Designers of anti-obesity drugs have suffered three major setbacks, but the potential reward from treating the world’s fat epidemic is so great that their quest is unlikely to be deterred.
After investing a sum rumored to be in the hundreds of millions of euros, Sanofi-Aventis of France announced this month it was abandoning its drug rimonabant, which had stoked huge expectations at its launch in 2006.
Rimonabant — brand name Acomplia — ran into a flurry of ever-tougher warnings from European watchdogs about potential psychiatric side effects, including depression.
Last month, the European Medicines Agency (EMEA) recommended that rimonabant be pulled from sale in Europe. The drug had never been able to gain approval in the all-important US market.
Also this month, the US giant Pfizer put a stop to tests of a prototype in late-stage development called CP-945,598, citing regulatory hurdles.
“The risk/benefit profile in this class of drugs was lower than expected for obtaining market authorization,” said Catherine Baulac, in charge of new products with Pfizer’s French subsidiary.
And on Oct. 2, Merck of the US pulled the plug on its own experimental obesity fighter, taranabant, because of concerns about anxiety and depression at high doses.
The main causes of obesity — overconsumption of fatty or sugary food and a sedentary lifestyle — are well known. But the molecular machinery that drives it is in many ways obscure and it is now suspected, more complex than thought.
Treating obesity entails a limited basket of options, from lifestyle changes to drugs and gastric-bypass surgery.
But when it comes to that middle choice, the most promising class of new prescription medicines for treating long-term obesity has just been wiped out.
The three scratched drugs belong to a group called cannabinoid receptor antagonists.
They take on the same target in the central nervous system as marijuana. But instead of sharpening appetite — the “munchies” associated with smoking cannabis — they work in reverse, dulling the urge to eat.
“There are now just two drugs left, orlistat and sibutramine,” said Colin Waine, a doctor who is chairman of a British organisation, the National Obesity Forum.
Anders Sjoedin, a specialist in obesity drugs at the University of Copenhagen, Denmark, said cannabinoid receptor antagonists had now been discredited as an approach.
“Cannabinoid receptors not only regulate the appetite, they also affect mood,” he said.
Orlistat, marketed as Xenical or alli, curbs absorption of fat in the intestine by blocking a pancreatic enzyme. Sibutramine, sold as Reductil or Meridia, affects levels of a brain chemical called serotonin, believed to influence feelings of hunger or satiety.
Both are “very useful,” Waine said.
But they come with a list of side effects, including, in orlistat’s case, the risk of sudden, oily feces. As proof of the glittering allure of the obesity market, drug engineers are exploring unusual paths.
The WHO said around 400 million adults were obese in 2005, and the tally is expected to balloon to more than 700 million in 2015.
In the lab, at least, are potential rivals to orlistat in the field of lipase inhibitors, new neurotransmitter inhibitors that reduce appetite and even a hydrogel pill that expands in the stomach to give a sense of fullness.
But, should these prototypes ever get the green light to go on sale, will they meet the hopes of people desperate to lose dozens of kilos in a year rather than just a few? Even more important, are they safe?
Eleven years ago, the search for an obesity drug ran into controversy when fenfluramine, an appetite suppressant, was banned in the US over fears of its effect on the heart. This month, a study published in the journal BioMed Central found fenfluramine’s damage to cardiac valves was visible seven years later.
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