The heavy road to a weight-loss drug

(Fortune) -- The market potential for a weight-loss wonder drug is enough to make any Big Pharma CEO salivate. Trouble is, safe and effective fat-fighting treatments are a Holy Grail that continues to elude pharmacological researchers.

The reason, according to some medical experts? Pharma companies - and overweight individuals - are approaching the problem all wrong. First, consider the facts: The United States is the world's wealthiest and largest market for pharmaceuticals; it is also the fattest nation on Earth. Corpulence is fast becoming a global epidemic as well. The World Health Organization estimates that the worldwide number of obese adults could grow from 400 million today to roughly 700 million by 2015.

Effective anti-obesity drugs continue to elude Big Pharma, despite several high-profile attempts.

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All of this means that a growing portion of the world's population is at risk of developing heart troubles, diabetes and other recurring ailments. Although several obesity treatments are already on the market, many come with long lists of unattractive side effects. They generally possess questionable efficacy, and fail to produce long-lasting weight loss.

As a result, the current global market for obesity drugs - a little more than $1 billion a year - is much smaller than it could be. That number could grow significantly if Big Pharma were to develop better alternatives. That's the impetus, no doubt, behind the announcement this week that Pfizer (Charts, Fortune 500) and Bristol-Myers (Charts, Fortune 500) plan to collaborate on research into metabolic disorders including obesity and diabetes.

Both companies are in desperate need of a big-selling drug, since each has a mega-seller that will soon face generic competition. Pfizer's cholesterol pill, Lipitor - the biggest blockbuster ever, with $12.9 billion in sales last year - could lose patent protection as soon as 2010. And Bristol-Myers's blood-thinner Plavix, with $6.3 billion in 2006 revenues, is set to follow suit in 2011.

The two companies are treading in potentially lucrative, but dangerous, territory. Many a drugmaker has tried and failed to develop and market weight-loss medication. Most recently, French pharma giant Sanofi-Aventis, after creating what it considered to be an elegant solution, saw its appetite-suppressant, Acomplia, rejected by a U.S. federal advisory committee last June. (Sanofi had previously gained approval to sell Acomplia in Europe.)

And of course, medical history is littered with a litany of would-be slimming products that have received FDA rejections and worse. Two of the category's current best-sellers, Roche's Xenical and Abbott Laboratories's Meridia, carry long lists of uncomfortable side effects. Xenical, for instance, causes some patients to lose control of their bowel movements. Famously, in 1997, the FDA took Wyeth's (Charts, Fortune 500) fenfluramine (known as fen-phen) off the market after several patients developed heart complications. The ensuing product liability litigation cost more than $15 billion.

The challenges involved in developing a good weight-loss drug are myriad. There are essentially three types of fat-fighting medications today: Those that cause the body to absorb less fat; appetite suppressants; and another group that speeds the body's metabolism, causing it to burn fat faster. "Both mechanisms come with guaranteed side effects," says Dr. Paul Shekelle, a general internist who has reviewed all the currently marketed anti-obesity drugs to help set the American College of Physicians's treatment guidelines.

The side effects, says Shekelle, aren't worth the benefits. "Drug therapy has been disappointing, with weight-loss over a year of just a few pounds for the average patient. That's not going to get someone 30 to 40 pounds overweight interested."

Dr. Robert Lustig, a pediatric endocrinologist at the University of California/San Francisco School of Medicine insists that weight loss is more complex than current thinking allows. For instance, he points out that the body puts up natural defenses against weigh loss. "Our bodies are smarter than we are," says Lustig. "When patients are eating less, the body ratchets energy expenditure down, because it knows it's being starved. That's why you see rapid weight-loss over the first four to six months of drug treatment, then a plateau."

Lustig has harsh words for the current approach to Big Pharma's war on fat. "Too many obesity researchers think obesity is one problem," declares Lustig. "But obesity is not a disease or a behavior. It's a phenotype (a trait or characteristic present in a subset of the population), which is a manifestation of many things. We need personalized diagnosis and treatment targeted to the individual patient. There will never be a one-size-fits-all solution. I wish the drug companies understood this."

Pfizer and Bristol-Myers's collaborative effort isn't a so-called "personalized medicine" approach, but it is a significant departure from current obesity treatments. The project will look into "DGAT-1 inhibitors", a set of investigative compounds that seek to restraining an enzyme critical to fat creation and storage. Early studies suggest that DGAT-1 inhibitors have potential to treat obesity and diabetes. But DGAT-1 is still in the earliest of research phases. Even if the first to complete the race is bound to find a pot of gold, the road ahead remains long and hazardous.