Afamelanotide
Afamelanotide (Scenesse) — the approved MC1R agonist: the same molecule as Melanotan-1, the honest evidence

Class: peptide
INN: Afamelanotide
Synonyms: Afamelanotide
trade name Scenesse (Clinuvel)
Melanotan-1 / Melanotan I / MT-1 (the research-peptide name)
[Nle⁴, D-Phe⁷]-α-MSH (NDP-MSH)
CUV-1647
Trade names: Scenesse
Function tags: (approved:) photoprotection / EPP phototoxicity-prevention
MC1R-driven eumelanin synthesis
(gray-market, as "Melanotan-1":) cosmetic tanning
Overall evidence grade: A
WADA prohibited: no
Last updated: 2026-07-13

In brief: Afamelanotide is a synthetic α-MSH analog and selective MC1R agonist — and a genuinely approved, first-in-class drug (Scenesse, EMA 2015 / FDA 2019) for the rare disease erythropoietic protoporphyria (EPP), where a ferrochelatase defect causes protoporphyrin IX to build up and makes sunlight excruciatingly painful. By activating MC1R, it drives eumelanin (brown-black pigment) production independent of UV exposure, plus antioxidant and DNA-repair effects — letting EPP patients tolerate far more light: in Phase 3, patients on afamelanotide spent ~64 hours in direct sunlight pain-free over 180 days vs ~41 on placebo. The twist that matters for this register: afamelanotide is chemically identical to the gray-market "Melanotan-1," and its MC1R-selectivity is exactly what separates it from its two famous cousins — Melanotan II (#32), a non-selective analog that also hits MC3R/MC4R/MC5R (hence tanning plus appetite/libido/side-effects), and PT-141/bremelanotide (#46), an MC4R-selective analog approved for sexual desire. One α-MSH family, three receptor-selectivity profiles, three completely different destinies — approved-for-skin, unapproved-and-broad, approved-for-sex.

## Identity a synthetic **linear 13-amino-acid peptide** (tridecapeptide) analog of **α-melanocyte-stimulating hormone (α-MSH)**, engineered as a **potent, selective agonist of the melanocortin-1 receptor (MC1R)** — the receptor on skin melanocytes that controls pigment. Developed by **Clinuvel Pharmaceuticals**. Critically, afamelanotide **is the same molecule** sold on the gray market as "Melanotan-1" — but here as a pharmaceutical-grade, controlled-release implant. ## Mechanism (as proposed) afamelanotide is a potent, **MC1R-selective** α-MSH analog (MC1R affinity ~0.3 nM, roughly **1,000× lower** at MC3R/MC4R). MC1R sits on **melanocytes**; activating it shifts pigment synthesis toward **eumelanin** (brown-black, photoprotective) over pheomelanin, and does so **without UV** (bypassing the DNA-damage step that normal tanning requires). MC1R signalling *also* **induces antioxidant activity, enhances DNA repair, and modulates inflammation** — which is why, in EPP, more eumelanin plus these ancillary effects **absorb/scatter light and blunt the protoporphyrin-IX phototoxic reaction**. The Nle⁴/D-Phe⁷ substitutions are what give it the potency and metabolic stability the native hormone lacks.

Evidence grades by outcome:
outcome: EPP — phototoxicity prevention / pain-free light exposure (the approved use)
grade: A
base: 3 randomized vehicle-controlled Phase 3 trials (CUV029/030/039, 244 adults) → EMA 2015 + FDA 2019; ~64 vs ~41 pain-free sunlight hours/180 days
caveat: Approved, first-in-class for a genuine unmet need — but for an ultra-rare disease; effect is meaningful-but-modest (extra tolerated-light hours), not a cure; EU approval under exceptional circumstances
outcome: UV-independent skin pigmentation (eumelanin)
grade: B
base: Robust, well-characterised pharmacology (MC1R → eumelanogenesis)
caveat: The core mechanism is real and reproducible; it is what the drug does
outcome: Cosmetic tanning (the gray-market "Melanotan-1" use)
grade: D
base: Mechanistically works (same eumelanin pathway); no approval for this indication
caveat: The pathway works, but it's unapproved for cosmetics, uses an injectable systemic drug for vanity, and gray-market product quality is unverified; approved-disease data don't transfer to cosmetic safety
outcome: Other explored uses (vitiligo, PLE, solar urticaria, acne)
grade: D
base: Early Clinuvel trials 2007-2011
caveat: Mostly unpublished or not pursued; vitiligo saw some further work; not established
outcome: Photoprotection in the general (non-EPP) population
grade: F
base: Not an approved or established use
caveat: The EPP approval is disease-specific; it is not a general "safe tanning / sun-protection" drug
outcome: Safety
base: Approval-grade dataset (244 patients + post-marketing)
caveat: Implant-site reactions, nausea, oropharyngeal pain, cough, fatigue, skin hyperpigmentation, dizziness, melanocytic nevi (new/changing moles). A theoretical melanoma risk → full-body skin exam twice yearly is recommended; MC1R-selectivity gives it a cleaner systemic profile than Melanotan II

Legal status:
region: INT
status: approved in Australia (TGA)
note: approved in Australia (TGA); available for EPP in various markets.

Cosmetic claims:

Note: The approved melanocortin — and the anchor that closes the register's melanocortin trio. Three points make this entry land: (1) it is a genuinely FDA- and EMA-approved drug (Scenesse) — a first-in-class rare-disease therapy — for erythropoietic protoporphyria; (2) it is chemically identical to the gray-market "Melanotan-1" (same molecule, NDP-MSH) — the clean "approved formulation vs unregulated research peptide" split; (3) its MC1R-selectivity is exactly what distinguishes it from Melanotan II (#32, non-selective) and PT-141 (#46, MC4R-selective) — three peptides, one hormone family, three different receptor targets and three different fates.
Status note: approval status stable; note ongoing post-marketing safety surveillance and any label/indication changes

Sources:
SCENESSE (afamelanotide) FDA label + FDA approval (Oct 2019, first-in-class); EMA authorisation (2015, exceptional circumstances).
Sawyer TK, et al. [Nle⁴,D-Phe⁷]-α-MSH: a highly potent α-melanotropin with ultralong biological activity. PNAS. 1980 (the molecule's origin).
Phase 3 EPP trials (CUV029, CUV030, CUV039); Medscape/NEJM-reported outcomes (~64 vs ~41 pain-free sunlight hours).
Wensink D, et al. Afamelanotide for prevention of phototoxicity in erythropoietic protoporphyria. Expert Rev Clin Pharmacol. 2021 (review).
Comparative melanocortin pharmacology (MC1R vs MC4R selectivity) — afamelanotide vs Melanotan II vs bremelanotide.