First Results of Mercks Taranabant Promising for Weight Loss

Initial experimental studies of a new endocannabinoid agaonist drug are showing that obese patients taking it for 12 weeks lose weight, even at very low doses. The drug, dubbed Taranabant is the second drug that has been developed to fight obesity via blocking of cannabinoid receptors in the brain.

The study suggests that taranabant causes people to both consume fewer calories and burn more. Results appear in the January issue of Cell Metabolism [1]. Cannabinoid receptors are responsible for the psychological effects of marijuana (Cannabis sativa), and natural endocannabinoids are important regulators of energy balance.

“The effects of marijuana on appetite have been known for millennia from its medicinal and recreational use,” according to study author Steven Heymsfield. “The ingredient responsible stimulates cannabinoid receptors. When you block the cannabinoid system with an antagonist like taranabant, you suppress appetite.”

However, the drug, developed by Merck, also comes with an increased risk of adverse side effects at higher doses, the study shows, including mild to moderate gastrointestinal and psychiatric effects.

Rimonabant vs. Taranabant

First proof of concept that so-called cannabinoid 1 receptor (CB1R) inverse agonists might offer an obesity therapy came from studies of another drug, developed by Sanofi-Aventis, called rimonabant, and marketed as Acomplia and Zimulti. That drug is now in use for weight loss in several European countries as an adjunct to diet and exercise but has not received FDA approval for use in the United States.

Taranabant is a structurally unique and highly selective CB1R inverse agonist, according to the researchers. Preclinical studies in animals showed that it can cause weight loss at doses that block just 30 percent of cannabinoid receptors. To extend those findings to humans in the new studies, the researchers first used positron emission tomography (PET) imaging to identify a dose that would bind about 30 percent of cannabinoid receptors in the human brain. They found that 4 to 6 milligrams of taranabant was enough to achieve that goal.

Cannabinoid receptor agonists have also been shown to be neuroprotective against excitotoxicity [2], a process in which nerve cells are damaged and killed by glutamate and similar substances. So a potential positive side effect of taranabant may be added protection against development of degenerative central nervous system diseases like Alzheimer’s disease, Multiple sclerosis, Amyotrophic lateral sclerosis (ALS), and Parkinson’s disease, in those who are at risk for them.

Promising Results

A double-blind, placebo-controlled clinical trial of 533 obese patients showed that the drug induces significant weight loss at doses ranging from 0.5 to 6 milligrams. The researchers then conducted separate food intake and energy expenditure studies in overweight and moderately obese people who took a single 4- or 12-milligram dose of taranabant. Those studies showed that people taking 12 milligrams of the drug consumed 27 percent fewer calories than those taking a placebo. People taking the drug also expended more energy while at rest and appeared to burn more fat.

The studies also found that higher doses of the drug caused two types of adverse events, Heymsfield said. Side effects included gastrointestinal upset, including nausea and vomiting, as well as increased irritability. Marijuana is often used to combat the nausea associated with chemotherapy drugs, Heymsfield noted, and it also tends to make people mellower. “Here, again, [these drugs] have the opposite effect.”

A larger, phase III clinical trial of taranabant is now underway to further explore its effects, Heymsfield said. “All we have here is 12 weeks; we dont yet know what will happen at six months or a year.”Taranabant is being actively worked on by Merck towards the obesity market, and the company intends to file for FDA approval of taranabant in 2008 [3].

References

1. The Acyclic CB1R Inverse Agonist Taranabant Mediates Weight Loss by Increasing Energy Expenditure and Decreasing Caloric Intake Cell Metabolism, Volume 7, Issue 1, 9 January 2008, Pages 68-78
Carol Addy, Hamish Wright, Koen Van Laere, Ira Gantz, Ngozi Erondu, Bret J. Musser, Kaifeng Lu, Jinyu Yuan, Sandra M. Sanabria-Bohórquez, Aubrey Stoch, Cathy Stevens, Tung M. Fong, Inge De Lepeleire, Caroline Cilissen, Josee Cote, Kim Rosko, Isaias N. Gendrano III, Allison Martin Nguyen, Barry Gumbiner, Paul Rothenberg, et al.

2. Neuroprotection by 9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, against Ouabain-Induced In Vivo Excitotoxicity, M. van der Stelt, W. B. Veldhuis, P. R. Bär, G. A. Veldink1, J. F. G. Vliegenthart, and K. Nicolay, The Journal of Neuroscience, September 1, 2001

3. Convenient total synthesis of taranabant (MK-0364), a novel cannabinoid-1 receptor inverse agonist as an anti-obesity agent Tetrahedron Volume 63, Issue 52, 24 December 2007, Pages 12845-12852

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