13AA (linear) Approved (Prescription)
Melanotan 1
The only MC1R agonist with EMA and FDA approval β clinically proven to shield photosensitive skin and drive eumelanin synthesis.
In Plain English:
Melanotan 1 (afamelanotide, brand name Scenesse) is a 13-amino-acid synthetic analogue of alpha-melanocyte-stimulating hormone. It binds selectively to MC1R on melanocytes, shifting pigment production toward photoprotective eumelanin, and also carries anti-inflammatory and DNA-repair-enhancing effects. Unlike Melanotan 2, it has minimal activity at MC3R/MC4R, so it does not meaningfully affect libido or appetite. It is EMA-approved (2014) and FDA-approved (2019) as a subcutaneous bioresorbable implant for erythropoietic protoporphyria (EPP), a rare genetic disorder causing severe phototoxic pain. Phase 3 trials are ongoing for vitiligo repigmentation.
Research Maturity
Approved (Prescription) (134 results on PubMed for 'afamelanotide OR melanotan I' (verified 2026-05-04)+ Studies)
Focus
Dermatology
Photoprotection
Pigmentation
Origin
Synthesised at the University of Arizona in the 1980s as a linear, metabolically stabilised alpha-MSH analogue. D-Phe substitution at position 7 and N-terminal acetylation increase receptor affinity and plasma half-life. Licenced to Clinuvel Pharmaceuticals (AU) and developed through Phase 3 trials for EPP; EMA conditional approval granted December 2014, FDA approval October 2019.
Mechanism
Potent and selective agonist of melanocortin receptor 1 (MC1R) on epidermal melanocytes. MC1R activation stimulates adenylyl cyclase, raising intracellular cAMP and activating MITF transcription factor, which upregulates tyrosinase and TYRP1/2 enzymes β the rate-limiting steps in eumelanin synthesis. Eumelanin accumulates in melanosomes and distributes to surrounding keratinocytes, forming a broad-spectrum UV and visible-light absorbing shield. Secondarily, afamelanotide promotes nucleotide excision repair of UV-induced DNA photoproducts and modulates NF-ΞΊB-driven skin inflammation, reducing post-UV cytokine release.
Outcome
In Phase 3 RCT (CUV039/CUV029, n=93 US + European EPP patients): median pain-free sun hours over 180 days was 64 h (afamelanotide) vs 41 h (placebo); EPP-QOL improved from 31% to 74% of maximum. Long-term observational cohort (n=115, Biolcati 2015): QoL improved from 32% to 74% within 6 months, sustained over 314 patient-years, no melanoma detected. Vitiligo RCT (Lim 2015, n=55): afamelanotide + narrowband UVB achieved 48.6% repigmentation at day 168 vs 33.3% UVB monotherapy.
