ACOMPLIA - 等待FDA 審查通過的肥胖症新藥

Under development by Sanofi-Aventis (formerly Sanofi-Synthelabo), Acomplia (rimonabant) is a selective CB1 endocannabinoid receptor antagonist indicated for the treatment of obesity. The drug, which has progressed to phase III development, 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 only endocannabinoid receptor antagonist in clinical development and thus offers a unique therapeutic approach to appetite control and weight reduction. The drug also has potential as a treatment for smoking cessation because the endocannabinoid system is also involved in the body's response to tobacco dependence. On the back of successful clinical trials in overweight and obese subjects, Sanofi-Aventis plans to file an NDA with the FDA during the first half of 2005 and, if successful, hopes to bring the drug to market in early 2006. 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 overconsumption 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. There 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. PHASE III DATA HIGHLIGHT EFFICACY AND SAFETY The promising preclinical findings with Acomplia (rimonabant) have been confirmed in studies in man. Results from a 16-week phase II trial showed that treatment with rimonbant produced significant weight loss in obese patients and was well tolerated. Phase III trials involving over 6,000 obese subjects are now ongoing in both the US and Europe. These trials will compare rimonabant at doses of 5mg and 20mg with placebo with respect to weight reduction and prevention of weight gain. Two additional trials involving about 1,000 patients each will assess the efficacy and safety of rimonabant in obese patients with concomitant type 2 diabetes and dyslipidaemia. At the European Society of Cardiology (ESC) meeting in August 2004, data were presented from the first year of the two-year multicentre Rimonabant In Obesity - Europe (RIO-Europe) phase III trial. Results showed that overweight and obese patients taking rimonabant 20mg/d achieved significant reductions in body weight, waist circumference (an indicator of abdominal obesity) and improved lipid and glycaemic profiles. Rimonabant also had a significant impact on metabolic CVD risk factors; greater than that expected by weight loss alone. These findings are consistent with results from the RIO-Lipids trial, the results of which were presented at the 2004 meeting of the American College of Cardiology. Again, treatment with rimonabant 20mg/d was associated with significant benefits in terms of weight loss, waist circumference and lipid and glycaemic profiles in overweight and obese subjects. Efficacy and safety in long-term use is important feature of any antiobesity drug. Some potential antiobesity medications have proved effective in the first six months of treatment only to lose effectiveness as subjects develop resistance to treatment. Long-term safety is a major concern. In the US, the FDA generally requires two years of safety data before approving antiobesity drugs. Results from the phase III RIO trial programme suggest rimonabant is well tolerated. More safety data, including drop-out rates and weight rebound after treatment, awaits the release of final results from the two-year trial which is anticipated in early 2005. MARKETING COMMENTARY The market for weight-reducing drugs has had a somewhat chequered history, characterised by major product withdrawals. Although the statistics suggest a market with enormous opportunity, pharmaceutical companies have so far been unable to capitalise on the need for antiobesity agents. Only two drugs are approved for long-treatment of obesity. They are the lipase inhibitor orlistat, the leading medicine for weight reduction, and sibutramine. Use of both products has been limited by side effects. In the prevailing market there is a clear opportunity for an effective and well tolerated antiobesity drug. Acomplia (rimonabant) is a promising candidate that appears devoid of the side effects seen with current agents, which restricts their clinical use.