One pill to make you smaller?

For an activity that seems to come so naturally to so many Americans, getting fat is actually quite complicated. Not surprisingly, then, so is developing a pill that will help reverse that process.

Day after day, the appetite must be energized and the urge to eat activated -- frequently, and for the right foods. These foods must be eaten in volume, digested and rendered into usable form as fuel. Energy used in daily activity must not exceed available stores. And unused calories must be deposited as love handles, thunder thighs, double chins and pot bellies.

In principle, there’s good news in that calculus. Disrupt that complex process at any step along the way and -- voila! -- the obese patient should begin inching his or her way toward a healthy weight. In the multibillion-dollar sweepstakes to discover or develop an effective medication to combat obesity, scientists and drug makers have many points to target.

For those awaiting weight-loss help from a physician’s prescription pad, the result is a panoply of candidate medicines.

Since 1997, the FDA has approved only two weight-loss medications -- sibutramine (marketed as the prescription drug Meridia) and orlistat (marketed as the over-the-counter fat-blocker Alli). PhRMA, the drug manufacturers’ trade association, counts about 35 more candidates under development -- from the embryonic to the nearly hatched. Many are in wide use to treat other conditions, including epilepsy, vertigo and high blood pressure. Some are variants of psychiatric drugs that are known to have weight loss as a side effect. A few are novel agents that may reverse weight gain -- and some of its medical consequences -- in ways never tried before.

Ken Johnson, senior vice president of PhRMA, says that drug developers and manufacturers are scrambling to find ways to lessen the health effects of obesity. Johnson underscores the importance of proper diet and lifestyle management in weight reduction and disease prevention. But, he adds, “Several new treatments in the research pipeline . . . may help.”

Complex challenges

But the complexity of becoming overweight poses remarkably steep challenges to drug developers. With so many systems at work in the fat-making process, different people climb the BMI charts for different reasons.

A sweet tooth might be one person’s biggest vulnerability. An inability to push the plate away -- say, because of inattention to feelings of fullness -- might be another’s. A third might wring every calorie from food consumed, quickly storing the excess as fat.

In short, there are many different ways to gain weight and, likely, as many ways to lose it. And the pill that will work for one overweight patient may be no more effective than a sugar pill for another. There simply is no magic bullet, experts say.

Even if you could treat obesity one patient at a time, fighting fat is tough. The brain, endocrine system and gut work in close coordination to extract energy from food, store fat deposits and -- most important -- protect those energy stores from going, or staying, away.

With the neurological, metabolic and digestive processes so closely intertwined, it’s hard for a pill to fool one system without another stepping in to preserve a person’s body mass. Cap the sweet tooth and the engine may slow to resist the loss of weight. Rev up the fat-burning engine, and the “I’m full” light may take longer to come on. Tinker with the brain’s reading of fullness sensations and the body’s system of transporting fuel to organs could short-circuit.

“What happens when you mess with one of them is that the others sort of compensate,” says Barbara Corkey, a biochemist and director of Boston University’s Obesity Research Center. “That’s why things so often don’t pan out.”

The reason the brain has so many ways to bypass whatever targets you’re hitting is because fat has a survival value,” Corkey adds. “Something in your system fights to regain any weight that is lost.”

To circumvent the human body’s guerrilla tactics against weight loss, scientists and drug developers will need to be crafty or lucky, experts say. They will need to find a mechanism that, when manipulated, will allow weight loss without alerting the body’s forces of weight-preservation. Or they will have to combine forces -- devise combination therapies -- so that every end run against weight loss is denied.

“I don’t think money is going to be enough” to crack the problem of obesity by pharmacological means, says Mike Cawthorne, director of metabolic research at the University of Buckingham’s Clore Laboratory. “Fundamental research, insight, brilliant chemists and probably most of all, a sleight of luck will be necessary. And we will need to use a combination of drugs, in part to block the redundancy in the system.”

In the pipeline

It’s probably just as well, then, that the field of candidate drugs is so crowded and diverse. That field includes drugs that influence signaling processes in the brain, drugs that manipulate the way energy is processed in the gut and organs, and drugs that alter the body’s energy use and storage.

* The most imminent prospect is Acomplia, also known by its chemical name rimonabant, the subject of an FDA advisory panel deliberation June 16. Along with several of the candidate drugs in the research pipeline, rimonabant suppresses the activity of a group of neurons active in the hypothalamus called cannabinoid receptors.

By quieting these brain cells -- which help drive arousal and pleasure-seeking behavior such as feeding -- rimonabant appears to quiet the appetite. It also has been found -- likely by influencing other cells in the hypothalamus -- to rev up the body’s calorie-burning engine.

In a yearlong trial in Europe, dieting subjects on rimonabant lost almost four times as much -- an average of about 14.6 pounds -- as those taking a placebo. On average, it reduced subjects’ waist circumferences, improved cholesterol levels and reduced insulin resistance.

But the drug also appeared to double rates of depressive symptoms and suicidal thinking -- a possible side effect of the medication’s intended dampening effect on appetite and arousal. In June 2007, that finding prompted the FDA’s advisory committee to reassess the drug’s risks and benefits and to send rimonabant’s maker, Sanofi-Aventis, back to conduct additional research on rimonabant’s safety.

At least three of the candidate drugs making their way through the FDA’s approval process affect weight loss by manipulating this unique class of neurons. But many others target other cells in the hypothalamus, the nether region of the brain that processes many of the primitive drives -- to self-comfort with cheesecake or drink to excess -- that tend to get humans who live in a world of plenty into dietary trouble.

* Lorcaserin, another drug candidate in the final stages of clinical trials before FDA consideration, would increase the availability of serotonin -- the neurochemical boosted by many antidepressants -- in the hypothalamus. The result appears to be appetite suppression and a greater feeling of satiety, as well as changes in metabolism that reduce some of the hallmarks of metabolic syndrome, which often precedes obesity-related diabetes.

* A combination of the anti-alcoholism drug naltrexone and the antidepressant bupropion, called Contrave, appears to amp up satiety signals from the brain and calm cravings.

* An Israeli company is exploring the fat-fighting properties of an anti-vertigo drug long used in Europe and elsewhere. The drug, called Histalean, works on the brain’s histamine system and appears to suppress the impulse to eat fatty foods as well as to increase the body’s energy expenditure. Though Histalean has been found to have modest effects in broad populations, it seems to work more robustly for women younger than 50.

* The high blood pressure drug Telmisartan, in early trials, appeared to prevent the development of belly fat and reduced early signs of metabolic problems that can lead to diabetes. Another drug used as part of the “morning after” pill mifespristone also has been found to curb some subjects’ penchant for laying down fat.

Side effects

Drugs that target the brain to promote weight loss have two potential weaknesses. For starters, because they act on a complex organ with many other functions, these drugs can trigger a wide array of unforeseen side effects. Second, scientists increasingly suspect that the brain is not the controller of appetite-related signals, but a switching station for them; if that’s the case, then drugs that work on the brain are more easily circumvented by the body’s natural tendency to hold onto or regain fat.

In the long run, scientists say, a safer and more direct route to inducing weight loss might be through a patient’s gut and the peripheral tissues -- the pituitary gland, pancreas and fat stores -- that are involved in metabolism. Those increasingly are the targets for weight-loss drugs further out on the horizon.

These medications might try to mimic the positive effects of bariatric surgery. When a patient’s gastrointestinal tract is altered, federally sponsored studies suggest, the effect is greater than just a shrinking tolerance for food intake: Appetites contract, food cravings abate, metabolism shifts upward and many of the early signs of heart disease and diabetes improve dramatically.

“It’s more than just a plumbing issue: The effects are in excess of what might be predicted by virtue of what’s been changed,” says Columbia University’s Dr. Rudolph Leibel, a leading obesity researcher and co-director of the New York Obesity Research Center. “If we knew what it is that blunts regain in a surgically treated patient, that would be something interesting to pursue.”

The result of that thinking is a crop of drug prospects that would act on the body parts -- the pituitary gland, gastrointestinal tract, pancreas and stores of fat -- that produce peptide hormones involved in digestion and metabolism.

Early research suggests that drugs that manipulate the production and circulation of these hormones may have wide-ranging effects on a patient’s appetite, energy use and fat deposition. In the process, they may curb some of obesity’s downstream medical consequences, including insulin resistance, dangerous cholesterol levels and inflammation.

Further, Leibel says, researchers have begun to shift their attention to the most daunting challenge of the nation’s obesity epidemic: If Americans can lose weight, how will they keep it off? In the face of powerful evolutionary forces, can a drug prevent the cycle of losing and regaining weight that afflicts most patients who lose a substantial portion of their body mass?

The hunt for such a drug, researchers say, will help reframe obesity as a chronic condition that needs lifelong management.