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Another promising obesity drug bites the dust

October 3, 2006 By Heidi Ledford This article courtesy of Nature News.

Therapy failure highlights difficulties of tricking the body into shedding pounds.

Efforts to hold back the world's expanding waistline have been dealt another blow this week, as scientists announce disappointing results from a clinical trial of their latest obesity drug.

The test shows that the drug, developed by Merck & Co, Inc. in New Jersey and named MK-0557, works but only a little bit. Overweight or obese patients receiving MK-0557 lost only 1.6 kilograms more than those who were given a placebo over the course of a year.

The results, reported in this month's issue of Cell Metabolism, are statistically significant1. But they are also clinically irrelevant.

"We consider this a negative study," says Steven Heymsfield, a clinical researcher at Merck who evaluated the drug.

Growing failures

The pharmacological rubbish heap has become littered with failed obesity drugs as the pharmaceutical industry rushes to treat the over 1 billion overweight and obese people worldwide.

Many formulations have been discarded because of intolerable side effects, and even the weight-loss aids currently on the market can have unpleasant consequences. Sibutramine causes high blood pressure, and taking Orlistat can produce extremely unpleasant gastrointestinal distress. The up-and-coming drug rimonabant (Acomplia), already approved for use in Europe, causes depression in some users.

Other drugs, like MK-0557, simply don't work well enough to make them worthwhile.

In earlier tests, the drug was the very model of success. MK-0557 entered the brain and bound tightly to the protein that it was designed to inhibit: an appetite-stimulating molecule called neuropeptide Y. Mice ate less when given MK-0557. Human patients experienced no severe side effects. But with such a small impact on weight loss, the nearly decade-long quest to develop MK-0557 has met with a disappointing conclusion.

The results are reminiscent of clinical trials for another candidate obesity drug that targeted leptin, an appetite-modulating hormone produced in fat tissue. Again, the basic research looked promising, but clinical trials indicated that the drug has little effect on obesity.

Fat chance

Heymsfield attributes difficulties with MK-0557 and other obesity drugs to the complexity of the human response to food. Interfering with one pathway may not have a dramatic effect, he argues, because there could be other pathways serving as backup systems.

"I think monotherapies in obesity will have poor prospects," agrees Michael Cowley, a neuroscience professor at Oregon Health & Science University in Portland. "There are well-developed systems and pretty good evolutionary reasons to overeat. So there are likely to be multiple, parallel systems present to help us get big."

Satya Kalra, a neuroscience professor at the University of Florida, Gainesville, argues that a single drug is unlikely to prove a 'magic bullet' as the cause of obesity varies so much between people. "We all know it's very hard to produce appreciable effects in obese patients," says Kalra. "These patients are very heterogeneous"

Kalra argues that scientists should evaluate the ability of MK-0557 to prevent age-related weight gain.

Heymsfield agrees that prevention is important and potentially easier to achieve than weight loss. But he says that consumer demand for a preventative therapy just isn't strong enough. "If insurers would pay for it, and people would buy it, we'd be cranking it out down here," he says. "But the public wants drugs that help them lose weight."

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  1. Erondu N., et al. Cell Metabolism, 4 . 275 - 282 (2006).


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