Endocrine Abstracts

Obesity is a complex condition associated with numerous increased health risks caused by reduced physical activity and an increased consumption of energy-dense foods. It affects all ages and socio-economic groups, and is rising to global epidemic proportions.

Lifestyle changes in diet and physical activity are capable of treating all but the severest cases of obesity, although low compliance is fuelling interest in effective therapies, including gastrointestinal surgery (efficacious and long-lasting, but costly and with associated risks) and pharmacological interventions.

Despite the market potential, the value of currently approved therapies is modest due to limited efficacy and side-effect profiles. A significant requirement exists for a safe, ethical and efficacious treatment.

Two drugs are currently approved in the United States for the long-term treatment of obesity: orlistat (Xenical; Roche) and sibutramine (Meridia; Abbott). Orlistat blocks the absorption of dietary fat by inhibiting gastrointestinal lipases, whereas sibutramine acts within the CNS to reduce energy intake and increase energy expenditure. Both display limited efficacy and are compounded by side effect profiles.

Recently approved in Europe for the treatment of obesity is Rimonabant (Acomplia; Sanofi-Aventis) a first-in-class cannabinoid CB1 antagonist, which yielded 12-month weight loss of 6.3 kg versus 1.6 kg for placebo.

The pipeline of compounds currently in development for the treatment of obesity includes Arena’s serotonin receptor agonist (APD356), Vivus’ amphetermine/anticonvulsant combination (Qnexa), Orexigen’s Contrave, Alizyme’s Cetilistat and Metabolic Pharmaceutical’s AOD9604.

Understanding of the roles gut peptides play in energy homeostasis has identified several that are known to modulate eating behaviour, including GLP-1, oxyntomodulin, PP and PYY(3–36), all of which respond to nutrients within the gut to regulate appetite. Subsequently several compounds based on gut peptides are now in development for the treatment of obesity, including Nastech’s intranasal PYY(3–36), 7TM Pharma’s TM30338, Amylin Pharmaceuticals’ Pramlintide, and Thiakis’ oxyntomodulin.