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Seeking a Slim Victory, Drugmakers Press FDA

Pipeline Is Bulging With Diet Pills

By Rob Stein
Washington Post Staff Writer
Friday, September 17, 2004; Page A01

Eyeing a potential gold mine in the global obesity epidemic, the pharmaceutical industry has launched a massive drive to develop new diet pills and an intense campaign to persuade the government to make it easier to get weight-loss drugs onto the market.

Dozens of companies are testing scores of experimental compounds designed to curb appetite, block weight gain and burn fat. Although most are in the earliest stages, many have moved into preliminary tests in people, and a handful have progressed further. One is generating widespread excitement and could make it onto pharmacy shelves by the end of next year.

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"It's a hot field," said Donny Wong, an analyst at Decision Resources Inc., a Waltham, Mass., market research firm. "Every large pharmaceutical company has an obesity program, and if they don't have one, they are trying to get one."

To encourage and prepare for the flood of drugs that could emerge, the Food and Drug Administration has initiated its first review in nearly a decade of how it assesses new obesity medications. The industry -- joined by some obesity experts and advocates alarmed by the burgeoning health crisis -- is pressing the agency to demand less stringent testing and to speed approval of new agents.

"Our feeling is they have a different standard for weight-loss drugs than they do for other drugs for important health problems," said Jonathan Hauptman of the pharmaceutical maker Hoffmann-La Roche in Nutley, N.J. "We'd like them to be treated on a level playing field. We'd like people to start thinking about weight loss not as a cosmetic issue but as a medical benefit."

The push is occurring as a growing number of scientists and doctors have become convinced that overcoming the body's imperative to stockpile fat will require an assortment of drugs, mixed and matched in various combinations, and that many patients will be taking these cocktails for years -- perhaps for life -- along with dieting and exercising. That could create a market akin to those for other major chronic illnesses.

"It's commonplace to use multiple drugs for complex diseases," said Arthur Frank, an obesity expert at George Washington University. "Most people with AIDS take combination drugs. Most people with cancer take combinations of drugs. Most people with heart disease use a combination of drugs. That's probably what we'll have to get to with the management of obesity."

But the intensifying pressure for new obesity drugs is raising fears among some consumer advocates who worry it could produce little more than the next round of marginally effective, unsafe diet pills.

"These drugs have a 40- to 50-year history of clearly doing more harm than good," said Larry D. Sasich of the Public Citizen Health Research Group. "None of them have ever been shown that they can be taken safely for a long enough time to reduce deaths from chronic illness caused by obesity."

The campaign for new weight-loss drugs is shadowed by a checkered history of bogus cure-alls and addictive amphetamines that were more salves for the vain than cures for the ill. More recent efforts to develop safe and effective drugs were marred by the discovery that the popular "fen-phen" drug combination caused life-threatening heart-valve problems. The FDA pulled it from the market in 1997.

Since then, only two drugs have been approved in the United States for weight loss: Xenical and Meridia. Both can help people lose weight, but both have major shortcomings. That leaves the two-thirds of Americans who are overweight, including the one-third who are obese, with scant options beyond often ineffective or marginally effective diet and exercise programs and expensive, possibly risky stomach surgery.

But scientists have been parsing the intricacies of how the body regulates appetite, stores fat and burns flab, leading to the discovery of dozens of hormones, brain signals and physiological mechanisms that offer a host of promising new targets for drugs.

Eager to exploit the potential multibillion-dollar market being created by the vast and rapidly increasing number of overweight Americans, drug companies are racing to capitalize on these advances. By some estimates, 180 drugs are already being tested by more than 70 companies.

The drug closest to pharmacy shelves, called rimonabant, blocks a pathway in the brain that produces the craving for food that occurs when people smoke marijuana. Studies so far, including findings released last month, have found that the drug enables people to safely lose significant amounts of weight, while cutting risks for heart disease and diabetes. It also helps people quit smoking, which has analysts predicting it could be a blockbuster drug. The company hopes to seek FDA approval next spring.

Aside from rimonabant, which would be marketed as Accomplia, three other drugs have undergone fairly extensive testing. Regeneron Pharmaceuticals Inc.'s Axokine suppresses appetite. While it has not worked in as many people as the company initially hoped, Axokine may prove useful for selected patients. A small British biotech company, Alizyme PLC, is developing ATL-962, which blocks fat absorption. And Ortho-McNeil Pharmaceutical's epilepsy drug, Topamax, also helps many people shed weight.

But most attention is focused on dozens of novel molecules further back in the pipeline. There are compounds that block a hormone called ghrelin, which the stomach sends to the brain to rev up an appetite, and agents that mimic another hormone, called PYY, that the gut uses to signal that chow time is over. There are drugs that could prevent a belly full of food from being converted into flab, and others that might act as a workout-in-a-pill by firing up the body's natural fat-burning systems.

While many drugs are showing promise, experts say it remains unlikely a single potent agent will be found to cure obesity, given the multiple metabolic signals that humans have evolved to prevent starvation.

"The body's system for storing fat is so strong that if you pull, it pushes back, and if you push, it pulls," said Kishore M. Gadde, a Duke University obesity researcher. "We block something here, and over the long haul the body will develop a mechanism to defeat what you're trying to do."

Even if many of the experimental agents fall short of expectations, experts say many may still prove useful by at least preventing weight gain, squeezing out modest weight loss and fighting the tendency to regain hard-lost pounds.

"There was this concept that if you lose weight with a drug and you stop the drug, you're going to stay there," said Eric Ravussin of the Pennington Biomedical Research Center in Baton Rouge, La. "That's not the case. It's like hypertension. If you take the pill, it stays down, but if you stop, it goes up high again. I think it's going to be the same with weight loss. You'll have to take them for life, because if you quit, it's going to go back up."

Because the food-and-fat system is so closely entwined with other important metabolic functions, many compounds are likely to have multiple effects. Drug companies hope these multitasking agents will win approval for several conditions, giving them a bigger market.

The FDA is under pressure to take these scenarios into consideration, particularly after Medicare's watershed decision in July to drop a long-standing policy that obesity is not a disease. The drug industry and obesity experts hope to extend that victory to drug treatments as new pills make their way to patients.

"It's really a matter of making sure there's not a certain prejudice or bias against the use of medications for the treatment of obesity," said Morgan Downey, executive director of the American Obesity Association, a Washington advocacy group.

The FDA is being pressed to consider blessing drugs based on shorter studies with less demanding criteria, even if they carry some risks.

"I think they should be willing to tolerate more risks," said Richard L. Atkinson, the obesity association's president. "If a person has a disease, you have to balance the risks versus the benefits, as we do with all other diseases."

A panel of experts the FDA convened last week recommended approving new obesity drugs based on only one year of safety data, instead of the two currently required.

The agency wants to encourage obesity drug development while avoiding another fen-phen debacle. The FDA also knows that anything approved for the obese may end up in the hands of people who are only overweight. For them, the risk-benefit calculus is less clear.

"We will take some time to review the discussions at the meeting and go to work to make any changes . . . ultimately deemed appropriate to facilitate the development of obesity drugs for the U.S. market without sacrificing standards for safety and efficacy," said the FDA's David Orloff.

It may take a few years to shake out, but many experts say at least a handful of safe and effective agents probably will emerge, transforming obesity therapy in the same way cholesterol and blood pressure drugs revolutionized the treatment of heart disease.

"As we get more and more drugs in this area, we'll hopefully get better at managing obesity," said Louis J. Aronne, president-elect of the North American Association for the Study of Obesity. "I think it's the beginning of a whole new era in the management of obesity."


© 2004 The Washington Post Company


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