A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway.
Hyperpigmentation
Leptin receptor
Leptin-melanocortin pathway
Melanocortin-1 receptor
Melanocortin-4 receptor agonist
Proopiomelanocortin
Journal
Skin pharmacology and physiology
ISSN: 1660-5535
Titre abrégé: Skin Pharmacol Physiol
Pays: Switzerland
ID NLM: 101188418
Informations de publication
Date de publication:
2021
2021
Historique:
received:
21
10
2020
accepted:
25
03
2021
pubmed:
1
6
2021
medline:
14
1
2022
entrez:
31
5
2021
Statut:
ppublish
Résumé
Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist setmelanotide in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with setmelanotide, changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist setmelanotide. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of setmelanotide treatment. Setmelanotide treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.
Sections du résumé
BACKGROUND AND OBJECTIVES
OBJECTIVE
Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist setmelanotide in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with setmelanotide, changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety.
METHODS
METHODS
In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist setmelanotide. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study.
RESULTS
RESULTS
We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of setmelanotide treatment.
DISCUSSION
CONCLUSIONS
Setmelanotide treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.
Identifiants
pubmed: 34058738
pii: 000516282
doi: 10.1159/000516282
doi:
Substances chimiques
Leptin
0
Melanocortins
0
Receptor, Melanocortin, Type 4
0
Types de publication
Clinical Trial, Phase II
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
307-316Informations de copyright
© 2021 S. Karger AG, Basel.