Melanotan 1

Also known as: Afamelanotide, Scenesse, CUV1647, NDP-α-MSH, Melanotan I, MT-I, [Nle4,D-Phe7]-alpha-MSH

Evidence: Clinical

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Overview

Synthetic alpha-MSH analog (afamelanotide, [Nle4,D-Phe7]-alpha-MSH) and MC1R agonist; a 16 mg implant is approved in the EU (2014) and US (2019) for erythropoietic protoporphyria.

Melanotan 1 is the research name for afamelanotide, made at the University of Arizona in 1980 as an enzyme-resistant, longer-acting alpha-MSH analog. Daily subcutaneous injections darkened skin in healthy men in a 1991 randomized trial. A 16 mg controlled-release implant (SCENESSE) was authorised by EMA in December 2014 under exceptional circumstances and approved by FDA in October 2019 (NDA 210797) to increase pain-free light exposure in adults with erythropoietic protoporphyria; it is still marketed in both regions. A phase 3 vitiligo trial with NB-UVB is active. The lyophilized powder sold as 'Melanotan 1' for self-injection is not the approved implant and has no approval or quality standard of its own.

Benefits

Skin darkening without UV (human RCT, SC injection), more pain-free light exposure in erythropoietic protoporphyria (approved implant, phase 3 RCTs), faster vitiligo repigmentation with NB-UVB (1 RCT, implant)

Dosing reference

Research dose: 500 to 1000 mcg daily loading: community range for the unlicensed powder. Approved product is a 16 mg implant every 2 months; early SC trials used 0.08 to 0.21 mg/kg daily
Range: 500 to 1000 mcg, 1x daily (loading)
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 10 mg

Approved use: one 16 mg SCENESSE implant inserted subcutaneously by a trained professional every 2 months (FDA label). Early saline-injection trials gave 0.08 to 0.21 mg/kg SC daily on weekdays for 2 weeks (10 doses), 10x or more above the community 0.5 to 1 mg loading range, which has no published protocol. Oral dosing produced no measurable plasma levels.

Mechanism

Afamelanotide is labeled as a melanocortin 1 receptor (MC1R) agonist. MC1R activation on melanocytes increases eumelanin synthesis, the proposed basis of reduced phototoxicity in erythropoietic protoporphyria. The Nle4 and D-Phe7 substitutions make it resistant to serum enzymes, with prolonged activity and about 26 times the potency of alpha-MSH in a melanoma adenylate cyclase assay (Sawyer et al., 1980). MC1R signaling is also reported to induce antioxidant activity and DNA repair and to modulate inflammation (Minder et al., 2017). Its activity at MC3R and MC4R is not characterized in the cited sources.

Evidence

Clinical: at least one published human trial or an approved drug

Randomized double-blind trial in 28 healthy men: 10 SC injections over 12 days darkened skin in both poor and good tanners, with no change on saline; peak 1 to 3 weeks after dosing (Levine et al., 1991)
SC doses of 0.08 to 0.21 mg/kg were fully bioavailable relative to IV, oral dosing gave no detectable plasma levels, and the beta half-life was 0.8 to 1.7 h (Ugwu et al., 1997)
Two phase 3 RCTs of a 16 mg implant every 60 days in erythropoietic protoporphyria (EU n=74, US n=94) increased pain-free direct sunlight time (US median 69.4 vs 40.8 h; EU 6.0 vs 0.8 h) (Langendonk et al., 2015)
Implant plus NB-UVB gave faster and greater repigmentation than NB-UVB alone in nonsegmental vitiligo (48.6% vs 33.3% at day 168; n=55) (Lim et al., 2015)
Observational study of 115 EPP patients over up to 8 years: quality of life rose from 31% to 74% of maximum, with mainly nausea as the attributable adverse event (Biolcati et al., 2015)
Regulatory and trial status: SCENESSE 16 mg implant authorised by EMA 22 Dec 2014 and approved by FDA 8 Oct 2019 (NDA 210797) for adults with EPP, still marketed; phase 3 vitiligo trial NCT06109649 active. Approvals cover the implant, not the injectable powder sold as Melanotan 1

References

Side effects

EPP trials of the implant through month 6 (n=125 vs 119 vehicle): implant-site reaction 21% vs 10%, nausea 19% vs 14%, oropharyngeal pain 7% vs 5%, cough, fatigue, skin hyperpigmentation 4% vs 0%, melanocytic nevus 4% vs 2% (FDA label). The label warns of darkening of pre-existing nevi and freckles, calls for twice-yearly full-body skin exams, and lists serious hypersensitivity including anaphylaxis. Saline-injection studies reported occasional GI upset and facial flushing (Ugwu et al., 1997). No quality data exist for the unlicensed powder. Commonly reported (anecdotal): nausea, flushing, darkening of moles.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: Implant: apparent ~15 h, median Tmax 36 h (human, label). SC injection in saline: beta phase 0.8 to 1.7 h (human, n=3)
Bioavailability: SC injection: complete relative to IV (human, n=3). Oral: no detectable plasma levels (human). Implant: controlled release, one implant every 2 months
Molecular weight: 1646.88 Da
Sequence: [Ac-S]YS[Nle]EH[D-F]RWGKPV[NH2]