Melanocortin Receptor Agonist (predominantly MC1R; α-MSH analogue)

Afamelanotide

Also Known As: Melanotan I, Melanotan-1, MT-I, [Nle⁴, D-Phe⁷]-α-MSH, NDP-α-MSH, NDP-MSH, EPT-1647, CUV1647, Scenesse

Afamelanotide is a synthetic 13-amino-acid linear peptide and a superpotent analogue of human α-melanocyte-stimulating hormone (α-MSH), defined by two substitutions — norleucine at position 4 (replacing methionine) and D-phenylalanine at position 7 (replacing L-Phe) — that markedly extend its proteolytic stability and MC1R receptor residence time. By activating MC1R on epidermal melanocytes it engages the cAMP/PKA/MITF signalling cascade and increases the synthesis of photoprotective eumelanin. It is approved as a 16 mg bioresorbable subcutaneous PLGA implant (Scenesse®) for adults with erythropoietic protoporphyria (EPP) by the European Commission / EMA since 22 December 2014 (under exceptional circumstances), by the U.S. FDA since 8 October 2019 (NDA 210797), and by the Australian TGA since October 2020, and must be carefully distinguished from melanotan II, an unapproved cyclic peptide associated with documented safety harms in unregulated use.

Identity & Chemistry

Skeletal chemical structure of afamelanotide ([Nle⁴, D-Phe⁷]-α-MSH), a 13-residue acetylated and C-terminally amidated linear peptide analogue of α-melanocyte-stimulating hormone with norleucine at position 4 and D-phenylalanine at position 7.
Image credit: Anagkai, via Wikimedia Commons · Public Domain (CC0)
Amino Acid Sequence
Ac-S-Y-S-Nle-E-H-d-F-R-W-G-K-P-V-NH₂
Molecular Formula
C₇₈H₁₁₁N₂₁O₁₉
Molecular Weight
1646.87 g·mol⁻¹
CAS Number
75921-69-6
PubChem CID
16154396
DrugBank ID
DB04931
IUPAC Name
N-acetyl-L-seryl-L-tyrosyl-L-seryl-L-norleucyl-L-α-glutamyl-L-histidyl-D-phenylalanyl-L-arginyl-L-tryptophyl-glycyl-L-lysyl-L-prolyl-L-valinamide
Solubility
Water-soluble; lyophilised powder is typically reconstituted with sterile or bacteriostatic water for injection or 0.9% sodium chloride. The clinical product is formulated as a bioresorbable poly(lactide-co-glycolide) implant (~1.7 cm × 1.5 mm) containing 16 mg of drug.
Storage
Lyophilised peptide stored at −20 °C protected from light. Reconstituted solutions stored at 2–8 °C protected from light. The commercial Scenesse® implant is refrigerated per the SmPC.

Mechanism of Action

Afamelanotide is a superpotent MC1R agonist on melanocytes that drives cAMP/PKA/CREB-mediated transcription of MITF and thereby up-regulates tyrosinase, TRP-1 and TRP-2; the result is enhanced production of photoprotective eumelanin, which absorbs incident light in EPP before cutaneous protoporphyrin IX can be excited to reactive oxygen species.

Afamelanotide was synthesised in the 1980s at the University of Arizona by Hruby, Hadley, Sawyer and colleagues, who substituted methionine-4 of native α-MSH(1–13) with norleucine (eliminating an oxidation-prone residue) and inverted phenylalanine-7 to its D-isomer (locking the active conformation). The combined [Nle⁴, D-Phe⁷] modifications produce a peptide that resists enzymatic degradation, exhibits prolonged MC1R occupancy and is "superpotent" in stimulating melanoma tyrosinase activity (Sawyer 1980; Hadley & Dorr 2006). MC1R activation couples through Gαs to adenylyl cyclase, generating cAMP that activates PKA and CREB-mediated transcription of MITF, the master regulator of melanocyte differentiation; MITF in turn drives expression of the enzymes that convert L-tyrosine into eumelanin. In erythropoietic protoporphyria — where deficient ferrochelatase activity causes excess protoporphyrin IX (PPIX) to accumulate in skin and absorb visible/UV-A light — the eumelanin produced under afamelanotide stimulation absorbs and scatters incident light before it can excite cutaneous PPIX, thereby reducing the photochemical generation of the reactive oxygen species responsible for the characteristic phototoxic pain (Langendonk 2015).

Molecular Targets

  • MC1R (melanocortin-1 receptor) — primary target on melanocytes; full-agonist potency reported as ~100-fold greater than native α-MSH in melanoma tyrosinase-activation assays
  • MC3R / MC4R / MC5R — weaker activity, clinically relevant for transient adverse events such as nausea and flushing but not the basis of the photoprotective indication
  • Eumelanogenesis axis (MITF → tyrosinase / TRP-1 / TRP-2) — downstream up-regulation of eumelanin-synthesising enzymes in melanocytes

Signaling Pathways

  • MC1R → Gαs → adenylyl cyclase → ↑ cAMP → PKA → CREB phosphorylation → MITF transcription
  • MITF → up-regulation of tyrosinase, TRP-1 and TRP-2 → shift of melanogenesis toward eumelanin (photoprotective) over pheomelanin
  • MC1R signalling also modulates antioxidant responses, nucleotide-excision DNA repair and pro-inflammatory cytokine release — proposed ancillary contributors to clinical photoprotection

Research Applications

Afamelanotide has been studied in two pivotal Phase III RCTs in EPP (Langendonk 2015, NEJM), a long-term Italian/Swiss observational registry of 115 patients with up to 8 years of follow-up (Biolcati 2015, Br J Dermatol), and a randomised combination trial with NB-UVB phototherapy in vitiligo (Lim 2015, JAMA Dermatology). Additional Phase II programmes target polymorphic light eruption, solar urticaria and actinic-keratosis prevention in organ-transplant recipients.

Erythropoietic protoporphyria — EU pivotal CUV029 (n=74, 270 days)

Phase III

Studies report that 16 mg implants every 60 days (5 implants over 9 months) produced a median pain-free sun-exposure time of 6.0 h vs 0.8 h on placebo (P = 0.005), with reduced phototoxic-reaction frequency and improved DLQI scores.

— Langendonk et al., N Engl J Med 2015;373(1):48–59

Erythropoietic protoporphyria — US pivotal CUV039 (n=94, 180 days)

Phase III

Studies report that 3 implants over 6 months produced a median pain-free sun-exposure time of 69.4 h vs 40.8 h on placebo (P = 0.04), with a safety profile similar to the EU pivotal trial.

— Langendonk et al., N Engl J Med 2015;373(1):48–59

Italian/Swiss compassionate-use registry (n=115; up to 8 years follow-up)

observational

Studies report a long-term cohort with 1,023 implants administered in total; quality-of-life scores improved from 31% at baseline to 74% with sustained compliance and low discontinuation rates, and the long-term safety profile was consistent with the pivotal RCTs.

— Biolcati et al., Br J Dermatol 2015;172(6):1601–1612

Generalised vitiligo — combination with NB-UVB (RCT, n=55, 168 days)

Phase II

Studies report that monthly 16 mg implants plus NB-UVB delivered statistically superior and faster repigmentation than NB-UVB monotherapy: 48.64% vs 33.26% mean repigmentation rate at day 168.

— Lim et al., JAMA Dermatology 2015;151(1):42–50

Polymorphic light eruption (PLE) — Phase III, NCT04704713

Phase III

Studies report the launch of a randomised, double-blind, placebo-controlled Phase III trial of 16 mg implants in adults with PLE; primary endpoints centre on phototoxic-reaction frequency and quality of life — the mechanistic rationale is that induced eumelanogenesis acts as a photoprotective alternative to prophylactic phototherapy.

— ClinicalTrials.gov NCT04704713

Clinical Status

Regulatory Status
Approved by the European Commission / EMA on 22 December 2014 under exceptional circumstances (EMEA/H/C/002548; indication: prevention of phototoxicity in adult EPP patients); approved by the U.S. FDA on 8 October 2019 as Scenesse® for increasing pain-free light exposure in adults with EPP (NDA 210797, distributed under a REMS requiring certified-clinic administration); approved by the Australian TGA on 27 October 2020; authorised in Israel and Switzerland. A post-Brexit MHRA licence is not publicly listed. In September 2025 the CHMP issued a positive opinion on year-round Scenesse® dosing.
Show more
Highest Trial Phase
Phase III approved (EPP, FDA/EMA/TGA); Phase III ongoing in PLE (NCT04704713); Phase II in solar urticaria, actinic-keratosis prevention, vitiligo (combination with NB-UVB) and acne
Sponsor
Clinuvel Pharmaceuticals Limited (Melbourne, Australia; formerly Epitan, renamed in 2006); EU marketing authorisation holder: Clinuvel Europe Limited, Dublin. Originator peptide [Nle⁴, D-Phe⁷]-α-MSH invented by Hruby/Hadley/Sawyer/Castrucci at the University of Arizona (1980s); rights licensed via Competitive Technologies.
Show more

Key Clinical Trials

  • EU pivotal: afamelanotide implants every 60 days in adults with EPP (CUV029)
    Phase III
    NCT00979745
  • US pivotal: afamelanotide implants every 60 days in adults with EPP (CUV039)
    Phase III
    NCT01605136
  • Confirmatory long-term safety/efficacy of afamelanotide in EPP
    Phase III
    NCT04053270
  • Afamelanotide implants in adults with polymorphic light eruption
    Phase III
    NCT04704713
  • Pilot study of afamelanotide in solar urticaria
    Phase II
    NCT00859534
  • Afamelanotide for actinic keratosis prevention in organ-transplant recipients
    Phase II
    NCT00829192
  • Afamelanotide + NB-UVB pilot in generalised vitiligo
    Phase II
    NCT01382589
  • Afamelanotide + NB-UVB in non-segmental vitiligo (proof-of-concept)
    Phase II
    NCT01430195
  • Afamelanotide dose-regimen study in moderate acne vulgaris
    Phase II
    NCT04943159

Safety Profile

Observed in research settings

In the Phase III EPP programme, the long-term registry, and post-marketing surveillance, the adverse-event profile of afamelanotide observed in research settings has been dominated by transient mild-to-moderate gastrointestinal and constitutional symptoms in the first ~72 hours after implantation, plus expected pigmentary effects (skin darkening, ephelides, and darkening of melanocytic naevi). Serious adverse events were not statistically distinguishable from placebo in the pivotal RCTs except for implant-site discoloration.

Adverse Events Reported in Studies

  • Nausea (very common, > 10%)
  • Headache (very common, > 10%)
  • Implant-site reactions including pain, erythema, hyperpigmentation and bruising (common to very common; implant-site hyperpigmentation reported in roughly one-third of patients)
  • Fatigue / lethargy / somnolence (common, 1–10%)
  • Dizziness and migraine (common, 1–10%)
  • Back pain, upper-respiratory-tract infection (common, 1–10%)
  • Hot flushes, abdominal pain, diarrhoea, vomiting (common, 1–10%)
  • Appearance or darkening of melanocytic naevi, ephelides, lentigines (common, 1–10%) — drives the mandatory dermatologic-monitoring requirement

Serious Adverse Events

  • Pigmentary lesion monitoring (post-marketing risk-management): because afamelanotide darkens existing melanocytic naevi, the FDA Prescribing Information and the EMA SmPC require periodic full-skin photography and dermatologic examination every 6 months; certified-clinic administration is mandated under a REMS, and post-marketing requirements were partially relaxed in April 2026 after surveillance review
  • Class caution: review-level evidence documents serious harms in unregulated use of α-MSH analogues — predominantly melanotan II, occasionally illicit afamelanotide — including melanoma, dysplastic-nevi proliferation, posterior reversible encephalopathy syndrome and rhabdomyolysis; these reports are NOT from clinical use of the regulated 16 mg implant and motivate the strict EU/US prescribing restrictions
  • No drug-attributable serious hepatotoxicity: LiverTox classifies afamelanotide as Likelihood Score E (unlikely cause of clinically apparent liver injury)

References

  1. Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, Hadley ME [Nle⁴, D-Phe⁷]-α-melanocyte-stimulating hormone: a highly potent α-melanotropin with ultralong biological activity Proc Natl Acad Sci USA 1980;77(10):5754–5758. 1980 .

    DOI: 10.1073/pnas.77.10.5754 PMID: 6777774 View Source

  2. Hadley ME, Dorr RT Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization Peptides 2006;27(4):921–930. 2006 .

    DOI: 10.1016/j.peptides.2005.01.029 PMID: 16412534 View Source

  3. Langendonk JG, Balwani M, Anderson KE, Bonkovsky HL, Anstey AV, Bissell DM, Bloomer J, Edwards C, Neumann NJ, Parker C, Phillips JD, Lim HW, Hamzavi I, Deybach JC, Kauppinen R, Rhodes LE, Frank J, Murphy GM, Karstens FPJ, Sijbrands EJG, de Rooij FWM, Lebwohl M, Naik H, Goding CR, Wilson JHP, Desnick RJ Afamelanotide for erythropoietic protoporphyria N Engl J Med 2015;373(1):48–59. 2015 .

    DOI: 10.1056/NEJMoa1411481 PMID: 26132941 View Source

  4. Biolcati G, Marchesini E, Sorge F, Barbieri L, Schneider-Yin X, Minder EI Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria Br J Dermatol 2015;172(6):1601–1612. 2015 .

    DOI: 10.1111/bjd.13598 PMID: 25494545 View Source

  5. Lim HW, Grimes PE, Agbai O, Hamzavi I, Henderson M, Haddican M, Linkner RV, Lebwohl M Afamelanotide and narrowband UV-B phototherapy for the treatment of vitiligo: a randomized multicenter trial JAMA Dermatology 2015;151(1):42–50. 2015 .

    DOI: 10.1001/jamadermatol.2014.1875 PMID: 25230094 View Source

  6. Minder EI, Barman-Aksoezen J, Schneider-Yin X Pharmacokinetics and pharmacodynamics of afamelanotide and its clinical use in treating dermatologic disorders Clin Pharmacokinet 2017;56(8):815–823. 2017 .

    DOI: 10.1007/s40262-016-0501-5 PMID: 28063031 View Source

  7. Habbema L, Halk AB, Neumann M, Bergman W Risks of unregulated use of α-melanocyte-stimulating hormone analogues: a review Int J Dermatol 2017;56(10):975–980. 2017 .

    DOI: 10.1111/ijd.13585 PMID: 28266027 View Source

  8. U.S. Food and Drug Administration / Clinuvel Inc. SCENESSE® (afamelanotide) implant, for subcutaneous use — Highlights of Prescribing Information (NDA 210797) FDA prescribing information, 2019. 2019 .

    View Source

  9. European Medicines Agency Scenesse — EPAR product information (afamelanotide), EMEA/H/C/002548 EMA, marketing authorisation 22 December 2014 (under exceptional circumstances). 2014 .

    View Source

  10. National Institutes of Health (LiverTox) Afamelanotide LiverTox: clinical and research information on drug-induced liver injury, 2024 update. 2024 .

    View Source

Frequently Asked Questions

What is afamelanotide?
Afamelanotide (also known as Melanotan I, NDP-α-MSH or [Nle⁴, D-Phe⁷]-α-MSH; brand name Scenesse®) is a synthetic 13-amino-acid linear peptide analogue of α-melanocyte-stimulating hormone. It binds principally to the melanocortin-1 receptor on melanocytes, stimulating cAMP/PKA/MITF signalling and increasing the production of photoprotective eumelanin in skin. It is approved as a 16 mg subcutaneous implant by the U.S. FDA, the EMA, the Australian TGA and the Israeli Ministry of Health for the prevention of phototoxicity in adults with erythropoietic protoporphyria.
How does afamelanotide differ from melanotan II?
Afamelanotide and melanotan II are two distinct peptides. Afamelanotide is a 13-residue linear [Nle⁴, D-Phe⁷]-α-MSH analogue developed and manufactured as a regulated drug (Scenesse®) approved by the FDA and EMA for EPP. Melanotan II, by contrast, is a shorter, cyclic 7-residue α-MSH analogue with broader melanocortin-receptor activity (including stronger MC4R agonism, which is why it has been investigated for erectile dysfunction); melanotan II is not approved by any major regulator, is sold only on the grey market for cosmetic tanning, and has been linked in case reports to melanoma, dysplastic naevi, rhabdomyolysis and posterior reversible encephalopathy syndrome. The two peptides should not be conflated.
Is afamelanotide approved by regulatory agencies?
Yes. The European Commission / EMA granted marketing authorisation under exceptional circumstances on 22 December 2014; the U.S. FDA approved it on 8 October 2019 (NDA 210797); the Australian TGA approved it on 27 October 2020; it is also authorised in Israel and Switzerland. The approved indication in every market is for adult patients with erythropoietic protoporphyria; distribution is via certified clinics under risk-management programmes.
What is erythropoietic protoporphyria (EPP)?
EPP is a rare inherited photosensitivity disorder caused most commonly by reduced activity of the enzyme ferrochelatase (FECH gene), with a smaller subset (X-linked protoporphyria) due to gain-of-function variants in ALAS2. The enzyme defect causes accumulation of protoporphyrin IX in red blood cells, plasma and skin; when light reaches the skin, protoporphyrin IX is photo-excited and generates reactive oxygen species, producing burning pain, erythema and oedema within minutes of exposure.
How is afamelanotide administered in clinical use?
The approved formulation is a bioresorbable poly(lactide-co-glycolide) (PLGA) subcutaneous implant, approximately 1.7 cm × 1.5 mm, containing 16 mg of afamelanotide. In approved use, a single implant is inserted into the suprailiac subcutaneous tissue every two months by a trained healthcare professional in a certified clinic, with up to four implants per calendar year (an extension to year-round dosing received a positive CHMP opinion in September 2025). The implant releases drug over approximately 5–10 days; the resulting eumelanin-mediated photoprotection persists much longer.
What are the most commonly reported adverse events in afamelanotide studies?
The most frequently reported adverse events in the Phase III EPP programme and the long-term Italian/Swiss registry were nausea, headache, fatigue, implant-site reactions (including local hyperpigmentation), back pain, dizziness, hot flushes, abdominal symptoms, and the appearance or darkening of melanocytic naevi. Most events were mild to moderate and resolved within roughly 72 hours after implantation. Because afamelanotide darkens pre-existing pigmented lesions, regulators require periodic full-skin photography and dermatologic surveillance to detect potential melanoma.

Related Peptides

PT-141

≥98%

Melanocortin Receptor Agonist (MC4R-preferring; α-MSH analogue)

Synthetic cyclic 7-residue α-MSH analogue with preferential MC4R activity; approved as Vyleesi® by the U.S. FDA on 21 June 2019 for acquired, generalised hypoactive sexual desire disorder (HSDD) in premenopausal women.

View Details

Thymosin Alpha-1

≥98%

Thymic peptide hormone analogue / immune modulator (slug: immune-other; pleiotropic TLR2/TLR9-mediated effect rather than a classical single-receptor agonist)

Synthetic 28-amino-acid N-acetylated thymic peptide (thymalfasin / Zadaxin); pleiotropic TLR2/TLR9-mediated immune modulator — approved as Zadaxin in 35+ countries (Italy, China, Vietnam, Mexico and others) for chronic hepatitis B and as a vaccine adjuvant in immunocompromised populations, but NOT FDA-approved in the United States — only orphan-drug designations exist there.

View Details

Sermorelin

≥98%

GHRH(1-29) Receptor Agonist (Growth-Hormone Secretagogue, GRF Class)

Synthetic GHRH(1-29) amide (Geref); the shortest fragment of human growth-hormone-releasing hormone that retains full biological activity — historically FDA-approved for pediatric GH deficiency and voluntarily withdrawn from the US market in 2008 for commercial reasons.

View Details