Mechanism of action

Melanotan I is an agonist of the melanocortin-1 receptor (MC1R) on cutaneous melanocytes. Receptor activation stimulates the cAMP/PKA cascade and the transcription factor MITF, upregulating tyrosinase and increasing synthesis of the dark, photoprotective pigment eumelanin; the pharmacology of the melanocortin receptors and their synthetic analogs is summarized in review articles (Hadley and Dorr, 2006). This MC1R effect is not confined to overall skin tone: according to the US prescribing information, the licensed implant may lead to generalized increased skin pigmentation and to darkening of pre-existing nevi and ephelides. Compared with native α-MSH, the two substitutions norleucine at position 4 and D-phenylalanine at position 7 increase receptor potency and stability against enzymatic degradation (Hadley and Dorr, 2006); in the first clinical description, subcutaneous administration produced measurable skin darkening without UV irradiation as the triggering stimulus, with all participants using a high-potency sunscreen during the trial (Levine et al., 1991). Unlike the cyclic Melanotan II, which non-selectively also activates central MC3R and MC4R signalling, Melanotan I remains structurally close to linear α-MSH (Hadley and Dorr, 2006; Langan et al., 2010); in the pharmacokinetic study in three volunteers, occasional gastrointestinal upset and facial flushing were described as side effects (Ugwu et al., 1997). Pharmacokinetically, subcutaneous injection showed complete bioavailability, no plasma levels were detectable after oral administration, and the beta-phase half-life was 0.8 to 1.7 hours (Ugwu et al., 1997). Those pharmacokinetic observations concern the solution studied in three volunteers, not the release characteristics of Scenesse. The authorized medicine is a subcutaneous implant; its formulation and delivery profile must not be equated with a research vial.

State of evidence

The early human data come from the University of Arizona: a randomized, placebo-controlled, double-blind trial in 28 healthy white men showed significant skin darkening after repeated subcutaneous administration, in both poorly tanning skin types (I/II) and well tanning skin types (III/IV). Pigmentation peaked one to three weeks after treatment ended, while placebo produced no darkening (Levine et al., 1991). A separate pharmacokinetic study in three volunteers reported complete subcutaneous bioavailability and beta-phase half-lives of 0.8 to 1.7 hours for the studied solution (Ugwu et al., 1997). These solution measurements are not implant-release parameters. Under the INN afamelanotide, the substance was subsequently developed as a subcutaneous implant: two multicenter, randomized, placebo-controlled phase 3 trials in 74 European and 94 US patients with erythropoietic protoporphyria (EPP) found longer pain-free time in direct sunlight. Medians were 69.4 versus 40.8 hours over six months in the US study and 6.0 versus 0.8 hours over nine months in the European study; the latter also reported fewer phototoxic reactions (Langendonk et al., 2015). Scenesse received EU marketing authorization under exceptional circumstances on December 22, 2014, reflecting incomplete evidence in this rare disease; FDA approval followed on October 8, 2019 (NDA 210797). The EMA EPAR identifies prevention of phototoxicity in adults with EPP, whereas the cited 2019 FDA document concerns increased pain-free light exposure in adults with EPP. These sources concern the named implant in that clinical context: they establish neither a cosmetic-tanning authorization nor regulatory status in every world region. Implant product information also addresses hypersensitivity and pigmentation changes, including darkening of existing nevi, with associated monitoring requirements. The dermatological review by Langan et al. (2010) discusses needle sharing, unclear purity and rapidly darkening nevi with unregulated Melanotan I/II products, which can complicate assessment of pigmented lesions. Neither implant efficacy and safety nor its quality and release characteristics can be transferred to arbitrary Melanotan I research vials.

Questions about the research

What has Melanotan I been investigated for in research?

Melanotan I was first studied as a pigmentation agent: a placebo-controlled trial in healthy men examined skin darkening without UV exposure, and a small pharmacokinetic study characterized a subcutaneous solution. Under the INN afamelanotide, the substance was later tested as an implant in phase 3 EPP trials examining pain-free light exposure and phototoxic reactions. Mechanistic research also examines MC1R-mediated pigmentation and photoprotection. The solution studies and the implant studies concern different preparations.

Is Melanotan I approved as a medicine?

The named afamelanotide implant Scenesse received EU authorization in December 2014 under exceptional circumstances and FDA approval in October 2019. The EMA source concerns prevention of phototoxicity in adults with EPP; the cited FDA document concerns increased pain-free light exposure in adults with EPP. These records do not establish authorization for cosmetic tanning or determine status in every world region. They also do not cover arbitrary research vials or establish equivalence to the implant's efficacy, safety, quality or release profile.

Sources

1. Levine et al., JAMA 1991DOI: 10.1001/jama.1991.03470190078033PMID: 1658407
2. Langan et al., Br J Dermatol 2010, dermatological review of unregulated melanotan productsDOI: 10.1111/j.1365-2133.2010.09891.xPMID: 20545686
3. Ugwu et al., Biopharmaceutics & Drug Disposition 1997DOI: 10.1002/(sici)1099-081x(199704)18:3<259::aid-bdd20>3.0.co;2-xPMID: 9113347
4. Langendonk et al., NEJM 2015DOI: 10.1056/NEJMoa1411481PMID: 26132941
5. FDA: Scenesse approval letter, NDA 210797 (2019)
6. EMA: Scenesse (EPAR)

Mechanism of action

Melanotan I is an agonist of the melanocortin-1 receptor (MC1R) on cutaneous melanocytes. Receptor activation stimulates the cAMP/PKA cascade and the transcription factor MITF, upregulating tyrosinase and increasing synthesis of the dark, photoprotective pigment eumelanin; the pharmacology of the melanocortin receptors and their synthetic analogs is summarized in review articles (Hadley and Dorr, 2006). This MC1R effect is not confined to overall skin tone: according to the US prescribing information, the licensed implant may lead to generalized increased skin pigmentation and to darkening of pre-existing nevi and ephelides. Compared with native α-MSH, the two substitutions norleucine at position 4 and D-phenylalanine at position 7 increase receptor potency and stability against enzymatic degradation (Hadley and Dorr, 2006); in the first clinical description, subcutaneous administration produced measurable skin darkening without UV irradiation as the triggering stimulus, with all participants using a high-potency sunscreen during the trial (Levine et al., 1991). Unlike the cyclic Melanotan II, which non-selectively also activates central MC3R and MC4R signalling, Melanotan I remains structurally close to linear α-MSH (Hadley and Dorr, 2006; Langan et al., 2010); in the pharmacokinetic study in three volunteers, occasional gastrointestinal upset and facial flushing were described as side effects (Ugwu et al., 1997). Pharmacokinetically, subcutaneous injection showed complete bioavailability, no plasma levels were detectable after oral administration, and the beta-phase half-life was 0.8 to 1.7 hours (Ugwu et al., 1997). Those pharmacokinetic observations concern the solution studied in three volunteers, not the release characteristics of Scenesse. The authorized medicine is a subcutaneous implant; its formulation and delivery profile must not be equated with a research vial.

State of evidence

The early human data come from the University of Arizona: a randomized, placebo-controlled, double-blind trial in 28 healthy white men showed significant skin darkening after repeated subcutaneous administration, in both poorly tanning skin types (I/II) and well tanning skin types (III/IV). Pigmentation peaked one to three weeks after treatment ended, while placebo produced no darkening (Levine et al., 1991). A separate pharmacokinetic study in three volunteers reported complete subcutaneous bioavailability and beta-phase half-lives of 0.8 to 1.7 hours for the studied solution (Ugwu et al., 1997). These solution measurements are not implant-release parameters. Under the INN afamelanotide, the substance was subsequently developed as a subcutaneous implant: two multicenter, randomized, placebo-controlled phase 3 trials in 74 European and 94 US patients with erythropoietic protoporphyria (EPP) found longer pain-free time in direct sunlight. Medians were 69.4 versus 40.8 hours over six months in the US study and 6.0 versus 0.8 hours over nine months in the European study; the latter also reported fewer phototoxic reactions (Langendonk et al., 2015). Scenesse received EU marketing authorization under exceptional circumstances on December 22, 2014, reflecting incomplete evidence in this rare disease; FDA approval followed on October 8, 2019 (NDA 210797). The EMA EPAR identifies prevention of phototoxicity in adults with EPP, whereas the cited 2019 FDA document concerns increased pain-free light exposure in adults with EPP. These sources concern the named implant in that clinical context: they establish neither a cosmetic-tanning authorization nor regulatory status in every world region. Implant product information also addresses hypersensitivity and pigmentation changes, including darkening of existing nevi, with associated monitoring requirements. The dermatological review by Langan et al. (2010) discusses needle sharing, unclear purity and rapidly darkening nevi with unregulated Melanotan I/II products, which can complicate assessment of pigmented lesions. Neither implant efficacy and safety nor its quality and release characteristics can be transferred to arbitrary Melanotan I research vials.

Questions about the research

What has Melanotan I been investigated for in research?

Melanotan I was first studied as a pigmentation agent: a placebo-controlled trial in healthy men examined skin darkening without UV exposure, and a small pharmacokinetic study characterized a subcutaneous solution. Under the INN afamelanotide, the substance was later tested as an implant in phase 3 EPP trials examining pain-free light exposure and phototoxic reactions. Mechanistic research also examines MC1R-mediated pigmentation and photoprotection. The solution studies and the implant studies concern different preparations.

Is Melanotan I approved as a medicine?

The named afamelanotide implant Scenesse received EU authorization in December 2014 under exceptional circumstances and FDA approval in October 2019. The EMA source concerns prevention of phototoxicity in adults with EPP; the cited FDA document concerns increased pain-free light exposure in adults with EPP. These records do not establish authorization for cosmetic tanning or determine status in every world region. They also do not cover arbitrary research vials or establish equivalence to the implant's efficacy, safety, quality or release profile.

Sources

1. Levine et al., JAMA 1991DOI: 10.1001/jama.1991.03470190078033PMID: 1658407
2. Langan et al., Br J Dermatol 2010, dermatological review of unregulated melanotan productsDOI: 10.1111/j.1365-2133.2010.09891.xPMID: 20545686
3. Ugwu et al., Biopharmaceutics & Drug Disposition 1997DOI: 10.1002/(sici)1099-081x(199704)18:3<259::aid-bdd20>3.0.co;2-xPMID: 9113347
4. Langendonk et al., NEJM 2015DOI: 10.1056/NEJMoa1411481PMID: 26132941
5. FDA: Scenesse approval letter, NDA 210797 (2019)
6. EMA: Scenesse (EPAR)