Heat Is On to Deliver Diet Drug
In tall, stainless-steel vats that look like they belong in a microbrewery, Amgen Inc. of Thousand Oaks is brewing up batches of what could be a new anti-obesity drug--a naturally occurring human protein now 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 gut--cutting calories even without a change in diet.
On the heels of discovering several natural chemicals that make rats and mice ravenously hungry, several companies are moving as quickly as they can to develop drugs that can block that effect and suppress appetites in overweight humans.
With more than half the adult population of the U.S. now labeled “overweight,” or “obese,” dozens of drug and biotechnology companies are in hot pursuit of new medications designed to shed excess pounds by curbing appetite, blocking fat digestion or increasing the rate that the body burns calories.
An eruption of discoveries over the last several years has given fire to the chase for a new generation of anti-obesity drugs. The science has delivered an increasingly sophisticated understanding of why some are insatiable eaters, adding pounds to the detriment of their health, and why others eat whatever they like with impunity.
And in a culture that values the thin--even as the number of overweight Americans creeps steadily upward--a useful weight-loss drug could tap into a vast market, one not limited to those with strong medical reasons to drop extra pounds.
But the wide use of any medication for prolonged periods--perhaps for a lifetime--raises safety questions that are not easily answered in the usual clinical trials.
And because many healthy people will take diet pills for appearance’s sake alone, new medications will have to meet higher safety standards than other drugs, said Dr. Rudolph Leibel, an obesity expert and director of molecular genetics at Columbia University’s College of Physicians and Surgeons. “You never heard of a person taking a blood pressure drug or a cholesterol-reducing drug for cosmetic reasons,” he said.
Company officials and researchers say that attitudes about obesity have changed--that carrying an extra layer of fat around the midsection is seen as a significant health problem, not just a question of cosmetics. And for increasing numbers of Americans, cutting calories and increasing exercise--the preferred prescription for dealing with obesity--may well not be enough.
“As a culture, we have to recognize that diet and exercise are not an overwhelmingly effective way to deal with the problem,” said Dr. Jeffrey M. Friedman, a Rockefeller University scientist and leading obesity researcher. “There appears to be a biological system that tends to maintain weight.”
Health Implications of Excessive Weight
Excessive weight brings with it added risk of high blood pressure, diabetes, cancer, heart disease and stroke.
And this year, the National Heart, Lung and Blood Institute issued guidelines that redefined “overweight” in a way that classifies 97 million American adults as too heavy--55% of the adult population compared to about 35% under the older yardstick. The institute put a $100-billion-a-year price tag on obesity-related disease.
The sheer size of the market has attracted wide interest among companies, said Matthew M. Geller, senior biotechnology analyst with CIBC Oppenheimer. “If you come up with a favorable compound, it could be a multibillion-dollar drug.”
But Geller pointed out that developing an obesity drug has proved difficult. “Obesity is a very complicated phenomenon. It is not a disease like chickenpox,” he said.
Health systems and insurers that balked at paying for Viagra, the male impotence drug, would welcome an effective diet drug, said James D. McCamant, editor of the Medical Technology Stock Letter. “There are a large number of people costing the system a lot already and there won’t be much reluctance to pay for the drugs, if they are effective,” he said.
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.
Redux remains a cautionary tale on the dangers of seeking weight loss in a pill. The drug was banished from the market last year along with fenfluramine--the “fen” in fen-phen--after researchers linked the medications to heart damage in obese patients.
Before the crisis, Redux and fenfluramine were selling more than 7 million prescriptions a year and had combined sales of $322 million, according to IMS Health, a company that tracks prescription sales.
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 Co.’s Meridia--developed a decade ago as an antidepressant. It failed to help patients battling depression, but investigators noticed that the subjects were losing weight.
One problem: In a small number of patients--fewer than 1%--the drug causes a substantial increase in blood pressure. As a result, doctors will have to monitor all patients taking the drug.
Meridia quickly became the highest-grossing diet pill in the U.S.--with total sales of $60.8 million from its mid-February launch through May, according to IMS Health. Knoll’s parent company estimates worldwide sales could eventually reach as much as $500 million a year.
Another new drug, still waiting in the wings for final 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 in the human gut that breaks down fats and allows them to be digested.
Roche Engineers Scour World for Slime
For decades, Roche engineers as they traveled the world would collect samples of soil, molds and slimes--”anything icky”--to send back to corporate headquarters, said L. Arthur Campfield, with the department of metabolic diseases at Hoffmann-La Roche. The first version of Xenical was scooped up by an engineer on vacation in Majorca, he said.
Developing a stable version of the chemical and testing it has taken two decades. One concern raised in the tests was a higher incidence of breast cancer among women taking the drug than among those given a placebo.
The company argued that the cancers developed before the volunteers began taking the medication, and in February, the FDA issued “a letter of approvability” for the drug. The company expects final approval early next year, subject to a review of safety data.
But Hoffmann-La Roche is not placing all of its bets on Xenical.
Buoyed by the rush of scientific discoveries, the company, like a number of the world’s pharmaceutical giants, is investing in obesity research and forming partnerships with smaller biotech firms in the hunt for pills with minimal side effects.
One of the most stunning of the new findings solved 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 for the obesity--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, which they 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.
The discovery of leptin and other recent findings have triggered a “whole new era of scientific investigation into the regulation of body weight,” said Dr. Andrew S. Greenberg, who directs an obesity research center at Tufts University in Boston, one of six centers that conducted the Amgen trial.
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. “Whenever you can avoid that in drug development, that is desirable.”
So Amgen and other companies are scrambling to find an oral medication, a small molecule that would survive in the gut and 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. The ideal drug would mimic leptin, making it easier for obese patients to stick to a diet.
Companies Search for Target Protein
Two biotech companies--Progenitor Inc. in Menlo Park and Millennium Pharmaceuticals Inc. in Cambridge, Mass.--are working on the problem.
Progenitor, which is collaborating with Amgen, was the first to find the target protein.
Millennium independently found the same protein and is working with Hoffman-La Roche to find a drug that will act like leptin but “‘move like an aspirin” from the intestine into the bloodstream to its target in the brain, said Louis A. Tartaglia, the company’s senior director of metabolic diseases and oncology.
In the early 1980s, a team of Rockefeller scientists found another naturally occurring chemical called neuropeptide Y, that, when injected into the brains of laboratory rats, sent the animals into a feeding frenzy.
Now two biotech companies are working with giant pharmaceutical firms to develop small molecules that could be taken by the mouth and block the chemical.
Working with Pfizer Inc., Neurogen Corp. in Branford, Conn., has a promising compound. But the company had to shut down its human safety tests last year when researchers identified liver changes in healthy, obese volunteers just three weeks into the trials.
Pfizer and Neurogen are now reviewing the findings and looking at similar drugs for possible testing on human subjects sometime next year.
Synaptic Pharmaceutical Corp. in Paramus, N.J., is collaborating with Novartis to design a molecule to block neuropeptide Y.
Taking an entirely different tack, other groups are searching for chemicals that stimulate “uncoupling proteins”--substances found inside cells that, when activated, burn up calories, giving off small amounts of heat, rather than storing the excess as fat.
Originally found in the fat cells of hibernating bears and newborn babies, similar proteins have now been identified in the cells of adult humans as well.
About a year ago, researchers from Hoffmann-La Roche and Millennium Pharmaceuticals announced they had found and patented the gene for one of those proteins.
Amylin Pharmaceuticals in San Diego has identified a different human uncoupling protein. The company is already investigating compounds that stimulate the protein and are testing these chemicals in laboratory animals.
Variety of Drugs for Types of Obesity
The evidence is now overwhelming that a number of genes are involved in human weight regulation. And many researchers now believe that it will take a pharmaceutical arsenal containing a variety of medications to treat the several different forms of obesity.
“What we’ll see in the next millennium is that there are a number of pathways for the development of obesity,” said Dr. Ernest Noble, an obesity researcher who heads UCLA’s alcohol research center. “The treatment will depend on what genetic form these obese people have and [the drug companies] will target the specific forms.”
But Noble cautions against hoping for easy fixes.
“All kinds of drugs have been proposed or developed, but I’m not so convinced that this barrage of drugs will do any good,” he said. “And some of these drugs will have problems themselves.”
