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

Collet TH; Dubern B; Mokrosinski J; Connors H; Keogh JM; Mendes de Oliveira E; Henning E; Poitou-Bernert C; Oppert JM; Tounian P; Marchelli F; Alili R; Le Beyec J; Pépin D; Lacorte JM; Gottesdiener A; Bounds R; Sharma S; Folster C; Henderson B; O'Rahilly S; Stoner E; Gottesdiener K; Panaro BL; Cone RD; Clément K; Farooqi IS; Van der Ploeg LHT

doi:10.1016/j.molmet.2017.06.015

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Journal article

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

Collet TH University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom; Service of Endocrinology, Diabetes and Metabolism, University Hospital of Lausanne, Lausanne, 1011, Switzerland.
Dubern B Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Trousseau and Pitié-Salpêtrière Hospitals, F-75013, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMR_S 1166, INSERM, F-75013, Paris, France.
Mokrosinski J University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom.
Connors H Rhythm Pharmaceuticals, 500 Boylston Street, Boston, MA, 02116, USA.
Keogh JM University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom.
Mendes de Oliveira E University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom.
Henning E University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom.
Poitou-Bernert C Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Trousseau and Pitié-Salpêtrière Hospitals, F-75013, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMR_S 1166, INSERM, F-75013, Paris, France.
Oppert JM Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Trousseau and Pitié-Salpêtrière Hospitals, F-75013, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMR_S 1166, INSERM, F-75013, Paris, France.
Tounian P Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Trousseau and Pitié-Salpêtrière Hospitals, F-75013, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMR_S 1166, INSERM, F-75013, Paris, France.
Marchelli F Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Trousseau and Pitié-Salpêtrière Hospitals, F-75013, Paris, France.
Alili R Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Trousseau and Pitié-Salpêtrière Hospitals, F-75013, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMR_S 1166, INSERM, F-75013, Paris, France.
Le Beyec J Assistance Publique, Hôpital Pitié-Salpêtrière-Charles Foix, Department of Endocrine and Oncological Biochemistry, F-75651, Paris, France; Sorbonne Université, UPMC Univ, Paris 06, France; Inserm UMR1149, F-75890, Paris, France.
Pépin D Assistance Publique, Hôpital Pitié-Salpêtrière-Charles Foix, Department of Endocrine and Oncological Biochemistry, F-75651, Paris, France.
Lacorte JM Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Trousseau and Pitié-Salpêtrière Hospitals, F-75013, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMR_S 1166, INSERM, F-75013, Paris, France; Assistance Publique, Hôpital Pitié-Salpêtrière-Charles Foix, Department of Endocrine and Oncological Biochemistry, F-75651, Paris, France.
Gottesdiener A Rhythm Pharmaceuticals, 500 Boylston Street, Boston, MA, 02116, USA.
Bounds R University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom.
Sharma S Rhythm Pharmaceuticals, 500 Boylston Street, Boston, MA, 02116, USA.
Folster C Rhythm Pharmaceuticals, 500 Boylston Street, Boston, MA, 02116, USA.
Henderson B Rhythm Pharmaceuticals, 500 Boylston Street, Boston, MA, 02116, USA.
O'Rahilly S University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom.
Stoner E Rhythm Pharmaceuticals, 500 Boylston Street, Boston, MA, 02116, USA.
Gottesdiener K Rhythm Pharmaceuticals, 500 Boylston Street, Boston, MA, 02116, USA.
Panaro BL Lunenfeld-Tanenbaum Research Institute, Department of Medicine, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada; Vanderbilt University, Department of Molecular Physiology and Biophysics, Nashville, TN, 37235, USA.
Cone RD Vanderbilt University, Department of Molecular Physiology and Biophysics, Nashville, TN, 37235, USA; Life Sciences Institute and Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, 48105, USA.
Clément K Institute of Cardiometabolism and Nutrition (ICAN), Assistance Publique-Hôpitaux de Paris, Trousseau and Pitié-Salpêtrière Hospitals, F-75013, Paris, France; Sorbonne Université, UPMC Univ Paris 06, UMR_S 1166, INSERM, F-75013, Paris, France. Electronic address: karine.clement@aphp.fr.
Farooqi IS University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Box 289, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 0QQ, United Kingdom. Electronic address: isf20@cam.ac.uk.
Van der Ploeg LHT Rhythm Pharmaceuticals, 500 Boylston Street, Boston, MA, 02116, USA. Electronic address: lvanderploeg@rhythmtx.com.

2017-10-17

Published in:

Molecular metabolism. - 2017

Receptor, Melanocortin, Type 4

English 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.

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