MIT News Office - February 5, 1997
Redux, the well-publicized weight-reduction drug developed
by Professor Richard Wurtman, took more than a decade to get
to market in the United States. But when it won approval last
April, more than two million prescriptions were written in the
first six months.
Professor Wurtman said Redux is an example of why
universities, in addition to pharmaceutical companies, should
continue basic research and development of drugs. He detailed
at an IAP session how the first long-term anti-obesity drug
came into being.
"In the United States we have the National Science
Foundation, which supports basic research, and the National
Institutes of Health, which funds projects to ameliorate the
human condition, so we apply our discoveries," said Professor
Wurtman, who conducts both basic and applied research as
professor of neuropharmacology and Cecil H. Green
Distinguished Professor in the Department of Brain and
Cognitive Sciences and director of the Clinical Research
Center (CRC).
Professor Wurtman used the example of another drug to
illustrate the downside of not following through with medical
inventions. About 25 years ago, he discovered L-tryptophan, a
chemical that induces sleep. He and MIT did not patent it
because at the time they did not know much about medical
patents.
However, in 1988 a Japanese company introduced into America
L-tryptophan, and some two million Americans bought it at
health food stores. "Because there was no patent on it, no
legitimate US drug maker took it on, and it became a
health-store curiosity that was not subject to FDA
regulation," Professor Wurtman said.
"It was made using a newly generated bacterium that was
very efficient and that made a lot of tryptophan. But it also
made some brand-new impurities which no one recognized and
which ended up killing 48 people," he said.
"So that really taught me something. If I discover
something that might be useful for treating a medical
condition, I've got to stay involved with it; otherwise it's
not going to get done [properly]."
That was the case with Redux or dexfenfluramine, a
substance for the treatment of obesity discovered by Professor
Wurtman and his wife, Dr. Judith Wurtman, a research scientist
in brain and cognitive sciences. (The patent is held by MIT
and the Wurtmans.) It was first marketed in Europe and France
about 10 years ago and subsequently sold in 65 countries
outside the United States, where it finally won FDA approval
last spring.
Redux had its roots in research that Wurtman and a student
were conducting in 1971 on tryptophan, an amino acid that is
converted into serotonin in nerve cells in the brain.
Carbohydrates increase serotonin, which acts as an
antidepressant.
"We discovered that there are chemical changes in the
brain, particularly when people eat carbohydrates and sugars
and starches," explained Professor Wurtman. "A few years
later, we discovered that the brain uses this change in
serotonin levels as a signal to determine what you are
eating."
Dr. Judith Wurtman was at the same time was studying
carbohydrate craving in relation to obesity. She suspected
that there is carbohydrate craving which drives some people to
snack on an extra 1,200 to 1,400 calories per day--usually in
the form of carbohydrates and fats.
"Then we went back to our earlier discovery that
carbohydrates increase brain serotonin. We realized that any
drug that increases brain serotonin is also an
antidepressant," Professor Wurtman said. "We came up with a
hypothesis that the reason these people were overeating these
snacks is because they didn't feel good. and that for the few
hours after they ate the carbohydrate snack, they felt better.
We tested this in large numbers of patients and found it to be
the case."
The brain normally maintains a balance in the intake of
carbohydrates, proteins and other nutrients. But Professor
Wurtman said people who crave carbohydrates are different. He
speculated that a chemical or drug that would fool the brain
into thinking it was getting carbohydrates would basically
decrease food intake.
FENFLURAMINE FIRST
The first drug he developed and MIT patented more than a
decade ago was fenfluramine, a molecule that occurs in both
right-handed and left-handed varieties. Even though they look
much the same, their biological actions are quite different.
All the "good" activity--the serotonin-related
activity--resides in the right-handed molecule, and all the
bad side effects results from the left-handed molecule,
Professor Wurtman said. MIT licensed the drug to Servier Co.
of France.
Servier later discovered that there was a commercially
feasible way to separate left-handed and right-handed
fenfluramine, and asked MIT to isolate the right-handed
chemical and see if it would work. It did, and MIT patented
the drug, which was eventually marketed as Redux by
Wyeth-Ayerst Laboratories.
Servier did not have a US branch, so Professor Wurtman and
the company tried to get US drug companies interested in
marketing Redux. There was little interest, he said, because
at the time--about 8 to 10 years ago--obesity was considered a
problem of willpower and was not yet clearly linked with high
death rates in related diseases. Obesity is now considered the
second-largest preventable killer of Americans after smoking;
about 300,000 people a year die from diabetes, high blood
pressure, heart attacks and other side effects of obesity.
LEFT-SIDE `ANTIDOTE'
Unable to move ahead with dexfen-fluramine in this country,
US diet researchers decided to go back to fen-fluramine and
add a third chemical, an "antidote" to the left-handed side.
The third chemical was phentermine, and the drug became
marketed under the name Fen-Phen. But phentermine is a form of
amphetamine, and thus is addictive. Other side effects of
Fen-Phen included drowsiness, dry mouth, pulmonary
hypertension and possible brain damage.
But dexfenfluramine is now on the market, "so at this point
there's no reason for anyone to give Fen-Phen because you're
giving three chemicals, including an amphetamine-like
compound," Professor Wurtman explained. "Now you can give
people only one chemical called Redux."
Professor Wurtman said that some 58 million adult Americans
qualify to take Redux. These people are at least 38 percent
heavier than they should be, or they are 20 percent overweight
and have diabetes, high blood pressure or high blood lipids.
For most people, Redux is a six-to-nine-month treatment; for
others, it is a lifelong treatment combined with education to
manage obesity and lifestyle changes.
"This is the first drug ever to be approved for long-term
treatment of obesity," Professor Wurtman said. "And 12 million
people have taken it in Europe over the past 10-12 years, so
there are more data perhaps than on any other drug that's ever
been introduced in the United States."
The Wurtmans are conducting a year-long weight loss study
at the CRC using Redux combined with a nutritional supplement.
Subjects will be healthy, non-smoking women who are 55-90
pounds overweight.
If you have questions regarding your legal options or
Fen-phen, please contact
us.
