Melanotan I

Overview

Melanotan I (MT-I), now marketed as afamelanotide under the brand name Scenesse, is a synthetic analog of alpha-melanocyte stimulating hormone (α-MSH). It is a potent melanocortin 1 receptor (MC1R) agonist that stimulates melanogenesis, producing protective skin tanning.

Melanotan I is notable as an FDA-approved first-in-class medication for erythropoietic protoporphyria (EPP), a rare photosensitivity disorder. It represents one of the few peptide-based drugs to achieve regulatory approval for dermatological use.

Molecular Structure

The peptide was modified from native α-MSH to improve stability and receptor binding affinity.

Mechanism of Action

MC1R Activation

Melanotan I activates the melanocortin 1 receptor:

1. Receptor Binding: High-affinity binding to MC1R on melanocytes
2. cAMP Increase: Intracellular cyclic AMP elevation
3. MITF Activation: Microphthalmia-associated transcription factor upregulation
4. Tyrosinase Induction: Key enzyme for melanin synthesis
5. Melanogenesis: Production of eumelanin (brown/black pigment)

Photoprotective Effect

The increased eumelanin production provides:

• UV absorption and scattering
• Free radical scavenging
• DNA damage protection
• Reduced sunburn cell formation

Clinical Development History

University of Arizona Research

Melanotan I was originally developed at the University of Arizona:

• Initial goal: Sunless tanning agent
• Three Phase 1 trials demonstrated safety
• Combined with UV-B light or sunlight

Phase 1 Trial Results

Controls required 50% more sun-exposure time for equivalent tanning.

Formulation Development

Early trials showed the peptide required frequent injections due to short half-life:

• Original: ~10 injections daily needed
• Solution: Depot formulation (subcutaneous implant)
• Result: Slow-release implant requiring less frequent administration

Regulatory Approvals

Approved Indication: Erythropoietic Protoporphyria

EPP is a rare genetic condition causing severe photosensitivity:

• Patients experience extreme pain from light exposure
• Severely limits outdoor activities
• No previous effective treatments

Afamelanotide provides:

• Increased pain-free sun exposure time
• Improved quality of life
• Protective eumelanin production

Long-term Safety Data

Over 1,000 patients have been exposed to afamelanotide:

• No melanoma events reported
• Many patients on continuous treatment for 5+ years
• Some patients treated for more than 10 years
• Demonstrates favorable long-term safety profile

Other Research Applications

Vitiligo

A 2015 randomized multicenter trial found:

• Subcutaneous afamelanotide + narrow band UVB phototherapy
• Superior repigmentation vs UVB monotherapy alone
• Suggests potential for skin pigmentation disorders

Ongoing/Planned Trials (2022-2023)

• Xeroderma pigmentosum
• Variegate porphyria
• Additional vitiligo studies

Differences from Melanotan II

Safety Considerations

Clinical Use (Afamelanotide)

• Well-tolerated in trials
• Minor side effects: nausea, headache, fatigue
• Injection site reactions possible
• Long-term monitoring for skin changes recommended

Unregulated Products Warning

Products sold online as "melanotan" or "melanotan-1":

• Not legally sold without prescription in most jurisdictions
• Potentially dangerous without medical supervision
• May contain impurities or incorrect dosing
• Reported issues: changes in moles, new moles, skin cancer cases (in uncontrolled use)

Comparison with Sunless Tanners

Regulatory Status

• Approved: EMA and FDA for erythropoietic protoporphyria (as Scenesse)
• Prescription only: Requires medical supervision
• Research: Ongoing for other photosensitivity conditions
• Unregulated: Cosmetic tanning use not approved

References

Key sources include JAMA Dermatology publications, FDA approval documentation, Clinuvel Pharmaceuticals clinical trial data, and PMC review articles on MC1R agonists.