Under development by Sanofi-Aventis, Acomplia (rimonabant) is a selective CB1 endocannabinoid receptor antagonist indicated for the treatment of obesity.

“Acomplia is a selective CB1 endocannabinoid receptor antagonist.”

It works by blocking endogenous cannabinoid binding to neuronal CB1 receptors. Activation of these receptors by endoegenous cannabinoids, such as anadamide, increases appetite. It is the most advanced endocannabinoid receptor antagonist in clinical development and offers a novel therapeutic approach to appetite control and weight reduction.

The drug also has potential as a treatment for smoking cessation because the endocannabinoid system is involved in the body’s response to tobacco dependence.

Acomplia (rimonabant) has been available in Europe since the middle of 2006, following regulatory approval by the EMEA in June 2006 for its use as an adjunct to diet and exercise for obese or overweight patients with associated risk factors, such as type 2 diabetes or dyslipidaeamia. However, it has had a less easy passage through the US regulatory system.

Filed for approval with the FDA in April 2005, it has encountered significant delays over the past two years. In February 2007, the company learnt that the FDA had extended their decision on whether or not to approve Acomplia by a further 3 months. Despite the repeated setbacks, analysts remain optimistic that it will eventually be approved in the US as an aid to weight loss.

OBESITY PREDISPOSES TO SERIOUS ILLNESS

Obesity is now the most common nutritional disorder in western industrialised countries. Defined as a body mass index of greater than 30, it arises from the accumulation of excess fat in the body from over consumption of fatty foods. Prevalence of obesity in the US and Europe has reached epidemic levels.

Data from the World Health Organisation’s MONICA project show that in some parts of Europe over 70% of men aged 55-64 years are clinically obese or overweight (BMI >25) and almost 70% of women in this age group. One in five of all Americans is obese and one in three overweight. Furthermore, increasing rates of childhood obesity are likely to exacerbate the trend towards increasing obesity in adulthood.

here is a strong association between obesity and increased risk of cardiovascular disease and diabetes and possibly certain cancers, such as breast and colorectal cancer.

The dramatic rise in the incidence of type 2 diabetes is due largely to the increased prevalence of obesity. Increases in body weight lead to changes in blood lipid and cholesterol levels, predisposing to increased risk of atherosclerosis.

THERAPEUTIC APPROACHES TO TREATMENT OF OBESITY

Not surprisingly, the growing prevalence of obesity has stimulated the search for drugs to treat this condition. Various therapeutic strategies have been explored, including:

• Serotonin and noradrenaline reuptake inhibitors (anorectic agents)
• Lipase inhibitors
• ß 3-adrenoreceptor agonists
• Leptin agonists
• Melanocortin-3 agonists

Sanofi-Aventis’ approach is completely different to the above. It developed from the knowledge that cannabis smokers often experience extreme hunger pangs, which cannabis smokers refer to as “the munchies”. Sanofi-Aventis worked on the premise that if cannabinoids stimulate appetite, blocking cannabinoid receptors in the brain might reduce appetite.

The central cannabinoid (CB1) receptors are believed to play a role in controlling food consumption and the phenomena of dependence / habituation. To develop suitable drugs against this target, the human cannabinoid receptor was first cloned and then expressed in cells.

Compounds with potential inhibitory activity against this receptor were then screened for inhibitory activity. Rimonabant emerged from this screening process as a potent CB1 receptor antagonist. Preclinical animal studies subsequently showed that it could reduce consumption of fats and sugars, which contribute to weight gain.