Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.

Abstract

OBJECTIVE:

Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.

METHODS:

We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.

RESULTS:

In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.

CONCLUSIONS:

Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

• Authors: Tinh-Hai Collet, Béatrice Dubern, Jacek Mokrosinski, Hillori Connors, Julia M Keogh, Edson Mendes de Oliveira, Elana Henning, Christine Poitou-Bernert, Jean-Michel Oppert, Patrick Tounian, Florence Marchelli, Rohia Alili, Johanne Le Beyec, Dominique Pépin, Jean-Marc Lacorte, Andrew Gottesdiener, Rebecca Bounds, Shubh Sharma, Cathy Folster, Bart Henderson, Stephen O'Rahilly, Elizabeth Stoner, Keith Gottesdiener, Brandon L Panaro, Roger D Cone, Karine Clément, I Sadaf Farooqi, Lex H T Van der Ploeg
• Journal: Molecular metabolism (Mol Metab) Vol. 6 Issue 10 Pg. 1321-1329 (10 2017) ISSN: 2212-8778 [Electronic] Germany
• PMID: 29031731 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

Chemical References

• MC4R protein, human
• MC4R protein, mouse
• Receptor, Melanocortin, Type 4
• setmelanotide
• alpha-MSH
• Pro-Opiomelanocortin

Topics

• Adrenal Insufficiency (drug therapy, metabolism)
• Adult
• Amino Acid Sequence
• Animals
• Female
• HEK293 Cells
• Humans
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Obesity (drug therapy, metabolism)
• Pro-Opiomelanocortin (deficiency, metabolism)
• Receptor, Melanocortin, Type 4 (agonists, deficiency, genetics, metabolism)
• alpha-MSH (analogs & derivatives, pharmacology)