Potent and Selective Agonism of the Melanocortin Receptor 4 With MK‐0493 Does Not Induce Weight Loss in Obese Human Subjects: Energy Intake Predicts Lack of Weight Loss Efficacy

MK‐0493 is a novel, potent, and selective agonist of the melanocortin receptor 4 (MC4R), one of the best‐validated genetic targets and considered one of the most promising for the development of antiobesity therapeutics. An ad libitum energy‐intake model was qualified with excellent reproducibility: the geometric mean ratio (GMR) with 95% confidence interval (CI) for total energy intake over a period of 24 h for 30 mg sibutramine/placebo was 0.82 (0.76, 0.88), and for 10 mg sibutramine/placebo it was 0.98 (0.91, 1.05). MK‐0493 showed a small and marginally significant effect on 24‐h energy intake, whereas 30 mg of sibutramine caused a significant reduction in total 24‐h energy intake; specifically, the GMR (95% CI) for 30 mg sibutramine/placebo was 0.79 (0.74, 0.85). MK‐0493 was associated with modest weight reduction from baseline but had only small, statistically insignificant effects relative to placebo after 12 weeks in a fixed‐dose study and also after 18 weeks of stepped‐titration dosing. We conclude that agonism of MC4R is not likely to represent a viable approach to the development of antiobesity therapeutics. Clinical Pharmacology & Therapeutics (2009) 86 6, 659–666. doi: 10.1038/clpt.2009.167 TRIAL REGISTRATION: This study has been registered at clinicaltrials.gov on 6/1/2007 (NCT00482196).