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.
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 eight to10 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.
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. For more information, call x3-3437.
A version of this article appeared in MIT Tech Talk on February 5, 1997.