Will a New Drug Melt the Pounds? It May, but Doctors Urge Caution - New York Times

December 5, 2004

By GINA KOLATA

o people who have struggled for a lifetime to lose weight, the new drug called rimonabant sounds like a dream come true.

It will make a person uninterested in fattening foods, they have heard from news reports and word of mouth. Weight will just melt away, and fat accumulating around the waist and abdomen will be the first to go. And by the way, those who take it will end up with higher levels of H.D.L., the good cholesterol. If they smoke, they will find it easier to quit. If they are heavy drinkers, they will no longer crave alcohol.

"Holy cow, does it also grow hair?" asked Dr. Catherine D. DeAngelis, editor of The Journal of the American Medical Association.

At obesity treatment centers, nearly every patient asks for rimonabant - or Acomplia, as it will be called if its maker, Sanofi-Aventis, gets approval to market it in the United States.

But many medical researchers say not so fast. While rimonabant may be intriguing, these experts say, the mythology in the making is hardly justified by what is known so far.

There are no published studies from clinical trials to justify any of the claims for what some patients are already calling a miracle drug. The data that the company has presented indicate that rimonabant is about as effective for weight loss in obese people as two other drugs already on the market. Nor are there any clinical tests to indicate how or whether it would work in people who are only moderately overweight, hoping to lose a few pounds after the holidays.

Rimonabant has not been approved for sale in the United States or anywhere else. Sanofi-Aventis has not yet submitted its application for marketing to the Food and Drug Administration. The company says it plans to apply early next year. If the agency decides it is a high-priority application, it must issue its decision within 6 months; if not, it has 10 months to decide.

All that adds up to a problem, says Dr. Madelyn Fernstrom, who directs the weight-management center at the University of Pittsburgh Medical Center.

"It's disturbing, in my view, the amount of attention this compound is getting," Dr. Fernstrom said. "I'm underwhelmed by the results so far."

Dr. Jeffrey Flier, an obesity researcher at Harvard Medical School who consults for several biotechnology companies, says he regularly gets calls from venture capitalists and other drug companies asking what he knows. "The question is, 'Is this stuff any good?' " Dr. Flier said. "Or, 'I hear it's not quite as good as somebody thinks it is.' " He tells them, he says, that "from what I hear it's not good enough to have this sort of hype around it."

Dr. Fernstrom says the enthusiasm of patients for rimonabant reflects the desperation that obese people often feel. Most have failed with diet after diet. The two drugs on the market for obesity, sibutramine (sold under the brand name Meridia), which diminishes appetite by affecting brain neurotransmitters, and xenical (sold as Orlistat), which blocks the absorption of fat from the intestines, result in modest weight loss. And rimonabant has a story that seems to make sense.

Rimonabant blocks a protein in brain cells that allows cannabis, the active ingredient in marijuana, to work. It also blocks the body's own versions of cannabis, the so-called endocannabinoids. Marijuana is supposed to increase appetite. So a drug that blocks cannabis, it seems logical, should suppress the appetite.

Obese people have more receptors for endocannabinoids than thin people, said Dr. F. Xavier Pi-Sunyer, a professor of medicine at Columbia University and the principal investigator of a large rimonabant study in the United States and Canada. The drug does not completely block these receptors, Dr. Pi-Sunyer said.

The idea of blocking these receptors worked in animals.

For example, mice that were genetically engineered so they could not respond to endocannabinoids ate less and were thinner than normal. And when scientists at Sanofi-Aventis gave rimonabant to obese mice, the animals ate much less, lost 20 percent of their body weight, and had lower levels of blood glucose and lipids, risk factors for diabetes and heart disease.

Rimonabant, said Dr. Jeffrey Friedman, an obesity researcher at Rockefeller University, "is the first in what I think will be a wave of rational therapies" that attack what has recently been learned about how eating is controlled. But with rimonabant, he said, "the issue is, what's the safety and efficacy?"

The company says it has enrolled more than 13,000 subjects in clinical trials asking if the drug helps with weight loss, or smoking cessation, and whether it improves cholesterol and triglyceride levels and reduces blood sugar levels. The weight loss studies are furthest along.

Dr. Pi-Sunyer's study involved 3,500 people at 74 medical centers. Eighty percent were women, weighing an average of 220 pounds. A year later, as a group, they had lost an average of about 14 pounds.

Half dropped out along the way. Some cited problems like nausea. Another reason, said Dr. Douglas Green, the company's vice president for regulatory affairs, is that the study subjects had expected to be thin, and they were not. "They are looking to go from being obese to someone who can suddenly show up in a swimsuit at a beach," Dr. Green said. "That's their expectation."

In presenting its findings, the company discarded thousands of participants who dropped out. Some say that is reasonable because it shows what can happen if people stay with a treatment. But statisticians often criticize it, saying it can make results look better than they are. "It's a well-known bias," said Dr. David Freedman, a statistician at the University of California, Berkeley.

With an analysis limited to those who stayed in the study, rimonabant resulted in an average weight loss of about 19 pounds, Dr. Pi-Sunyer said. In comparison, patients who received a placebo and who, like the rimonabant patients, were given a diet and consultations with a dietician, lost about 5 pounds in a year.

Patients hit plateaus after about 34 weeks, when their weight loss ceased. If they stopped taking the drug, they gained back all they had lost, but the hope is that if people continue taking the drug indefinitely, they can maintain that weight loss and gain health benefits, Dr. Pi-Sunyer said.

Those health benefits, he added, include higher levels of H.D.L. and lower levels of triglycerides, an effect that could reduce the risk of heart disease. They also include increased sensitivity to insulin, which could reduce the risk of diabetes. Blood pressure, however, was unchanged, even though weight loss normally results in lower blood pressure.

Dr. Louis Aronne, a researcher for the company's study in the United States and director of the Comprehensive Weight Control Program, a diet center in New York, said the goal was not to make fat people slender. "This is a disease-modification program," Dr. Aronne said. "This is not for looking better."

But other scientists say the health benefits remain to be seen.

Dr. Rudolph Leibel, an obesity researcher at Columbia Presbyterian Medical Center, noted that a side effect of rimonabant was nausea. "The patients who stick with it seem to get past that," he said. "But that's probably the reason for the significant dropout. One of the things that's going to be very critical to determine, and that we won't know until we see the papers, is whether there is an aversive quality to the drug."

Another concern, obesity researchers say, is possible long-term effects of taking the drug for life.

"What else is this doing to the brain?" Dr. Leibel asked. "We know little or nothing." Yet over and over again in drug development, he said, it has turned out that "long-term consequences are different than we might expect."

Still, he and others say, rimonabant is a start. It represents a new way to help people lose weight, and might become one of several drugs that hit the body's weight regulatory system in different places, enhancing each other's effects.

Dr. Pi-Sunyer says a combination of drugs may someday be found to effectively treat obesity. As for rimonabant, he said, "it's another drug in the armamentarium; it shouldn't be called a miracle."

Dr. Flier said he had similar advice for the drug companies and venture capitalists who call him: "I tell them, 'Don't stop doing research because of this.' "

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