Investigation of setmelanotide, an MC4R agonist, for obesity in individuals with Smith-Magenis syndrome.

BACKGROUND

Smith Magenis Syndrome (SMS) is a rare genetic disorder caused by RAI1 haploinsufficiency. Obesity in people with SMS is believed partially due to dysfunction of the proximal melanocortin 4 receptor (MC4R) pathway. We therefore studied effects of treatment with the MC4R agonist setmelanotide on obesity and hunger, as well as metabolic, cardiac and safety, in individuals with SMS.

METHODS

People with SMS received once-daily setmelanotide injections, with the dose titrated bi-weekly to a maximum of 3 mg over ∼1 month; and a full-dose treatment duration of 3mo. The primary outcome was percent change in body weight. Secondary outcomes included hunger, waist circumference, body composition, and safety.

RESULTS

12 individuals, ages 11-39 y, enrolled and 10 completed the full-dose treatment phase. Mean percent change in body weight at end-treatment was - 0.28 % [(95 % CI, -2.1 % to 1.5 %; n = 12; P = 0.66]. Participants experienced a significant decrease in total cholesterol associated with a significant decrease in HDL-cholesterol and a trend for lower LDL-cholesterol. Self-reported hunger was reduced at end-treatment (p = 0.011). All participants reported adverse events (AEs), most commonly injection-site reactions and skin hyperpigmentation. No AEs led to withdrawal or death.

CONCLUSIONS

In this trial, setmelanotide did not significantly reduce body weight in participants with SMS. Participants reported significant differences in hunger, but such self-reports are difficult to interpret without a placebo-treated group. The changes in lipid profiles require further investigation. Results of this study do not suggest that dysfunction of the proximal MC4R pathway is the main etiology for obesity in people with SMS.

Informations de copyright

Published by Elsevier Ltd.

Déclaration de conflit d'intérêts

Declaration of Competing Interest This research was sponsored by Rhythm Pharmaceuticals, Inc., which supplied setmelanotide, wrote the original protocol, organized data collection, and gave grant support to each Investigator’s Institution for this study. The Sponsor also had the opportunity to suggest edits to the manuscript and approved submission of the article for publication. JAY also reports grants given to his Institution to support unrelated clinical research from Soleno Therapeutics Inc., medication for an unrelated clinical trial from Hikma Pharmaceuticals, and support for murine studies from Versanis Bio. SRS reports receiving speaking fees from Rhythm Pharmaceuticals. SRS and JES also report grants to their institutions to support unrelated clinical research from Eli Lilly and Co. Jill Garrison is an employee of Rhythm Pharmaceuticals, Inc.