Neuropeptide Y5 receptor antagonism does not induce clinically meaningful weight loss in overweight and obese adults
Ngozi Erondu, Ira Gantz, Bret Musser, Shailaja Suryawanshi, Madhuja Mallick, Carol Addy, Josee Cote, George Bray, Ken Fujioka, Harold Bays, Priscilla Hollander, Sandra M Sanabria-Bohórquez, WaiSi Eng, Bengt Långström, Richard J Hargreaves, H Donald Burns, Akio Kanatani, Takehiro Fukami, Douglas J MacNeil, Keith M Gottesdiener, John M Amatruda, Keith D Kaufman, Steven B Heymsfield, Ngozi Erondu, Ira Gantz, Bret Musser, Shailaja Suryawanshi, Madhuja Mallick, Carol Addy, Josee Cote, George Bray, Ken Fujioka, Harold Bays, Priscilla Hollander, Sandra M Sanabria-Bohórquez, WaiSi Eng, Bengt Långström, Richard J Hargreaves, H Donald Burns, Akio Kanatani, Takehiro Fukami, Douglas J MacNeil, Keith M Gottesdiener, John M Amatruda, Keith D Kaufman, Steven B Heymsfield
Abstract
Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. The hypothesis was then tested in a 52 week, multicenter, randomized, double-blind, placebo-controlled trial involving 1661 overweight and obese patients. Although statistically significant at 52 weeks, the magnitude of induced weight loss was not clinically meaningful. These observations provide the first clinical insight into the human NPY-energy homeostatic pathway and suggest that solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy.
Source: PubMed