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.
Krishna
R
R
Merck and Co., Inc., Whitehouse Station, New Jersey, USA. rajesh_krishna@merck.com
Gumbiner
B
B
Stevens
C
C
Musser
B
B
Mallick
M
M
Suryawanshi
S
S
Maganti
L
L
Zhu
H
H
Han
T H
TH
Scherer
L
L
Simpson
B
B
Cosgrove
D
D
Gottesdiener
K
K
Amatruda
J
J
Rolls
B J
BJ
Blundell
J
J
Bray
G A
GA
Fujioka
K
K
Heymsfield
S B
SB
Wagner
J A
JA
Herman
G A
GA
D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D001066:Appetite / Q000187:drug effects*; D001067:Appetite Depressants / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018592:Cross-Over Studies; D003503:Cyclobutanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D002149:Energy Intake / Q000187:drug effects*; D004739:England; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D011759:Pyrrolidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists* / Q000378:metabolism; D013997:Time Factors; D017211:Treatment Failure; D014481:United States; D015431:Weight Loss / Q000187:drug effects*; D055815:Young Adult
D000081:Acetamides; D001067:Appetite Depressants; D003503:Cyclobutanes; C470072:MC4R protein, human; C545557:N-1-(2-(1-(tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl)-5-chlorophenyl)ethyl)acetamide; D011759:Pyrrolidines; D044105:Receptor, Melanocortin, Type 4; C058254:sibutramine