It's a crisp morning in early February, and Barbara Aukland has arrived at the Scripps Clinic's Center for Weight Management to get a checkup. She has been participating in a clinical trial for a new weight-loss drug, Contrave, for the past year. The drug was developed by Orexigen Therapeutics (OREX), one of 20-odd companies racing to develop new obesity treatments. Orexigen, it turns out, is based across the street, in a small office park in this neighborhood of northern San Diego.

Contrave is part of the next generation of obesity treatments now making its way through the pharmaceutical industry's pipeline. About a half-dozen of these new drugs are in critical phase III clinical trials—the final stage of human testing that's required for product approval from the Food & Drug Administration. The market is wide open: Of the $33 billion a year Americans spend on weight-loss products, only $200 million goes to prescription drugs. That's because most of the drug options out there only help people lose 5% to 8% of their weight, and they can cause side effects like jumpiness, insomnia, and upset stomach. Contrave is a combination of an antiaddiction medication and an antidepressant, which together seem to reprogram the way the brain thinks about food. Tiny Orexigen, which is five years old and has yet to get any product on the market, will spend the next two years trying to prove Contrave works safely.

Trial Regimen

Aukland's foray into obesity research began in late 2006, when she saw a news report about Orexigen's trials. At the time, Aukland was carrying 270 pounds on her six-foot frame. As the manager of a cat shelter, part-time student, and single mom, she struggled to find the energy to get through the day. "I had chronic hip and foot pain," says Aukland, 40. "I'd lie in bed and cry." Volunteering for the study wasn't an easy decision: She knew there was a 50/50 chance she would be taking a placebo. Plus as part of the study, she would have to exercise and participate in a support group. Still, she signed up.

Orexigen's trial is unusual in its complexity. Like most weight-loss studies, it is double-blind, placebo-controlled, meaning the company, doctors, and patients won't know who was actually on the drug until the trial ends. But some parts of the trial, including the one Aukland is participating in, also include intensive behavioral-modification programs. Patients are put on strict diets, and given round-the-clock access to dieticians who act as coaches. They meet with other patients in groups, creating Alcoholics Anonymous-type interactions meant to encourage patients to stick with the program. And they are hounded about exercising until they finally break down and do it. For Aukland, that was the hardest part. "They told me to try a stationary bike for 10 minutes, three times a week," she recalls. Once she realized it wasn't aggravating her painful joints, she kept riding, and today works out six days a week for at least 45 minutes. "I started loving it."

Additive Effects of Behavior Modification

The behavior modification part of the studies isn't likely to make the difference between an FDA approval and a rejection for Contrave. But it could very well determine how the label reads if it's approved, and that could make a competitive difference in the marketplace. In early trials, Contrave appeared to produce around 10% weight loss on its own. If diet and exercise add another 5% to that, Orexigen may be able to claim significant double-digit weight loss for an overall program including the drug, plus diet and exercise. "On one hand, it's important for us to know the effects of drug when used in isolation," says Dr. Gary Tollefson, chief executive officer of Orexigen. "But from a real-world perspective, you also want to know the additive benefits of these nonpharmaceutical interventions."

The coaching and support groups may help keep patients in the trials, too. That's important: The dropout rate in some weight-loss trials in the past has exceeded 50%, making it hard for companies to explain to the FDA what's going on with the patients who disappear. Many of the weight-loss drugs in development, including Contrave, act in the brain, raising the risk of psychiatric side effects such as depression. Companies that cannot define why some patients bail out could create a perception that the side effects were far worse than reported. Orexigen makes a deal with patients who join the behavior-modification arm of the Contrave studies: Even if they want to stop taking the drug, they can stay with their support groups and coaching. "That way, they're retained in the study for observation, even though they may no longer be taking the drug," says Tollefson, a psychiatrist by training who worked for Eli Lilly (LLY) before joining Orexigen in 2005.

When it comes to diet and exercise, Aukland has a strong ally in her doctor, Ken Fujioka, who runs clinical trials for several companies developing new obesity treatments. Fujioka struggled with his weight as a young man, at one point hitting a high of 225 pounds and suffering high blood pressure as a result. "Being a 30-year-old male with hypertension is just not normal," says Fujioka, now 54. He got down to his current weight of 170 by sticking to a low-fat diet, replacing one meal a day with a weight-loss shake, and exercising. Marrying a dietician helped, too, he jokes. "It's not easy. I literally have to put in my schedule every day when I'm going to exercise and what I'm going to eat." He is one of several obesity doctors who helped Orexigen design the behavior-modification arm of the study. Because it's so intense, he predicts: "They're going to get 5%-plus weight loss in the placebo group."

Safety Concerns

Aukland still doesn't know whether she's actually on Contrave, but her results so far make her suspect she is. She still vividly remembers taking her first pill in the early morning of May 25, 2007. "Usually by 9 [a.m.], I'm so ravenous I eat everything I can find at work. But I didn't feel my cravings," she recalls. For lunch, she ate a salad. "I felt like my priority was no longer 'what will I eat?'" Aukland has lost more than 60 pounds in the trial, and is now down to 202.

Orexigen has a long way to go before it proves to regulators and investors that Contrave has the makings of a hit. If all goes well, Tollefson says he'll file for approval in the last quarter of 2009. In the meantime, the challenges of proving an obesity drug is safe are clearly weighing on the minds of investors. Orexigen went public last May at $12 a share, and saw its stock spike at about $18 before falling to a recent $12.50. Tollefson understands the hesitation and knows what he has to do over the next couple of years. "The FDA has indicated to us that they see obesity as a significant public health concern. But we need to prove that there are no long-term, serious safety risks that would outweigh the benefits of weight loss."