Drug Makers Race to Cash In on Fight Against Fat

LOUISVILLE, Ky. - The L-Marc Research clinic stands at the geographic center of an American epidemic, where the meat-and-potatoes Midwest meets the chicken-fried South, and just across the street from a McDonald's.

The clinic is a leading recruitment post in the drug industry's multibillion-dollar war on fat. Desperate to be thin, overweight people eagerly respond to L-Marc's local newspaper ads for volunteers to test experimental weight-loss drugs. For each trial, the clinic is forced to turn away dozens of volunteers.

"I've had people crying on the phone," said Heather Hausberger, the dietitian who screens applicants. "They've tried everything. Nothing seems to work. A lot of people are looking for the quick fix, the magic pill."

Many drug makers, too, are seeking that magic pill. From pharmaceutical giants to tiny start-ups, the industry is spending billions of dollars developing obesity drugs. An estimated 200 possibilities are now in the research pipeline or under test among patients at dozens of clinics like L-Marc, according to MedMarket Diligence, a health care research firm.

Some drug makers say they are tackling fat in response to public health warnings of a national obesity epidemic - one that has been linked to diabetes, heart disease and other conditions and now accounts for more than $100 billion of the United States' $1.8 trillion annual medical bill. The obese are defined as those with a so-called body mass index of 30 or more. By that measure, obese people now make up one-third of the adult population.

But many drug industry analysts see a potentially even bigger market if such a drug also catches on among the more than 60 percent of adults in this country who are statistically overweight, those with a body mass index of 25 or more. Many experts also see a likelihood - some would say danger - that such a drug might appeal to millions who are by no means fat but would like to drop a few pounds.

"Everybody is just foaming at the mouth to make money" from obesity drugs, said Dr. Donna Ryan, an obesity researcher affiliated with Louisiana State University, which has received millions of dollars in government and drug-industry grants.

Industry forecasters say that an effective weight-loss drug could have annual sales far surpassing the current best-selling drug, the cholesterol treatment Lipitor, which reached $12 billion last year, especially now that Medicare says it will pay for "effective" obesity treatments.

Some experts caution that the complex variables of culture, environment, genetics and lifestyle that contribute to obesity may defy a mass-market solution. "One pill fits all doesn't seem like an outcome we'll be seeing on the horizon anytime soon," said Dr. Julie Gerberding, the physician who directs the federal Centers for Disease Control and Prevention.

But most of the biggest drug makers feel financially compelled to stay in the hunt. As it becomes more and more difficult to identify blockbusters, many companies see few other prospective best sellers in their research pipelines.

One of the most closely watched weight-loss treatments in late-stage clinical trials is Acomplia, made by Sanofi-Aventis, based in Paris. It works by blocking the same pleasure receptor in the brain that responds to the effects of marijuana. Test patients who took the drug for two years lost an average of 16 pounds, the company said. Sanofi-Aventis is expected to seek Food and Drug Administration approval for Acomplia by this summer.

Other approaches include a weight-loss nasal spray that a biotechnology company, Nastech Pharmaceutical, is testing in partnership with Merck. The spray contains a synthetic version of a human protein that signals a person's brain to stop eating when food reaches the intestines.

"Cures" for fat, of course, have long been staples of the herbal supplement and over-the-counter medicine businesses, as well as the diet industry. Amphetamines were widely used as diet pills in the 1950's and 1960's, before physicians recognized their addictive effects. More recently, amphetamine-like substances have been sold as over-the-counter treatments.

And the fen-phen prescription drug combination was popular during the mid-1990's, until it was found to damage patients' hearts. Indeed, the $21 billion that Wyeth estimates it will cost to settle legal claims related to fen-phen serves as a cautionary tale for any drug maker tempted to put a fat pill onto the mass market.

So might the reaction against another diet drug already on the market, Meridia, made by Abbott Laboratories, which has been linked to elevated blood pressure. Public Citizen, the consumer group, has asked for its withdrawal and an F.D.A. official listed it among five drugs that the agency needs to review.

Another currently approved diet drug, Xenical, by Roche, is considered safe and helps patients lose weight, but people often discontinue its use because of its embarrassing side effects: fatty stools and flatulence.

Despite the industry's risks, some medical experts worry that drug makers' big investments in obesity research will prompt companies to seek the broadest possible payback through the same type of aggressive promotion to doctors and consumers that helped turn the arthritis drugs Celebrex and Vioxx into widely prescribed general painkillers. Those drugs were taken by tens of millions of people before their safety risks became clear.

Dr. Donald A. Bergman, a Manhattan endocrinologist, predicts obesity drugs will end up being overprescribed and abused. "Some people are going to want to take them to get ready for an engagement, a TV appearance, whatever," he said. "Some people are going to take advantage of the system."

Still, Dr. Bergman, a founder of the American Association of Clinical Endocrinologists, said such concerns were not reason enough to discourage the development and approval of obesity drugs. The growing ranks of the obese are simply too alarming a problem, he said. "We have to do something to save them."

By the time Patricia Gallagher, a Louisville hairdresser, joined an L-Marc clinical trial last August, she was tired of shopping in what she called the "fat lady shop."

She had tried everything. Weight Watchers. A diet of cabbage soup. Even a four-day regimen of cauliflower, beets and hot dogs.

"If you followed it exactly, you lost 10 pounds," recalled Ms. Gallagher, 62. "But, oh, it was hard to get down." And it was always hard to keep the weight off, she said, because her retired husband does most of the cooking and his fare tends toward fried foods.

She learned to avoid catching her reflection in the beauty shop mirror. "I used to work away from it, and when I turned my lady around to the mirror, I looked at her," she said. "All day long, I never looked at myself."

When she entered the L-Marc trial, Ms. Gallagher was carrying 193 pounds on her 5-foot-6-inch frame, a weight that had pushed her over the line into statistical obesity.

She lost 23 pounds in the four-month L-Marc study, which she completed in December. She still does not know whether she took a placebo or a real pill twice a day. Nor does she know whether she was helped by a pill or by the nutritionists who counseled her and weighed her each week.

Ms. Gallagher still regularly returns to L-Marc to check her weight on the clinic's scale. She says she has lost an additional five pounds since completing the trial. "I guess I've changed my way of eating, too," said Ms. Gallagher, who now takes fruit with her to work, where she no longer fears catching a glimpse of herself.

Another L-Marc clinical trial participant, John Froman, 50, said he used to spend holidays eating his way from one family dinner to another, putting on weight at each stop.

"You do two Christmases, three Thanksgivings, two New Years; everybody is cooking real big," said Mr. Froman, who maintains locks on the Ohio River for the United States Army Corps of Engineers.

Mr. Froman lost 60 pounds and he credits the little white pill he took. But he says the advice he was given has changed his outlook on life, and he will no longer stuff himself.

Some people who complete L-Marc's studies continue to follow the dietary and lifestyle habits they were urged to adopt during the trials, said Dr. Harold E. Bays, the endocrinologist who directs L-Marc. "Unfortunately," he said, "many others do not, and weight recurs."

Scientists seem to agree that, while some people are programmed to be thin and others are destined to be overweight, obesity is partly an environmental condition. Most Americans work in sedentary jobs, arriving and leaving via door-to-door transportation. At the same time, they are constantly confronted with cheap, high-calorie food.

Dr. Barbara Corkey, an obesity researcher at Boston University School of Medicine, says the odds are against someone losing significant weight and not regaining it.

"There's a tremendous body drive to restore that weight," Dr. Corkey said. Some people do lose a lot of weight and keep it off, she said. "But their lives are spent keeping weight off. And that's kind of their profession."

Many scientists also believe that the body's heavily defended feeding system is the reason diets tend to fail and may also make it difficult for the industry to find a safe and effective diet drug.

Human metabolic pathways, the body systems that convert food to energy, are an intricate circuitry in which messages are continually shuttling between brain, stomach and intestine, signaling hunger or satiety. If one messenger or pathway is blocked, another is likely to take its place, as the body tries to protect itself against starvation.

Researchers at Rockefeller University in Manhattan thought they had cracked the code in 1994 with leptin, a protein found to be lacking in some obese rats. When injected with leptin, the rats became thin. Amgen, the big biotechnology company, invested millions in leptin research, but the rodent results could not be duplicated in humans.

More recently, Regeneron hoped it had a winner in Axokine, a genetically engineered version of a human protein that signals the brain to stop eating. But the company placed Axokine on the back burner last year after patients developed antibodies against the protein, blocking its effectiveness.

GlaxoSmithKline, meanwhile, is still smarting from the defeat of one of its promising weight-loss drugs, called 771. In February, after 14 years of development and millions in costs, the company announced that it would no longer pursue the drug because it simply had not worked in clinical trials.

"We get to the point that, after years of blood, sweat and tears, we're left with tears," said Dr. Kenneth Batchelor, a scientist who directs metabolic disease research for Glaxo. But the company is now trying several other ideas, still hoping to solve the human metabolic puzzle.

At Boston University, Dr. Corkey and four other scientists have formed their own small company, AdipoGenix. They hope to outwit the metabolic system by locating a drug that attacks fat cells directly, bypassing all the circuitry. The idea is intriguing enough that Johnson & Johnson has agreed to invest, in a deal worth up to $60 million if all benchmarks are met.

The temporary offices of AdipoGenix are within walking distance of the Boston Medical Center. That is also where the company gets the bulk of its raw material: fat harvested from surgical patients.

Most of those patients have undergone gastric bypass surgery or paniculectomies, in which doctors cut away excess fat and sagging abdominal skin from people who have lost lots of weight. "People are so happy to give us their fat," Dr. Corkey said.

In the operating room, the fat is transferred to a sterile water bottle, then placed in an insulated cooler for the short trip to AdipoGenix's labs. There, the company has been testing what happens when fat is mixed with each of 41,000 chemical compounds from Johnson & Johnson's library or from AdipoGenix's smaller collection of compounds.

Under a microscope in AdipoGenix labs, fat cells normally look like big round globes. But Dr. Corkey said that some of the compounds have been observed actually changing fat cells - whether by making them shrink, inhibiting their ability to replicate, stimulating their burn rate or causing them to break down faster.

The company now plans to proceed to animal testing of some of the compounds, according to Dr. L. Edward Cannon, its chief executive. "A drug that comes through this," he said, "you almost have a certainty that it's going to be efficacious in man."

Matt Stone for The New York Times
John Froman, who lost 60 pounds in a drug trial, eating his lunch: fruit, a chicken salad sandwich and baked potato chips.
Baked potato chips?

Robert Spencer for The New York Times
At AdipoGenix, a researcher works with some of the fat cells the company is testing.

Antimunchies drug. Cool.

I was slim until menopause took my youth away. Stupid menopause! Now I constantly struggle to keep my blobs to a minimum. Life can suck sometimes.

Let's say everybody gets an anti-fat drug. Great. When they ARE hungry, what will they eat? That's the real question. Are they going to go for fruits and veggies? Guess again. So they'll take nutritional supplements! Every meal is a pill! When we get sick, MORE PILLS! Yay! With more Judge Greers, we'll be sentenced to death, and take a PILL to kill ourselves!

Eventually we'll be able to take a pill when we WANT to get pregnant - that'll round out our unnatural lives very nicely.

Keeping people ignorant and unmotivated to do anything for themselves is the Master Plan of the left.

Eventually we'll be able to take a pill when we WANT to get pregnant - that'll round out our unnatural lives very nicely.

Don't you know that the world is in a series over population crisis? ITS HUGH!!!! (and its ALL BUSH'S FAULT)

Besides, now that our planet is more concerned about death than life, a drug like that would never sell. Not compared to its counter, RU486

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