New drugs promise no gain, no pain Research: Pharmaceutical companies are developing, or already marketing, medications that help fight obesity.

October 18, 1998|By Paul Jacobs | Paul Jacobs,LOS ANGELES TIMES SERVICE

In tall, stainless-steel vats that look as if they belong in a microbrewery, Amgen Inc. of Thousand Oaks, Calif., is brewing up what could be a new anti-obesity drug - a naturally occurring human protein being tested in patients.

At a plant in Nutley, N.J., Hoffmann-La Roche hopes to begin mass-producing a new diet pill called Xenical, the first chemical of a class that blocks the uptake of fats from the digestive system.

On the heels of discovering several natural chemicals that make rats and mice ravenously hungry, several companies are moving quickly to develop drugs that suppress appetite, block digestion of fat or increase the rate at which the body burns calories. With more than half the adult population of the United States now labeled "overweight" or "obese," the market for such drugs is expected to be phenomenal.

An eruption of discoveries over the last several years has given fire to the chase. Science has delivered an increasingly sophisticated understanding of why some people are insatiable eaters and pay for it with poundage, and why others eat whatever they like.

For some Americans, it appears, cutting calories and increasing exercise - the traditional prescription for dealing with obesity - may well not be enough.

"There appears to be a biological system that tends to maintain weight," says Jeffrey M. Friedman, a Rockefeller University scientist and leading obesity researcher.

But drug approval can be slow, and many of the experimental drugs under development are years from the market. In 1996, when the Food and Drug Administration approved Redux, it was the first new diet medication in 20 years, and now it stands as a cautionary tale.

The drug was banished last year along with fenfluramine - the "fen" in fen-phen - after researchers linked the medications to heart damage in obese patients. Given that experience, companies are likely to be cautious in touting the virtues of new medications as they win regulatory approval.

Early this year, the FDA gave its blessing to Knoll Pharmaceutical's Meridia - developed a decade ago as an anti-depressant. It failed to help depression, but investigators noticed subjects lost weight.

One problem: In a small number of patients - less than 1 percent - the drug causes a substantial increase in blood pressure. As a result, doctors have to monitor all patients taking the drug.

Meridia quickly became the highest-grossing diet pill in the United States - with sales of $60.8 million from its mid-February launch through May, according to IMS Health. Knoll's parent company estimates worldwide sales could reach as much as $500 million a year.

Another new drug, awaiting FDA approval, is Xenical from Hoffmann-La Roche. The drug was discovered the old-fashioned way: in a search for drugs that would block an enzyme that breaks down fats and allows them to be digested.

Developing a stable version of the drug and testing it has taken two decades. One concern raised in the tests was a higher incidence of breast cancer among women. The company argued that the cancers developed before the volunteers began taking the medication, and in February, the FDA issued "a letter of approvability." The company expects final approval early next year, subject to a review of safety data.

One of the most stunning of the new findings in the hunt for a diet pill involved a decades-long mystery. In the 1950s, researchers discovered a mutant strain of obese mice that tipped the scales at three times the weight of their normal brethren.

In 1994, a team of researchers, led by Rockefeller's Friedman, found the reason: a defective gene. The scientists identified a hormone present in normal mice - missing in the obese ones - that plays an important role in limiting food intake and maintaining a target body weight.

They dubbed the hormone, found in humans as well as mice, "leptin" after the Greek word for "thin." The obese mice lost weight when injected with the hormone.

Amgen paid Rockefeller $20 million to license leptin - and agreed to many times that amount if the substance reaches the market, according to Amgen spokesman David Kaye. Using the tools of genetic engineering, the company is growing vats of bacteria that carry the human leptin gene and produce the hormone, which the company purifies for use as a drug.

But leptin is not the perfect weight-loss drug, even if it proves effective. Because it is a protein, which would be broken down in the intestines if taken by mouth, it must be injected.

"Nobody wants to take an injection," said Dr. Michael W. Schwartz, an endocrinologist and obesity researcher at the University of Washington.

So Amgen and other companies are scrambling to find an oral medication, a small molecule that would survive the digestive system to find its way to leptin's ultimate targets: proteins that sit on the surface of nerve cells in an area of the brain that helps regulate appetite.

"What we'll see in the next millennium is that there are a number of pathways for the development of obesity," says Ernest Noble, an obesity researcher at the University of California, Los Angeles. "The treatment will depend on what genetic form these obese people have."

Pub Date: 10/18/98

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