Melanotan I

Overview

Melanotan I (Afamelanotide) is a synthetic analog of alpha-MSH that selectively activates MC1R. FDA-approved as Scenesse for erythropoietic protoporphyria (EPP), it is distinct from Melanotan II and is studied for melanogenesis and photoprotection.

Mechanism of Action

Melanotan I selectively agonizes MC1R on melanocytes, activating adenylyl cyclase and the MITF-TYR-TYRP1 melanogenesis cascade, increasing eumelanin production without UV exposure. Two key modifications (Nle4 and D-Phe7) confer enhanced binding affinity and protease resistance. Unlike Melanotan II, it has minimal MC3R/MC4R/MC5R activity.

Research Summary

FDA-approved as Scenesse (Clinuvel, October 8, 2019) for increasing pain-free light exposure in adults with EPP, based on Phase III trials CUV039 and CUV040 showing more hours spent in sunlight without pain vs. placebo (Langendonk et al., NEJM, 2015; PMID 26132941). A randomized multicenter trial (Lim et al., JAMA Dermatology, 2015; PMID 25230094) also showed increased repigmentation when afamelanotide was combined with narrow-band UVB in vitiligo.

Dosing Information

Reported Side Effects

• Nausea (most frequently reported)
• Facial flushing
• Darkening of pre-existing moles and nevi
• Headache
• Implant site reactions

Research References

• Afamelanotide for Erythropoietic Protoporphyria (2015)
• Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo: a randomized multicenter trial (2015)