Obesity ArticlesThe articles that follow below relate to 2 early...

Obesity Articles
The articles that follow below relate to 2 early stage competitive obesity drug developments and a revised Medicare obesity policy.



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David Kenley
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Metabolic Pharmaceuticals Ltd

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"Revised Medicare Obesity Policy Opens Door to Evidence-based Coverage" Published by NAASO.

Health and Human Services Secretary Tommy G. Thompson announced a new policy today from HHS Centers for Medicare and Medicaid Services that removes language in the Medicare Coverage Issues Manual stating, "obesity is not an illness." This change opens the door to obesity coverage based on scientific evidence.

Secretary Thompson today, in testimony before the Senate Appropriations Subcommittee on Labor, Health an Human Services and Education stated, ""With this new policy, Medicare will be able to review scientific evidence in order to determine which interventions improve health outcomes for seniors and disabled Americans who are obese and its many associated medical conditions."

Louis J. Aronne, MD, NAASO President-Elect, commented "while this won't provide full access to medical treatment of obesity, this is a big step in the right direction." Gary Foster, PhD, Chairman, NAASO Public Affairs Committee added that NAASO is already working with other groups in Washington to follow-up on this important announcement. "We will keep working on this issue, it a priority for NAASO and our Public Affairs program," he said.


About NAASO

The North American Association for the Study of Obesity (NAASO) is the leading scientific society dedicated to the science of obesity research, treatment and management. Its members, many of them leaders in the field, include basic and clinical researchers and clinicians from diverse backgrounds and training. The official NAASO journal, Obesity Research, is a peer-reviewed, monthly publication and the premier publication in the obesity field.

Website: http://naaso.org




Fat hormone faces problems:
"In Nature, 12 labs fail to replicate effects of PYY3-36 on appetite and body mass" By Stuart Blackman


A paper published online with the July 8 issue of Nature delivers a heavy blow to the reputation of one of the prime candidates for a chemical treatment for obesity. Forty-two scientists, from 12 labs, report that they have failed to replicate the effects described in a 2002 study of the gut-derived hormone PYY3-36 on body mass and appetite in rodents.

In 2002, Steve Bloom's lab at London's Imperial College reported that peripheral administration of PYY3-36 reduced appetite and body mass in rats. They followed this up with data showing that it also suppressed appetite in humans over a 24-hour period. The finding that endogenous PYY levels were lower in obese subjects suggested that the peptide plays a causal role in obesity. Furthermore, PYY levels dipped and peaked, respectively, before and after eating—evidence that it regulates appetite on a meal-to-meal basis.

Matthias Tschöp's group at the University of Cincinnati's Obesity Research Center set about repeating the rodent work. Tschöp, first author of the 42-name paper, says he realized the significance of his own failure to find an effect of PYY when heard of similar experiences from other groups. "We decided to get together and share our data," he told The Scientist. "The credibility of our paper is largely derived from the fact that a large number of independent groups found these results."

"We're cited as being the only other group to have supported [Bloom's work] and that's true to some extent," said Cambridge University geneticist Steve O'Rahilly, who is involved with neither Bloom's nor Tschöp's papers. "We show that if you give injections under certain circumstances to one strain of mice, we can get a persistent 24-hour suppression of food intake." But, O'Rahilly told The Scientist, "we don't see a persistent effect over 7 days."

One potential reason PYY failed to work could be stress, according to an online response to Tschöp's paper. Bloom and his colleagues write that if appetite is already low, PYY will have less room for influence. As Jeffrey Flier of Beth Israel-Deaconess Medical Center explained, "more often than not, when you do something stressful to a laboratory mouse, it will eat less." Still, Bloom cited a new paper from Amylin Pharmaceuticals that supports the effect of PYY on food intake and body mass in a variety of rodent models.

Recent work by Roger Cone of Oregon Health and Science University, who coauthored Bloom's response, supports PYY's role in appetite, but only under certain, low-stress experimental conditions. "Cone describes precisely what he does to create the non-stressed condition," said Flier, who is not connected to either study. "And when he does that, he sees an effect of PYY. When he doesn't do that, all the animals eat less."

"We have reliable responses in nonstressed animals," said Bloom. "The fact that they [Tschöp et al.] are not getting responses makes me feel that their animals are stressed."

But Tschöp said that strict acclimation protocols were applied. "We are not stressing our animals," he said. "They are eating normally, and we can show suppression of food intake with several other drugs."

Meanwhile, Bloom's findings that PYY3-36 suppresses appetite in humans remain unchallenged, if unrepeated. Bloom said that longer-term human trials, which he had scheduled for this year, have been delayed by the implementation on May 1 of the European Union's clinical trials directive, which raises the requirements for animal toxicity testing before a molecule can be tried on humans.

Bloom doesn't expect stress to be an obstacle to potential therapies in humans. "It's not going to be useful for a condemned man, or the night before you have a heart transplant, but I think as far as humans are concerned, it's going to be useful in any ordinary circumstance," he said.

But few are so confident. "The bottom line is that PYY is less potent a factor than the earlier studies would have led you to believe," said Flier. "But I'm not prepared at this stage to say it's irrelevant."

"It's not often in the pages of Nature that you see such an obvious face-off between one group and another," said O'Rahilly. "And the truth will be in its usual boring place, somewhere in the middle."

"PYY is, at the very least, less robust as a factor than people had been thinking, hoping, or expecting," said Flier. "If this was a stock market for PYY, the price will have gone down substantially, but it may well be that this is a smart time for someone to buy!"




"Cancer Worries Dog New Anti-Fat Drugs"
Matthew Herper, 07.15.04, 6:00 AM ET

NEW YORK - Americans get fatter every year, and drug companies are racing to treat the resulting health problems--but first they have to prove to the U.S. Food and Drug Administration that their anti-fat drugs don't cause cancer. That hurdle is delaying the development of a particularly promising group of drugs for treating obesity-related health problems.


These drugs are the PPAR agonists, which aim to trip master switches in the cell that control the absorption of fat and sugar in the bloodstream. By modifying these switches, called peroxisome proliferator activated receptors (PPARs), these drugs would help treat diabetes and heart disease before they become serious. PPAR agonists could become a major treatment for the bad diets, bad exercise habits and bad genetics that lead to heart attacks and dangerously high levels of blood sugar.

That appeal has led nearly every major drug company--including GlaxoSmithKline (nyse: GSK - news - people ), Amgen (nadsaq: AMGN - news - people ) and Pfizer (nyse: PFE - news - people )--to set up programs to develop PPAR agonists. But several such drugs have been shown to cause cancer in rodents after years of exposure. That problem caused both Merck (nyse: MRK - news - people ) and Novo-Nordisk to drop their own PPAR drugs. So the Food and Drug Administration (FDA) is requiring companies developing drugs that hit any of the three PPAR receptors to conduct two-year rodent studies before conducting any human tests that will last longer than six months.

One entrant, a drug from Eli Lilly (nyse: LLY - news - people ) and partner Ligand Pharmaceuticals (nasdaq: LGND - news - people ), was just pushed back at least 18 months by the FDA. But two leaders in the PPAR race--AstraZeneca (nyse: AZN - news - people ) and Bristol-Myers Squibb (nyse: BMY - news - people )--say they have already conducted the required tests and submitted them to the FDA; the companies don't expect a delay. Still, two researchers closely associated with PPAR research are questioning whether the rat cancer can be extrapolated to humans in this case.

"I still think it's overplayed," says Ralph DeFronzo of the University of Texas Health Science Center in San Antonio. He points out that many people are dying from untreated diabetes or heart disease. Moreover, weak drugs targeting a PPAR receptor associated with heart disease have been around for decades. These PPAR alpha drugs include Lopid, which is available in generic form but developed by Pfizer. "To start raising issues about alpha drugs, which have been around for 30 years, to me is insane," DeFronzo says.

Besides, the two researchers say, mice and rats are especially susceptible to cancer. "They're a horrible model system!" says Ronald Evans, a Salk Institute researcher who did early work on the receptors. "We know that the overlap between toxicities in rodents and humans is significant, but it's far from perfect. It's probably a shared overlap of 30%." He predicts that the new requirements will cause fewer medicines to be developed.

But some researchers see caution as perhaps warranted. Steven Nissen, a cardiologist at the Cleveland Clinic who is working with some PPAR drugs, points out that hitting the PPAR receptors turns on dozens of genes. "It's not clear what all the genes turned on by the PPARs actually do," he says. "Some of these may be good, but others may not."

"These could be spectacular drugs," adds Nissen, "but right now they're a bit of a blunt instrument