Take Two of These, and Go to the Gym

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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."

Weintraub is a senior writer for BusinessWeek's science and technology department.