The obesity pipeline: current strategies in the development of anti-obesity drugs

Despite recognition as an epidemic, obesity remains largely an unsolved medical problem, caused by the increased consumption of energy-dense, nutrient-poor foods and reduced physical activity. Obesity is a complex condition associated with numerous increased health risks and affects all ages and socio-economic groups.All but the most severe of cases can be successfully managed through lifestyle changes in diet and physical activity alone, although low compliance has encouraged interest in effective therapies, including gastrointestinal surgery (efficacious and long-lasting, but limited in use because of associated risks and costs) and pharmacological interventions.The market for a safe and efficacious drug is potentially huge, but the value of currently approved therapies does not reflect this potential, this being evidence of their limited efficacy and side-effect profiles.Two drugs are currently approved in the United States for the long-term treatment of obesity: orlistat (Xenical; Roche) and sibutramine (Meridia; Abbott). Orlistat acts on the gastrointestinal system, blocking the absorption of dietary fat, whereas sibutramine acts within the CNS to reduce energy intake and increase energy expenditure. Both display limited efficacy and are compounded by limiting side effects.Rimonabant (Acomplia; Sanofi-Aventis) is a first-in-class cannabinoid CB1 antagonist, recently approved in the European Union for the treatment of obesity, which yielded 12-month weight loss of 6.3 kg versus 1.6 kg for placebo. There are concerns about CB1 antagonism, however.The pipeline of compounds currently in development for the treatment of obesity is reviewed, including APD356, Qnexa, Contrave, Cetilistat and AOD9604.Recent advances in the understanding of the roles gut peptides play in energy homeostasis has led to the identification of several that are known to modulate eating behaviour, including glucagon-like-peptide-1, oxyntomodulin, pancreatic polypeptide and peptide YY3–36, all of which respond to nutrients within the gut, interacting with specific receptors to regulate appetite.Several compounds based on gut peptides now in development for the treatment of obesity are reviewed, including Nastech's intranasal PYY(3–36), 7TM Pharma's TM30338, and Amylin Pharmaceuticals' Pramlintide.