For obesity sufferers, it's been a painfully long dry spell. The last new drug to treat the condition was approved in 1974, and it could only be used for three months. Since then, restrictive diets and exercise were the only treatment options for the 60 million or so obese adults. It's a strategy that has failed. Obesity costs Americans a staggering $100 billion in health-care costs and weight-loss schemes, according to the U.S. Surgeon General. Now, finally, there's hope for a little relief.
The Food & Drug Administration is considering two promising new treatments for obesity and a third is expected in a year or so. These drugs are not magic bullets. In clinical trials, they achieved only about a 10% reduction in weight even in conjunction with diet and exercise regimens. There's no guarantee that the drugs will work long term, and the FDA is likely to set high standards for approval. But the drugs' appearance is the first clear sign that such companies as Hoffmann-La Roche Inc. and Knoll Pharmaceutical Co. are pursuing what could be a $3 billion or more market. "We are seeing drug companies that we've not seen in years," says Dr. Susan Z. Yanovski, who heads the National Task Force on the Prevention and Treatment of Obesity.
The big change is related to a fundamental shift in how obesity is viewed. Doctors have concluded that obesity, once deemed a lack of will, is a chronic illness much like diabetes and must be treated long term. The FDA is following suit. All drugs up for approval must be safe and effective for at least a year, and most states are rescinding their three-month restriction on new drugs.
This view of obesity reflects a wave of recent findings. One key development was the discovery last March of the so-called Ob-gene and its related protein, leptin. Some 20 genes may play a role in obesity--and more are expected. Scientists are hunting down brain chemicals that regulate hunger, and they're exploring why one person burns fat faster than another. The result is a clearer picture of what causes obesity and how best to treat it. "New treatments will be designed on a rational basis having to do with our knowledge of how body weight is regulated at the molecular level," says Dr. Jeffrey M. Friedman, a researcher at the Howard Hughes Medical Institute at Rockefeller University in New York.
The first new generation of drugs is just beginning to meet this criterion. The drug closest to market, dexfenfluramine, made by Interneuron Pharmaceuticals Inc. in Lexington, Mass., already is available in 65 countries. It reduces appetite by increasing the levels of serotonin in the brain. Recommended by an advisory committee to the FDA, it now awaits approval. Next in line is sibutramine, which was submitted to the agency in August and is made by Knoll. It prevents uptake of serotonin as well as another brain chemical called noradrenaline, which is involved in metabolism.
GUT REACTION. The third drug nearing the market is Roche's orlistat, which prevents the intestines from absorbing about one-third of the fat a person consumes. The drug is in late clinical trials and could be approved within two years, says Dr. Arthur Campfield, a research leader in the department of metabolic diseases at Roche.
Beyond these early entries, a handful of other drugs may be ready within five years. Drugs called beta-3 adrenergic agonists work by increasing the body's energy expenditure. Wyeth-Ayerst Laboratories Inc. already has one in clinical trials. Another approach is to look at compounds that control when people are satiated. An example is CCK-A, a hormone produced by the gut that tells the brain a person is full. Researchers at Astra Arcus USA in Rochester, N.Y., are testing a drug that can boost this effect in humans.
Others are working on neuropeptide-Y, a substance in the brain that causes rats to overeat. The idea is to block its effect in people. Neurogen Corp. in Branford, Conn., along with Pfizer Inc., filed on Dec. 13 for permission to begin trials of such a drug. Synaptic Pharmaceutical Corp. in Paramus, N.J., also is pursuing an NPY blocker.
TOUGH SELL. Clinicians are most excited about the potential payoff from genetics research. Since discovering the Ob-gene last year, researchers have found that the Ob-protein, or leptin, is released by fat cells in the body. It travels to the hypothalamus, at the base of the brain. There it binds with the Ob-receptor and touches off a chemical cascade that suppresses appetite. Leptin also may tell the body to burn more fat.
So far, though, leptin's function in humans is murky. Amgen Inc. is hoping to inject people with the protein to see if they lose weight. The sticking point is that some obese people already have high levels of leptin in their bloodstream. Giving them more may not have an effect. "I think the jury's still out on whether leptin could be a drug or not," says Friedman, leader of the team that isolated the Ob-gene and -protein.
Campfield's group at Roche is focusing more on the Ob-receptor. The company, with Millennium Pharmaceuticals Inc. in Cambridge, Mass., found the receptor in December and determined that leptin does bind to it. The problem, says Campfield, seems to be getting the fat-fighting message through to cells in the hypothalamus. His group is working on finding small molecules that can facilitate this connection. "I think we could get lucky here," says Campfield.
Finding a profitable drug likely will require a little luck. Researchers believe obesity results from a number of genetic and environmental factors. The hope is that doctors will one day have an arsenal of drugs to tailor treatment.
There is still doubt about how effective any one treatment can be. Eating is an instinct: Use a drug to interfere with one pathway and another might take over, says Dr. Richard L. Atkinson, director of the Beers-Murphy Clinical Nutritional Center at the University of Wisconsin-Madison. "There may be a whole lot of signals telling the body it should be fatter."
Another hurdle for obesity drugs is the FDA. The agency released preliminary guidelines on these therapies in 1994, and they still are "evolving," says Dr. Leo Lutwak, an FDA medical officer. Questions remain as to how long studies must last and what amount of weight loss is optimal. Some FDA advisers want the drugs to also reduce the incidence of such obesity-related problems as diabetes or hypertension.
Because obesity isn't directly life-threatening like AIDS or cancer, the risk of taking a drug long term is weighed carefully against the benefit of weight loss. This hesitancy makes some weight-loss advocates impatient. "I don't think approval of antiobesity drugs falls on a very sympathetic advisory committee or FDA," says committee member Judith S. Stern, a professor of nutrition at the University of California at Davis.
Perhaps sensing this, Eli Lilly & Co. withdrew its obesity drug Lovan--a Prozac-like compound--from review at the FDA, citing costs required for two-year studies. Dexfenfluramine was narrowly recommended amid much dissent, including worries about its effect on the brain. It has opponents even among some obese people.
Still, this level of controversy is inevitable in such a new area, says Richard E. Gammans, vice-president for clinical research at Interneuron. "We're at the stage now in obesity drugs that we were with drugs for depression 15 years ago." It could take years before obesity suffering is truly alleviated.