Does a Drug for Many Ills
Cause Too Many of Its Own?
February 22, 2006
online.wsj.com
When a drug promises to be the health equivalent of a Swiss Army knife, it pays to be skeptical. The more versatile a drug aims to be inside the body, the more potential the medicine has to trigger unwelcome side effects.
A current cautionary tale for wonder drugs to cure a host of common ills is Sanofi-Aventis SA's experimental drug Acomplia, which strives to help the overweight shed pounds, assist smokers quit their habit and lower the risk of cardiovascular disease by restoring blood fats to healthier levels.
Acomplia hit a bump last week when the Food and Drug Administration turned down the French company's application to market the drug for smoking cessation and raised questions (which neither the agency nor the company detailed) about the drug as a diet aid. With obesity an epidemic in this country and growing elsewhere, there's enormous interest and need for a safe drug to melt fat. Analysts' sales forecasts for Acomplia have run upwards of $4 billion a year by 2010, but the market will have to wait at least a while longer as the drug's fate is decided by regulators. Sanofi has been bullish on the drug; even after the FDA setback last week, analysts said the company indicated that approval is expected within months.
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How Acomplia works isn't completely understood, and that may be part of the problem. The medicine, known generically as rimonabant, interferes with receptors in the brain that help regulate appetite and nicotine dependence. These targets are called cannabinoid receptors because marijuana (in Latin, cannibis) stimulates them, causing intense hunger, a side effect that fast-food makers and comedians have exploited for decades. These same receptors are found in fat cells, the liver and muscles, which raises the potential for unintended consequences from the medicine throughout the body.
The development of drugs that work in the brain is particularly tricky because human gray matter still contains vast amounts of uncharted territory. Derek Lowe, a full-time drug scientist and part-time blogger, knows the pitfalls first hand through his research. "Drugs that act on central nervous system receptors can do all kinds of odd stuff, and we most definitely do not know enough about brain chemistry to predict what those interesting surprises might be," Dr. Lowe observed this week in his blog, In the Pipeline. He continued that the understanding of the receptor that rimonabant goes after is even sketchier than others in the brain, a state of affairs that "should be enough to make anyone gaze thoughtfully out the window for a bit" before proceeding with a drug. Indeed, he mused about potential toxic side effects of rimonabant from his lab window two years ago.
Of course, no drug is free of risks. Some side effects for a medicine like Acomplia that affects the brain so profoundly are to be expected. The question for regulators, doctors and patients is whether the drawbacks from Acomplia will outweigh its purported myriad benefits.
Regulators are right to worry about Acomplia, because the drug could spark a fad. Wacky diet crazes fall outside the realm of regulation, but the diet-drug combination known as "fen-phen" was a runaway hit in the 1990s before the part of the cocktail sold by Wyeth was pulled from the market over a link to heart damage.
In overweight patients taking a high dose of Acomplia, some 11.2% developed nausea during the first year, or about twice the rate of those taking a sugar pill, according to a study published last week in JAMA, the Journal of the American Medical Association. Some 6.1% became anxious -- nearly triple the rate of the placebo group. Depressed mood affected 5.2% of patients on the high dose compared with 3.1% on placebo. By one year, nearly half of the patients taking the medicine had dropped out of the study. At the high dose (20 milligrams a day), the drug appeared to help patients lose a modest amount of weight, but the researchers concluded that more study is needed to assess the drug's long-term safety and effectiveness.
Some on Wall Street remain optimistic about Acomplia. Sanford C. Bernstein analyst Gbola Amusa writes that Sanofi most likely will be approved for weight management by the middle of this year. Dr. Amusa suggests that revising the instructions for the drug or agreeing to conduct additional studies post approval may be enough to satisfy the FDA. Sanofi said Friday that it would work with the FDA on the issues.
Acomplia may yet win approval. But the field of drug research is littered with good scientific ideas that failed after trouble popped up in unexpected places. Experimental drugs that inhibit an enzyme called phosphodiesterase-IV, a cousin of an enzyme targeted by impotence blockbuster Viagra, have held promise for helping patients with chronic obstructive pulmonary disease, a constellation of lung problems including emphysema that usually result from smoking. Yet several experimental medicines that work to block the enzyme have been stymied by side effects outside the lungs, where receptors for the same natural chemical also appear.
Meanwhile, the setback for Acomplia may help Pfizer in the short run. The New York drug maker is awaiting word on its novel smoking cessation pill Champix, which targets a specific receptor in the brain for nicotine. Champix isn't free of side effects either, with reports of nausea, headache and some sleep disturbance in clinical tests. Still, if FDA approves Champix later this year, Pfizer will have less to worry about with Acomplia bottled up with regulators.
Looking for risk-free drugs is a fool's errand, but it's equally foolish to ignore the fact that every benefit a medicine offers comes at a price. That price is paid over time in the side effects that patients suffer from medicines that may also help them. Makers of medicines with high promise, like Acomplia, must accept a high burden of proof as their price for admission to the market. |
