Identification
- Summary
Afamelanotide is an injectable subcutaneous implant used to mitigate phototoxicity secondary to erythropoietic protoporphyria (EPP).
- Brand Names
- Scenesse
- Generic Name
- Afamelanotide
- DrugBank Accession Number
- DB04931
- Background
Afamelanotide is a first-in-class, synthetic, 13-amino acid peptide analogue of the endogenous alpha melanocyte-stimulating hormone (α-MSH).4 It differs structurally from its endogenous counterpart by only two amino acids - these structural differences improve biological efficacy by imparting a greater affinity for its target and a longer biological half-life.2,3 Afamelanotide is currently the only approved drug therapy used in the management of erythropoietic protoporphyria, having received approval in the EU in December 20147 and subsequent FDA approval in October 2019.5 Despite its relatively recent approval, afamelanotide has been available for use as an orphan drug in both the US and EU since 2008.8,9
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Afamelanotide (DB04931)
- Weight
- Average: 1646.8452
Monoisotopic: 1645.836510475 - Chemical Formula
- C78H111N21O19
- Synonyms
- Afamelanotide
- Melanotan 1
- Melanotan I
- Melanotan-1
- MT-I
- External IDs
- CUV 1647
- CUV1647
- MBJ 05
- MBJ05
Pharmacology
- Indication
Afamelanotide is indicated for the prevention of phototoxicity in adult patients with erythropoietic protoporphyria (EPP).4
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Prevention of Phototoxicity •••••••••••• ••••• ••••••• - Contraindications & Blackbox Warnings
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Afamelanotide increases the production of eumelanin, an endogenous photoprotective agent, to attenuate UV-induced skin damage in patients with a condition that predisposes them to phototoxicity.4 It has a relatively long duration of therapeutic effect despite its short half-life due to its ability to increase melanosome density and therefore skin pigmentation.2 As afamelanotide may darken pre-existing skin pigmentary lesions, patients receiving afamelanotide should undergo a full body skin examination every 6 months to monitor for progression or worsening of any skin abnormalities.4 Standard sun safety measures should continue to be employed during afamelanotide therapy.4
- Mechanism of action
Patients with erythropoietic porphyria (EPP) have a deficiency of ferrochelatase (FECH), an enzyme involved in the final step of heme biosynthesis. FECH is required to insert iron into protoporphyrin IX (PPIX) to generate heme, and a deficiency in FECH results in accumulation of PPIX (particularly in the liver and superficial skin vasculature). PPIX molecules are photodynamic - exposure to UV radiation causes these molecules to form reactive oxygen species that lead to subsequent tissue damage.1
Afamelanotide mimics endogenous alpha melanocyte-stimulating hormone (α-MSH), a hormone typically released in response to UV-induced skin damage. Both afamelanotide and α-MSH bind to the melanocortin-1 receptor (MC1R) on melanocytes which stimulates the synthesis of eumelanin, a photoprotective compound. Eumelanin is incorporated into small vesicles called melanosomes which are then distributed to surrounding keratinocytes. Melanosomes are concentrated above the nucleus of these keratinocytes, thus protecting them from UV-induced damage.2 While endogenous α-MSH requires UV-induced skin damage in order to be produced, afamelanotide increases eumelanin biosynthesis independent of UV exposure.3
Activation of MC1R signalling by afamelanotide also instigates other protective processes, including an increase in antioxidant activity, DNA repair, and secretion of immunomodulatory proteins such as interleukin-10.2
Target Actions Organism AMelanocyte-stimulating hormone receptor agonistHumans - Absorption
Afamelanotide is administered as a subcutaneous implant that slowly elutes active drug. Most of the dose is released within the first 48 hours, with >90% released by day 5. Plasma levels of afamelanotide decrease slowly over the course of several days following administration - by day 10, plasma levels were undetectable in most clinical trial subjects.4 Following administration of a single subcutaneous implant, the median Tmax was 36 hours, the mean Cmax was 3.7 ± 1.3 ng/mL, and the mean AUC0-∞ was 138.9 ± 42.6 hr.ng/mL.10
- Volume of distribution
The apparent volume of distribution of afamelanotide following intravenous administration is approximately 0.54 L/kg.2
- Protein binding
Not Available
- Metabolism
Details regarding the metabolism and metabolites of afamelanotide are sparse. The drug is more resistant to degradation by serum and proteolytic enzymes than its endogenous counterpart, α-MSH, but presumably undergoes a relatively rapid hydrolysis given its short half-life.4,10 It has been suggested that afamelanotide may be degraded in the same manner as α-MSH but at a much slower rate, or may instead be degraded intracellularly via endocytosis or non-specific proteases.2
- Route of elimination
Minimal amounts of unchanged afamelanotide are recovered in the urine following administration, suggesting the drug is extensively metabolized and most likely eliminated primarily via fecal or biliary route.2
- Half-life
The half-life of afamelanotide is approximately 30 minutes.4 The apparent half-life following administration of a slow-release subcutaneous implant is 15 hours.10
- Clearance
Data regarding plasma clearance of afamelanotide are limited. Plasma drug levels are typically undetectable at day 10 following subcutaneous administration of the afamelanotide implant.4,3
- Adverse Effects
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Data regarding symptoms or treatment of afamelanotide overdose are currently unavailable.4
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Afamelanotide acetate 1XCC161YKC 1566590-77-9 VHLLBJXKNRAYGM-BHHWPIKXSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Scenesse Implant 16 mg/16mg Subcutaneous CLINUVEL INC. 2019-12-31 Not applicable US 
Scenesse Implant 16 mg Subcutaneous Clinuvel Europe Limited 2020-12-22 Not applicable EU 
Scenesse Implant 16 mg/16mg Subcutaneous CSM Clinical Supplies Management Europe GmbH 2019-02-21 Not applicable US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Scenesse Afamelanotide (16 mg/16mg) Implant Subcutaneous CSM Clinical Supplies Management Europe GmbH 2019-02-21 Not applicable US
Categories
- ATC Codes
- D02BB02 — Afamelanotide
- Drug Categories
- Amino Acids, Peptides, and Proteins
- Compounds used in a research, industrial, or household setting
- Dermatologicals
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Indicators and Reagents
- Laboratory Chemicals
- Melanocortin 1 Receptor (MC1-R) Agonists
- Melanocortin Receptor Agonists
- Melanocyte-Stimulating Hormones
- Peptides
- Protective Agents
- Protectives Against UV-Radiation
- Protectives Against UV-Radiation for Systemic Use
- Proteins
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as polypeptides. These are peptides containing ten or more amino acid residues.
- Kingdom
- Organic compounds
- Super Class
- Organic Polymers
- Class
- Polypeptides
- Sub Class
- Not Available
- Direct Parent
- Polypeptides
- Alternative Parents
- Peptides / Tyrosine and derivatives / Arginine and derivatives / Phenylalanine and derivatives / Histidine and derivatives / Glutamic acid and derivatives / Valine and derivatives / Proline and derivatives / N-acyl-alpha amino acids and derivatives / Tryptamines and derivatives show 28 more
- Substituents
- 1-hydroxy-2-unsubstituted benzenoid / 3-alkylindole / Acetamide / Alcohol / Alpha peptide / Alpha-amino acid amide / Alpha-amino acid or derivatives / Amine / Amino acid / Amino acid or derivatives show 55 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- QW68W3J66U
- CAS number
- 75921-69-6
- InChI Key
- UAHFGYDRQSXQEB-LEBBXHLNSA-N
- InChI
- InChI=1S/C78H111N21O19/c1-5-6-19-52(91-75(116)61(41-101)97-72(113)57(34-46-24-26-49(103)27-25-46)94-74(115)60(40-100)88-44(4)102)68(109)92-54(28-29-64(105)106)70(111)96-59(36-48-38-83-42-87-48)73(114)93-56(33-45-16-8-7-9-17-45)71(112)90-53(22-14-31-84-78(81)82)69(110)95-58(35-47-37-85-51-20-11-10-18-50(47)51)67(108)86-39-63(104)89-55(21-12-13-30-79)77(118)99-32-15-23-62(99)76(117)98-65(43(2)3)66(80)107/h7-11,16-18,20,24-27,37-38,42-43,52-62,65,85,100-101,103H,5-6,12-15,19,21-23,28-36,39-41,79H2,1-4H3,(H2,80,107)(H,83,87)(H,86,108)(H,88,102)(H,89,104)(H,90,112)(H,91,116)(H,92,109)(H,93,114)(H,94,115)(H,95,110)(H,96,111)(H,97,113)(H,98,117)(H,105,106)(H4,81,82,84)/t52-,53-,54-,55-,56+,57-,58-,59-,60-,61-,62-,65-/m0/s1
- IUPAC Name
- (4S)-4-{[(1S)-1-{[(1R)-1-{[(1S)-1-{[(1S)-1-[({[(2S)-6-amino-1-[(2S)-2-{[(1S)-1-carbamoyl-2-methylpropyl]carbamoyl}pyrrolidin-1-yl]-1-oxohexan-2-yl]carbamoyl}methyl)carbamoyl]-2-(1H-indol-3-yl)ethyl]carbamoyl}-4-carbamimidamidobutyl]carbamoyl}-2-phenylethyl]carbamoyl}-2-(1H-imidazol-5-yl)ethyl]carbamoyl}-4-[(2S)-2-[(2S)-2-[(2S)-2-[(2S)-2-acetamido-3-hydroxypropanamido]-3-(4-hydroxyphenyl)propanamido]-3-hydroxypropanamido]hexanamido]butanoic acid
- SMILES
- CCCC[C@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC1=CC=C(O)C=C1)NC(=O)[C@H](CO)NC(C)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC1=CN=CN1)C(=O)N[C@H](CC1=CC=CC=C1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC1=CNC2=CC=CC=C12)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(N)=O
References
- Synthesis Reference
Philippe Wolgen, "Alpha-MSH derivatives for the treatment of photodermatoses" E.U. Patent EP2865422A1, issued Oct. 18, 2017.
- General References
- Balwani M: Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019 Jan 24. pii: S1096-7192(18)30641-3. doi: 10.1016/j.ymgme.2019.01.020. [Article]
- Minder EI, Barman-Aksoezen J, Schneider-Yin X: Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders. Clin Pharmacokinet. 2017 Aug;56(8):815-823. doi: 10.1007/s40262-016-0501-5. [Article]
- Kim ES, Garnock-Jones KP: Afamelanotide: A Review in Erythropoietic Protoporphyria. Am J Clin Dermatol. 2016 Apr;17(2):179-85. doi: 10.1007/s40257-016-0184-6. [Article]
- EMA Approved Drugs: Afamelanotide [Link]
- FDA News Release: Scenesse [Link]
- CaymanChem: Afamelanotide MSDS [Link]
- EMA Summary for the Public: Afamelanotide [Link]
- FDA Orphan Drugs: Afamelanotide [Link]
- EMA Orphan Drugs: Afamelanotide [Link]
- FDA Approved Drugs: Afamelanotide [Link]
- External Links
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Prevention Erythropoietic Protoporphyria (EPP) 1 3 Completed Treatment Erythropoietic Protoporphyria (EPP) 3 3 Completed Treatment Polymorphic Light Eruption (PLE) 1 3 Recruiting Treatment Vitiligo 1 2 Completed Treatment Acne Vulgaris 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Implant Subcutaneous 16 mg/16mg Implant Subcutaneous 16 MG - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8334265 No 2012-12-18 2029-03-11 US US10076555 No 2018-09-18 2025-02-11 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.023 mg/mL ALOGPS logP -1.4 ALOGPS logP -8.2 Chemaxon logS -4.9 ALOGPS pKa (Strongest Acidic) 3.46 Chemaxon pKa (Strongest Basic) 11.58 Chemaxon Physiological Charge 2 Chemaxon Hydrogen Acceptor Count 24 Chemaxon Hydrogen Donor Count 23 Chemaxon Polar Surface Area 642.98 Å2 Chemaxon Rotatable Bond Count 50 Chemaxon Refractivity 434.35 m3·mol-1 Chemaxon Polarizability 171.61 Å3 Chemaxon Number of Rings 6 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9487 Blood Brain Barrier - 0.9862 Caco-2 permeable - 0.8823 P-glycoprotein substrate Substrate 0.8915 P-glycoprotein inhibitor I Non-inhibitor 0.8279 P-glycoprotein inhibitor II Non-inhibitor 0.7233 Renal organic cation transporter Non-inhibitor 0.7765 CYP450 2C9 substrate Non-substrate 0.783 CYP450 2D6 substrate Non-substrate 0.8117 CYP450 3A4 substrate Substrate 0.5913 CYP450 1A2 substrate Non-inhibitor 0.8458 CYP450 2C9 inhibitor Non-inhibitor 0.8044 CYP450 2D6 inhibitor Non-inhibitor 0.8743 CYP450 2C19 inhibitor Non-inhibitor 0.7707 CYP450 3A4 inhibitor Non-inhibitor 0.5729 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9007 Ames test Non AMES toxic 0.7223 Carcinogenicity Non-carcinogens 0.787 Biodegradation Not ready biodegradable 0.9916 Rat acute toxicity 3.0321 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9494 hERG inhibition (predictor II) Non-inhibitor 0.5648
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Agonist
- General Function
- Ubiquitin protein ligase binding
- Specific Function
- Receptor for MSH (alpha, beta and gamma) and ACTH. The activity of this receptor is mediated by G proteins which activate adenylate cyclase.
- Gene Name
- MC1R
- Uniprot ID
- Q01726
- Uniprot Name
- Melanocyte-stimulating hormone receptor
- Molecular Weight
- 34705.04 Da
References
- Balwani M: Erythropoietic Protoporphyria and X-Linked Protoporphyria: pathophysiology, genetics, clinical manifestations, and management. Mol Genet Metab. 2019 Jan 24. pii: S1096-7192(18)30641-3. doi: 10.1016/j.ymgme.2019.01.020. [Article]
- Minder EI, Barman-Aksoezen J, Schneider-Yin X: Pharmacokinetics and Pharmacodynamics of Afamelanotide and its Clinical Use in Treating Dermatologic Disorders. Clin Pharmacokinet. 2017 Aug;56(8):815-823. doi: 10.1007/s40262-016-0501-5. [Article]
- Kim ES, Garnock-Jones KP: Afamelanotide: A Review in Erythropoietic Protoporphyria. Am J Clin Dermatol. 2016 Apr;17(2):179-85. doi: 10.1007/s40257-016-0184-6. [Article]
- EMA Approved Drugs: Afamelanotide [Link]
Drug created at October 21, 2007 22:23 / Updated at April 16, 2024 15:54