized to receive either a placebo or the same dose of the drug.

In addition to the medication, subjects were instructed to reduce their food intake by 600 calories per day.

At the end of two years, more than 60% of those on the higher dose of rimonabant lost more than 5% of their body weight, and 33% of subjects lost more than 10%. Subjects taking the drug lost an average of 19 pounds, compared with 5.1 pounds in the placebo group, and 3.1 inches on their waistlines.

Aside from the weight loss, those on the higher dose of rimonabant had their high-density lipoprotein (HDL) level increase by 24.5%, compared with a 13.8% rise in the placebo group. Triglycerides were reduced by 9.9% among those taking the higher dose of rimonabant, compared with 1.6% among those receiving placebo.

About 13% of participants stopped taking rimonabant, compared with 7% among those who were given a placebo. Side effects of the higher dose of drug include a slightly increased incidence of depression, anxiety, irritability, and nausea.

Other experts greeted the findings of RIO-North America with guarded optimism. Rimonabant is "almost too good to be true," says George Bakris, MD, of Rush University Medical Center, Chicago.

However, more study is required to determine how rimonabant works and the long-term effects it may have on the body. The drug "blocks pleasure centers in the brain," says Bakris. "It works at a very deep level, and we need to understand what other effects it may have."

Clinical trials with rimonabant also appear to help people quit smoking cigarettes and avoid the excess weight gain that often plagues ex-smokers. The drug nearly doubles a person’s chance of successful smoking abstinence while avoiding weight gain, according to a phase III trial reported at November’s North American Association for the Study of Obesity (NAASO) Annual Meeting in Las Vegas.

In a study presented as part of a joint effort by NAASO and the American Diabetes Association, 787 subjects were randomized to receive placebo or rimonabant in either a 5-mg or 20-mg once-daily oral dose. At the end of the 10-week treatment phase, almost 28% of those who took the 20-mg daily dose stopped smoking for at least a month, compared with 16% of those in the placebo group. Those who quit smoking gained an average of 1 pound, compared with 6 pounds noted in the placebo-treated subjects who quit smoking.

Results of two other phase III clinical trials of rimonabant in smoking cessation are still pending, according to the company. Aside from RIO-North America, rimonabant is being studied in a second phase III trial for the treatment of obesity and two phase III trials for the treatment of high lipids.

Pi-Sunyer says that data from the RIO-North America trial are being prepared for publication.

Sanofi-Aventis is expected to file a new drug application for rimonabant during 2005, and the drug could be on the market the following year.

Research presented at the November American Heart Association Scientific Sessions in New Orleans.

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