During the 29th annual Great American Smokeout on November 17, thousands of the 44.5 million U.S. smokers will try to quit - and many will fail. But as early as next year, they can look forward to a boost from new smoking cessation pharmaceuticals. Designed with a thorough understanding of nicotine's effect on the body, these drugs and vaccines appear promising, but "the big question is whether they will outperform nicotine patches and gums," says Dr. Scott Leischow, former chief of NCI's Tobacco Control Research Branch.

"We know that, if used properly, nicotine replacement helps people quit," Dr. Leischow continues. "But real-world use doesn't lead to the same kind of quit rates we see in placebo-controlled clinical trials."

A recent meta-analysis found that only 7 percent of smokers who tried nicotine replacement quit for good. Overall, only 2.5 percent of smokers who try to quit each year succeed. "That's too low," says Dr. Leischow, who left NCI this month to join the Arizona Cancer Center as deputy director. "There really is a significant need for new medications."

About 21 percent of Americans over the age of 18 smoke regularly. That's half of the rate seen in the 1960s, but still far short of the 12 percent goal set by the Healthy People 2010 initiative. About 180,000 people died from smoking-related cancers in 2004.

The drug rimonabant (Acomplia), developed by Sanofi Aventis, is closest to market. Earlier this year the company reported a 36-percent quit rate among 787 U.S. smokers in a phase III clinical trial. About 20 percent of the smokers quit when given placebo. The company expects FDA approval in 2006.

Sanofi is also seeking FDA approval to market rimonabant as a weight-loss drug. Trial data show that the drug does help smokers keep off extra pounds, a second incentive for those who want to quit but fear weight gain, notes Dr. Leischow.

Rimonabant is the first drug to target and block cannabinoid receptors in the brain. These receptors reinforce pleasurable behaviors, such as smoking and eating, and stimulate the dopamine reward circuit. Deeply connected to memory, emotion, and motivation, the circuit is disrupted in people with addictions.

Several other types of brain receptors play key roles in the reward circuitry, a finding that has led researchers to the antinicotine potential of two other brain drugs already on the market, selegiline (Eldepryl) for Parkinson's disease and moclobemide (Manerix) for depression. Both are in clinical trials for smoking cessation.

Pfizer's new drug, varenicline, takes another tack: mimicking nicotine to block its effects without activating the reward circuit. According to company data released in June, 48 percent of smokers who took varenicline for 7 weeks quit, compared with 17 percent on placebo. The trial of 500 smokers also found a 33-percent quit rate among those who took buproprion (Wellbutrin, Zyban), a drug marketed for depression and smoking cessation since 1997.

Varenicline works much like the natural compound cytisine, which is sold in Eastern Europe without prescription. Safety testing of the drug is under way in Poland.

Three other companies are ramping up for phase III trials of nicotine vaccines. Although still 5 or 6 years from market, according to Dr. Frank Vocci, director of the National Institute on Drug Abuse's Division of Pharmacotherapies and Medical Consequences of Drug Abuse, the vaccines intrigue researchers for their potential as treatment and prevention agents. Instead of boosting the immune system to fight off pathogens, nicotine vaccines stimulate antibodies that bind to and inactivate nicotine before it acts on the brain.

In a phase II trial, counseling plus the Nicotine-Qbeta vaccine, developed by Swiss company Cytos, helped 40 percent of smokers quit for at least 6 months; counseling plus placebo led to a 31-percent quit rate. In another phase II trial, NicVAX, developed by Nabi, helped 33 percent of smokers quit, compared with 9 percent for placebo.

Despite the promise of the new approaches, Dr. Leischow cautions smokers and health care professionals to avoid pinning all of their hopes on new medications. "Tobacco use is a true addiction," he says. "We know that motivation combined with counseling and medications is the best approach."

Smokers who want to quit should call 1-800-QUIT-NOW or go to www.smokefree.gov.

By Brian Vastag