Washington Post - Wave of Anti-Obesity Drugs in the Works
45 Companies Vie for Piece of World's Biggest Pharmaceuticals Market
By Justin Gillis
Washington Post Staff Writer
Saturday, October 3, 1998; Page A01
At least 45 companies around the world are trying to develop obesity
drugs, seeking magic bullets that could help people control their weight.
One such drug, Xenical, recently went on sale in Europe and Asia and
could be licensed in the United States within months. The British press has
dubbed it "Viagra for fatties."
For drug companies, the stakes couldn't be higher. In a world where a
blockbuster drug is one with $1 billion a year in sales, analysts give $5
billion as the low estimate for sales of an important obesity drug. If a
company developed a truly safe, effective weight-loss drug and sold it for
$3 a day to one-quarter of the 97 million American adults estimated to be
overweight, sales would exceed $26 billion a year in this country alone.
"It's potentially the world's biggest market for a drug," said Louis Tartaglia,
a senior researcher at Millennium Pharmaceuticals Inc. of Cambridge,
Mass.
Lately, a few of these drugs have entered advanced testing on humans.
One, a drug that tinkers with the chemistry of the brain to make people feel
full sooner, won approval late last year from the Food and Drug
Administration. Xenical works in a different way, helping people lose
weight by blocking the absorption of fat in the intestine.
Many doctors hope these drugs will stem obesity worldwide, a problem so
severe the World Health Organization has labeled it an "epidemic." The
weight-loss drugs are the latest frontier in "lifestyle pharmacology," and
they demonstrate the potential that new biological insights hold to change
human lives.
Among some scientists, however, this new line of research raises serious
concerns.
There's no question that the incidence of obesity is steadily increasing, and
the social costs are staggering. Obese people run a higher risk of diabetes,
heart disease, arthritis and many other health problems. One respected
study put the costs associated with obesity at $99.2 billion in the United
States in 1995. The direct medical costs of obesity-linked diseases
represent nearly 6 percent of the country's entire budget for health care.
At the same time, history is replete with examples of obesity drugs being
misused. Like Viagra, they are sold on the black market, or dispensed by
unethical "pill mills" to people who just need to lose a few pounds. The
drugs can pose risks that may not become clear until they have been taken
for years by hundreds of thousands of people.
In the 1960s, many people took amphetamines to lose weight, with some
becoming addicted to the powerful stimulants. In the 1990s, doctors
combined two weight-loss drugs, fenfluramine and phentermine, that hadn't
been approved for use together. The combination, known as "fen/phen,"
helped many people lose weight, and the drugs came into wide use at
commercial diet centers.
But then an alert medical technician in Fargo, N.D., Pam Ruff, noticed that
some women taking the drugs were developing serious damage to their
heart valves.
Studies eventually confirmed her finding and showed that the damage
resulted largely from fenfluramine. A similar drug approved in 1996,
dexfenfluramine, was also implicated in heart damage. Under pressure
from the FDA, fenfluramine and dexfenfluramine were pulled from the
market last year.
This history of trouble means that new weight-loss drugs will likely be
placed under intensive scrutiny to ensure they are as safe as possible.
Whatever guidelines responsible doctors may offer, the FDA realizes that
these drugs are likely to find a broad market among the millions who want
to look better in a bathing suit.
At the same time, attitudes among doctors have loosened since the days
when drugs to help people look better weren't considered real medicine.
They're keenly aware that people find it difficult or impossible to keep
weight off by conventional methods, and doctors are becoming more open
to the idea of treating the problem with pharmaceuticals, if that can be
done safely.
It's plain that new diet drugs are high on the public's wish list.
Ellen Wallen of Janesville, Wis., says a new drug has made a big difference
in her ability to shed pounds. She has fought a weight problem all her life,
and diet and exercise haven't been enough to overcome it. In recent years,
the drive-through windows serving up fast, greasy food were a powerful
temptation.
Wallen describes an overwhelming need to eat, a craving as palpable as
any addiction to alcohol or cocaine. It's almost as though her brain were
missing the chemical signal that would say: Enough, already.
"In the morning, I'd hit a drive-through and have breakfast in the car," she
said. "I'd have lunch at a drive-through, go home and lie down. I'd get up,
hit the drive-through on the way back to work, and hit it again on the way
home. If I had the energy later in the evening, we'd probably go out to eat."
In March, Wallen started taking a new drug called Meridia, approved by
the FDA late last year. It's no miracle, she says, but it helps her more than
dieting alone ever did -- "it removes that sense of desperation to eat."
Now, she can drive by Burger King or Taco Bell without stopping. She
has dropped from 202 to 172 pounds, and feels better about life.
Scientists have long understood that a lot of what goes on in the human
body can be understood as a fine balance between brakes and
accelerators. In people like Wallen, science increasingly suggests that some
brakes are defective.
Slowly, researchers are unraveling these delicate signals -- figuring out
which are the brakes, which are the accelerators, and how they act on
each other. The research is far from complete, but scientists are using their
knowledge to design drugs that step harder on the brakes.
In modern research, being overweight or obese are defined as ranges on a
scale, called the body-mass index, that reflects the relationship between
weight and height. (See the box on this page for the ranges and to calculate
your own place on the index.) As of 1994, the latest year for which
complete figures are available, some 55 percent of the adult population of
the United States exceeded the healthy range, and 23 percent were
classified as clinically obese. For reasons that are unclear, these figures
have been rising for decades.
Scientists have long believed there was a genetic component to extreme
obesity, which tends to run in families. And many of them view even
garden-variety obesity -- being 20 or 30 pounds overweight -- as a
consequence of genes.
The human body evolved in a world where high-calorie foods, especially
sweet and fatty foods, were scarce. Our distant ancestors were
programmed by their genes to seek such foods as dense sources of
energy. Their bodies developed mechanisms to store surplus energy as fat,
to be burned during lean times.
Today, though, people are surrounded by doughnuts and cherry cordials
and pork chops, and for most Americans there are no lean times. However
hard they try, many people can't find the willpower to resist high-calorie
foods. Moreover, modern lives are so sedentary that people don't get
enough exercise to burn off the calories they do take in.
Drug companies would like nothing better than to solve this problem with
pharmaceuticals. At the moment, however, they don't have that much to
offer. With the withdrawal of the fen/phen combination, the handful of
available fat loss drugs offer only modest help in losing weight.
The newest drug to come to market is Meridia, developed by Knoll AG of
Ludwigshafen, Germany. The drug works by elevating the levels of certain
brain chemicals that cause people to feel sated when they eat. "It helps you
feel full sooner," said Tim Seaton, a senior researcher at Knoll.
When the drug is coupled with a diet and exercise program, many people
can lose 10 percent of their body weight, enough to offer notable health
benefits. However, the drug can raise blood pressure and heart rate in a
few people, so those with known heart disease shouldn't take it.
Coming soon is a drug that works in a different way. Xenical, developed
by F. Hoffmann-La Roche Ltd., the Swiss pharmaceutical giant, is the first
of a new class of drugs that block the absorption of fat in the intestine. It
has already gone on the market in parts of Asia and Europe, to frenzied
public interest. People who take Xenical absorb about one-third less fat.
However, the drug can cause gastric distress in some people.
A bigger concern is that in studies, women taking the drug seemed to have
an elevated incidence of breast cancer. Roche presented evidence
suggesting this was due to chance. The FDA has signaled its intention to
approve the drug in the United States, probably early next year, but the
cancer concern lingers, and many doctors are expected to use the drug
cautiously.
Once Xenical is on the market, there is likely to be a lull of three years or
so before the next anti-obesity drug. Coming along in the research
laboratories, however, are a slew of additional treatments.
One that has drawn considerable attention is a human protein known as
leptin. It is a chemical messenger that fat cells generate to tell the brain they
are full. When the discovery of leptin was announced in 1994, people were
electrified by pictures of a fat mouse and a skinny mouse next to each
other. The mice shared a genetic propensity to gain weight, but the skinny
mouse had received injections of leptin.
Amgen Inc. of Thousand Oaks, Calif., the nation's largest biotechnology
company, paid some $20 million for rights to the drug and agreed to pay
tens of millions more if it goes on the market. In the years since, hopes that
this compound would prove to be a wonder drug for weight loss have
largely evaporated. It turns out most grossly obese people aren't deficient
in leptin. The genetic characteristics that cause them to get fat lie
somewhere else, probably in the chemistry of the brain.
Still, Amgen has announced positive early results and launched advanced
human tests of leptin, believing it may prove useful for some people. The
biggest drawback is that leptin must be injected, but Amgen would
eventually like to get around that by developing oral drugs that mimic its
effect.
The real significance of the leptin discovery was that it energized research
into the biology of being fat. If leptin is the main signal telling the brain how
much fat the body has, researchers asked, what happens once that signal
enters the brain? It is here that many companies hope to make progress
toward something resembling a magic bullet for weight loss.
For instance, Pfizer Inc., the big New York drug company that developed
Viagra, is working with Neurogen Corp., a Connecticut biotech firm, on
potential weight-loss drugs. Their research relies in part on the discovery of
a brain chemical that, in high doses, makes animals ravenous. The
chemical, known as neuropeptide Y, seems to play an important role in
human appetite; when fat stores are depleted and the level of leptin in the
blood falls, the amount of neuropeptide Y in the brain goes up.
Pfizer and Neurogen want to block the action of this chemical to see if
doing so helps people lose weight. They abandoned research on their
leading drug last year, after it was found to cause liver abnormalities, but
they are testing other drugs.
Another strategy that companies are pursuing is to try to speed up the
body's metabolism. Drugs that work this way would cause people to burn
more calories, day and night, and therefore shed excess pounds. The body
might actually run a little hotter than the standard 98.6 degrees, much like
an engine running faster. Drugs of this type, though they are being studied
in the laboratory, are still somewhat speculative, because nobody is sure
what the long-term effect would be of revving up the body's metabolism.
In the end, most researchers think a host of drugs will be used to manage
obesity, and the right mix for a given person will depend on the specific
genetic variations that cause that person to gain weight. Few people
working in the field doubt such a day will come, though it could be another
decade or more before the range of available treatments is varied enough
to permit such a customized approach.
"I think it could take that long, just given the realities of pharmaceutical
development," said Tartaglia, the Millennium researcher. "But there's
certainly going to be exciting drugs that come on the market before that."
Are You Fat?
To calculate your body mass index, multiply your height in inches by your
height in inches and write down the result. Then take your weight in pounds
and multiply by 703. Divide that number by the result of the first
calculation. This is your body mass index.
Example: A man 6 feet tall, weighing 160 pounds, multiplies his height in
inches, 72, by itself to get 5,184. He then multiplies his weight in pounds
by 703 to get 112,480. He divides that number by 5,184 to get a body
mass index of 21.7, a healthy level.
Interpreting your number:
Less than 18.5: You're underweight. See a doctor to rule out hidden
disease. If she says you're okay, hit the pizza shop on the way home.
18.5 to 24.9: You're at a healthy weight. Have a Gummi Bear on your way
to the gym.
25.0 to 29.9: You're overweight and at elevated risk of disease. See a
doctor to plot a fitness program.
Over 30: You're a serious illness waiting to happen. See a doctor, ideally
one specializing in weight problems, for a comprehensive checkup and
fitness plan. Consider weight-loss drugs or, in the most extreme cases,
surgery.
NOTE: Visit www.washingtonpost.com on the Web to find a calculator
that will do the math for you. Note that the standard ranges don't work for
pregnant women or for competitive athletes and body builders with a large
proportion of muscle. They somewhat understate health risks for people
who already have high-blood pressure, heart trouble or other
obesity-linked ailments.
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