Afamelanotide

A 13-amino-acid alpha-MSH analog, [Nle4, D-Phe7]-alpha-MSH, approved as a 16 mg subcutaneous implant for erythropoietic protoporphyria that raises eumelanin through MC1R; the same molecule sold on the research market as melanotan I.

Also referenced as: Scenesse, CUV1647, [Nle4,D-Phe7]-alpha-MSH, NDP-MSH, NDP-alpha-MSH, Melanotan I, Afamelanotide acetate

Also appears in: Hormone

COA Public product evidence No certificate records are bound to a tracked Afamelanotide product page A record counts here only when a vendor publishes a certificate against one of its own tracked Afamelanotide product pages. Other certificates naming this compound may still exist — search the wider certificate database. →

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What is Afamelanotide?

Afamelanotide is a synthetic 13-amino-acid analog of alpha-melanocyte-stimulating hormone in which methionine at position 4 is replaced by norleucine and L-phenylalanine at position 7 by its D-enantiomer, giving the chemical name [Nle4, D-Phe7]-alpha-MSH. Those two substitutions, made in 1980, produced a melanotropin far more potent than the native hormone and resistant to the serum enzymes that clear alpha-MSH within minutes, which is what made the molecule a drug candidate. It is marketed as Scenesse, a 16 mg bioresorbable implant placed under the skin, approved by the European Commission on December 22, 2014 and by the FDA on October 8, 2019 to increase pain-free light exposure in adults with a history of phototoxic reactions from erythropoietic protoporphyria (EPP). Australia followed in 2020 and Health Canada issued a Notice of Compliance announced on July 13, 2026, each for the same adult EPP indication.

The same molecule has a second identity. Before Clinuvel developed it under the code CUV1647, University of Arizona researchers named it melanotan I and tested it as a sunless-tanning agent, and that is the name under which research-peptide vendors sell it today as a lyophilized powder. Afamelanotide, melanotan I, NDP-MSH, NDP-alpha-MSH, CUV1647 and Scenesse are one compound. The research-market product is sold as melanotan I; the parent hormone is alpha-MSH. It is distinct from melanotan II, a cyclic heptapeptide with a different sequence and a different receptor profile.

How it works

• A stabilized alpha-MSH that outlasts the hormone. The original characterization found that [Nle4, D-Phe7]-alpha-MSH was 26 times as potent as alpha-MSH in a melanoma adenylate cyclase assay, was resistant to degradation by serum enzymes, and kept acting on frog skin long after the native hormone had stopped (Sawyer et al., Proceedings of the National Academy of Sciences, 1980;77(10):5754-5758). Even so, the peptide itself is cleared fast in humans: the approved label gives an apparent half-life of about 15 hours after implantation, with the last measurable concentration in 9 of 12 subjects falling at 96 hours, so the implant’s clinical effect rests on a burst of melanin synthesis rather than on sustained drug levels.
• MC1R agonism drives eumelanin, with or without sunlight. Afamelanotide binds predominantly to the melanocortin-1 receptor on melanocytes, a Gs-coupled receptor whose activation raises cAMP and upregulates the melanogenic program toward brown-black eumelanin. Cryo-EM structures of the MC1R–Gs complex bound to alpha-MSH, afamelanotide and the synthetic agonist SHU9119 show the drug occupying the same calcium-dependent orthosteric pocket as the hormone, built around the shared His-Phe-Arg-Trp core (Ma et al., Cell Research, 2021;31(10):1061-1071). The pigment increase occurs independently of UV exposure, which is the point in EPP: more eumelanin absorbs and scatters the visible light that would otherwise excite protoporphyrin IX in the skin.
• Melanocortin signaling also protects melanocytes beyond pigment. In cultured human melanocytes, alpha-MSH blocked UVB-induced apoptosis and markedly reduced cyclobutane pyrimidine dimer formation, an effect that was not mediated by melanin synthesis and that appeared to depend on induction of nucleotide excision repair (Böhm et al., Journal of Biological Chemistry, 2005;280(7):5795-5802). Clinuvel has pursued this angle in a ten-volunteer DNA-repair study (CUV151, NCT05368857), but the contribution of non-pigmentary effects to the clinical benefit in EPP has not been separated from the pigment effect in patients.
• The first human tanning trial used this exact molecule. In a randomized, double-blind, placebo-controlled study, 28 healthy men received ten subcutaneous injections of the peptide or saline over 12 days while using high-potency sunscreen; skin darkened measurably in both poor-tanning (type I-II) and good-tanning (type III-IV) subjects, peaking one to three weeks after the last injection (Levine et al., JAMA, 1991;266(19):2730-2736). That study is the direct ancestor of both the EPP program and the research-market “melanotan” trade.

Research status

EPP pivotal trials. Two multicenter, randomized, double-blind, placebo-controlled Phase 3 trials of 16 mg afamelanotide implants were reported together (Langendonk et al., New England Journal of Medicine, 2015;373(1):48-59). In the US trial (CUV039, NCT01605136), 94 patients were randomized to three implants or placebo 60 days apart over 180 days; the median duration of pain-free direct sunlight exposure after 6 months was 69.4 hours versus 40.8 hours on placebo (P = 0.04). In the European trial (CUV029, NCT00979745), 74 patients received five implants or placebo over 270 days; median pain-free time in direct sunlight during the hours 10 am to 3 pm was 6.0 hours versus 0.8 hours (P = 0.005), and phototoxic reactions numbered 77 versus 146 (P = 0.04). Quality of life improved in both trials. The FDA label reports the same studies with slightly different analysis windows (64.1 versus 40.5 hours over 180 days in CUV039; 6.0 versus 0.75 hours over 270 days in CUV029) and explains that the small absolute hour counts in the European study arise because its endpoint counted only days on which “most of the day” was spent in direct sunlight, excluding days of mixed sun and shade. An earlier Phase 2 trial (CUV030, NCT01097044, 77 patients) and a correspondence-length report of early treatment experience from Swiss investigators (Harms et al., New England Journal of Medicine, 2009;360(3):306-307) preceded them.

Why the European approval was conditional. The CHMP adopted its positive opinion on October 23, 2014 and the European Commission authorized Scenesse under exceptional circumstances on December 22, 2014, because complete information about its benefits could not be obtained, partly owing to the rarity of the disease; the Committee described the additional time spent in sunlight as small, weighed the possible quality-of-life gains against it, and imposed a post-authorization safety study and a disease registry as conditions. The “exceptional circumstances” designation still stands, with the CHMP reconfirming the authorization at its eleventh annual reassessment on April 23, 2026. The EU orphan designation granted in 2008 lapsed in December 2024, when the product was withdrawn from the Community register of orphan medicines. The US review came five years later and granted a full approval with priority review and orphan status.

Observational follow-up. The real-world record is larger than the trial record. An Italian and Swiss cohort of 115 patients treated with 1,023 implants over up to eight years found that only three patients judged the drug not to have met their expectations, although 23% discontinued for other reasons such as pregnancy or cost; disease-specific quality-of-life scores rose from 31% to 74% of maximum and stayed there (Biolcati et al., British Journal of Dermatology, 2015;172(6):1601-1612). The EMA-directed Rotterdam cohort of 117 patients found time spent outdoors rose by 6.1 hours per week (95% CI 3.62-8.67), quality-of-life score improved by 14.01%, and phototoxic reactions became less painful without becoming less frequent (Wensink et al., JAMA Dermatology, 2020;156(5):570-575). The German arm of the post-authorization safety study, with 200 treated patients, reported a safety profile consistent with the trials and 91% treatment continuation (Homey et al., Photodermatology, Photoimmunology & Photomedicine, 2025;41(2):e13012). A Massachusetts General Hospital cohort of 29 US patients with EPP or X-linked protoporphyria reported median time to symptom onset in sunlight rising from 12.5 minutes to 120 minutes, with no change in protoporphyrin levels or liver tests (Leaf et al., Life, 2024;14(6):689). None of these studies has a concurrent untreated comparison group, drug-induced tanning unblinds patients to their treatment in any of them, and the sponsor funded data entry for the European registry.

Vitiligo. A four-patient pilot showed that adding afamelanotide to narrowband UV-B accelerated repigmentation (Grimes et al., JAMA Dermatology, 2013;149(1):68-73). The randomized multicenter follow-on enrolled 55 adults with nonsegmental vitiligo covering 15% to 50% of body surface area and Fitzpatrick skin types III to VI: after a month of UV-B alone, 28 patients added monthly implants for four months while 27 continued UV-B monotherapy. Repigmentation at day 168 was 48.64% (95% CI 39.49%-57.80%) with the combination versus 33.26% (95% CI 24.18%-42.33%) with UV-B alone, face and upper-extremity repigmentation began earlier (41 versus 61 days and 46 versus 69 days), and the benefit was concentrated in skin types IV to VI, with no significant difference in type III (Lim et al., JAMA Dermatology, 2015;151(1):42-50). The registry lists that study, CUV102 (NCT01430195), as Phase 1. A 15-patient companion study (CUV101, NCT01382589), a Phase 2 study (CUV103, NCT04525157, 21 patients, 2014-2016) and a small facial-vitiligo study (CUV104, NCT05210582) followed. The first Phase 3, CUV105 (NCT06109649), is an open-label trial that randomized patients aged 12 and older with skin types III to VI to afamelanotide plus NB-UVB or NB-UVB alone over 20 weeks, with the proportion reaching T-VASI 50 on the body as its primary endpoint; the sponsor put enrollment at 210. CUV105 has not yet reported. Clinuvel has announced a second Phase 3, CUV107, in skin types IV to VI. No regulator has approved afamelanotide for vitiligo.

Other indications, mostly small or suspended. Clinuvel has registered small trials, none larger than 31 patients, in polymorphic light eruption, solar urticaria, actinic keratosis in organ-transplant recipients, acne, variegate porphyria, xeroderma pigmentosum and arterial ischemic stroke (the last with both the implant and an experimental aqueous formulation), none of which has led to a regulatory submission; when it reported the CUV803 stroke results on March 26, 2025 the company said it had suspended further work on stroke in favor of vitiligo and the porphyrias. The oral, non-peptide MC1R agonist dersimelagon (MT-7117) is in late-stage development for EPP and X-linked protoporphyria and would be the first direct competitor to the implant (Barman-Aksözen et al., Expert Opinion on Pharmacotherapy, 2026;27(4):331-346).

Regulatory record, 2024 to 2026. On April 24, 2024, Clinuvel withdrew its EMA application to extend Scenesse to adolescents; the request had narrowed from ages 12 to 17 down to 15 to 17 and more than 60 kg, and the Agency’s provisional opinion was that registry data on seven adolescents treated with the adult implant could not establish efficacy, safety, or dose. A single-implant pharmacokinetic study, CUV052 (NCT06388642), then enrolled 28 EPP patients, 14 adolescents aged 12 to 17 and 14 adults; preliminary results announced on February 10, 2025 described exposure and tolerability in adolescents similar to adults, results were posted to the registry on July 27, 2026, and the company has said the data will support a renewed adolescent application. The US label was revised under a supplement approved on August 12, 2024 to add a contraindication for known severe hypersensitivity and a warning for anaphylaxis reported after marketing; the European SmPC gained the same hypersensitivity warning through a variation adopted on June 5, 2025. On September 23, 2025, Clinuvel announced a CHMP positive opinion removing the European label’s recommended maximum of four implants per year, allowing continuous every-two-month treatment in adults as in the US. On April 27, 2026, the company announced that the FDA had released the postmarketing requirement for a thorough QT study after reviewing accumulated safety data. Health Canada granted a Notice of Compliance for adult EPP, announced on July 13, 2026. The seven-year US orphan exclusivity that began with the October 8, 2019 approval ran out on October 8, 2026. No new indication was approved in any jurisdiction in 2025 or 2026, and adults with EPP remain the only labeled population.

Common dosage forms

• 16 mg subcutaneous implant (approved product). Scenesse is a 16 mg bioresorbable rod, roughly 1.7 cm by 1.45 mm, supplied individually in a glass vial.
• Investigational liquid formulation. An aqueous afamelanotide solution (PRÉNUMBRA Instant) was used in the CUV803 stroke study. It is not an approved or marketed product.
• Research supply. The molecule is listed as melanotan I, typically as lyophilized powder in sealed vials in the 10 mg range, often as the acetate or trifluoroacetate salt, labeled for laboratory use. These vials bear no relationship to the implant’s controlled-release matrix, and there is no approved injectable solution of afamelanotide.

Key considerations

• Regulatory status. The FDA Approved status reflects the October 8, 2019 approval of Scenesse (NDA 210797) for adults with erythropoietic protoporphyria. The labeled use is limited to adults with a history of phototoxic reactions from EPP, administered by trained healthcare professionals, and no other indication or age group is approved in any jurisdiction.
• The pivotal effect is real but modest and hard to measure. The primary endpoints were patient-recorded pain-free hours in sunlight, the absolute gains were small, and the drug’s tanning effect unblinds participants in any trial or registry. Quality-of-life gains were consistent across studies, but protoporphyrin levels and liver tests do not change.
• Safety signals. The most common adverse reactions in trials were implant-site reactions, nausea, oropharyngeal pain, cough, fatigue, skin hyperpigmentation and new or darkened melanocytic nevi, and serious hypersensitivity including anaphylaxis is a labeled warning. Both labels recommend a full-body skin examination twice a year because the drug darkens existing nevi and freckles; no causal link to melanoma has been shown, but the question has not been studied in a controlled way.
• One molecule, several names, two markets. Afamelanotide and melanotan I are the same peptide, while melanotan II is a different, cyclic molecule with broader melanocortin-receptor activity, and bremelanotide descends from it rather than from afamelanotide. The approval covers a specific controlled-release implant administered by trained clinicians; a reconstituted research-market vial sold as melanotan I is the same sequence delivered in a way no regulator has evaluated.
• Evidence gaps. There is no completed controlled efficacy trial in anyone under 18, no head-to-head comparison with any other photoprotective strategy, no controlled efficacy result published in any indication other than EPP and vitiligo, and no peer-reviewed report from the stroke, xeroderma pigmentosum or variegate porphyria studies.