Chemistry:Afamelanotide

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Afamelanotide, sold under the brand name Scenesse, is a medication used to prevent phototoxicity and to reduce pain from light exposure for people with erythropoietic protoporphyria.[1][2][3] It is a melanocortin 1 receptor (MC1 receptor) agonist[1] and a synthetic peptide and analogue of α-melanocyte stimulating hormone.[1] It is administered as subcutaneous implant.[4]

The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.[5]

Medical uses

In the European Union, afamelanotide is indicated for the prevention of phototoxicity in adults with erythropoietic protoporphyria.[4][2]

In the United States, afamelanotide is indicated for increasing pain-free light exposure in adults with a history of reactions to light (phototoxicity) from erythropoietic protoporphyria.[1]

Adverse effects

Very common adverse effects include nausea and headache (may affect more than 10% of people). Common adverse effects include injection site reactions, back pain, upper respiratory tract infections, melanocyte naevus, decreased appetite, migraine, dizziness, weakness, fatigue, lethargy, sleepiness, hot flashes, abdominal pain, diarrhea, vomiting, flushing, development of warts, spots, and freckles, and itchy skin (between 1% and 10% of people). Uncommon and rare adverse effects include cystitis, folliculitis, gastrointestinal infections, hypersensitivity reactions, changes in appetite, depression, insomnia, balance disorders, lethargy, restless leg syndrome, syncope, photophobia, presbyopia, tinnitus, confusion, palpitations, hypertension, hypercholesterolaemia, and weight gain.[4]

Pharmacology

Afamelanotide is a synthetic tridecapeptide and a structural analogue of α-melanocyte stimulating hormone (α-MSH). It is a melanocortin receptor agonist and binds predominantly to the MC1 receptor. Its binding lasts longer than that of α-MSH. This results in part from afamelanotide's resistance to immediate degradation by serum or proteolytic enzymes. It is thought to cause skin darkening by binding to the MC1 receptor which in turn drives melanogenesis.[4]

It has a short half-life of approximately 30 minutes. After administration with implantation into the skin, the majority of the drug is released within two days, with 90% released by the fifth day. By the tenth day, no drug is detectable in plasma.[4]

Drug distribution, metabolism and excretion were not understood as of 2017.[4]

Chemistry

Afamelanotide has the amino acid sequence; Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2.

It is also known as [Nle4,D-Phe7]-α-MSH, which is abbreviated to NDP-MSH or NDP-α-MSH.

Afamelanotide is the international nonproprietary name.[6]

History

α-MSH was first isolated in the 1950s and its primary structure determined. By the 1960s, its role in promoting melanin diffusion was understood.[7]

In the 1980s, the University of Arizona synthesised more potent analogs of a-MSH, including afamelanotide. Afamelanotide was initially named melano-tan (or melanotan-I) due to its ability to tan skin with minimal sun exposure. Later, melanotan-II was synthesised.[8][9][10][11]

Following initial development at the University of Arizona as a sunless tanning agent, the Australian company Clinuvel conducted further clinical trials in that and other indications, and brought the drug to market in the European Union, the United States, and Australia.

To pursue the tanning agent, melanotan-I was licensed by Competitive Technologies, a technology transfer company operating on behalf of University of Arizona, to an Australian startup called Epitan,[12][11] which changed its name to Clinuvel in 2006.[13]

Early clinical trials showed that the peptide had to be injected about ten times a day due to its short half-life, so the company collaborated with Southern Research in the US to develop a depot formulation that would be injected under the skin, and release the peptide slowly. This was done by 2004.[12]

Multiple studies on the clinical effects of afamelanotide were conducted.[14][15] According to ClinicalTrials.gov, Clinuvel sponsored several trials between 2007 and 2011 to explore its effects on erythropoietic protoporphyria, vitiligo, polymorphous light eruption, solar urticaria and acne vulgaris.[16][17][18] Additionally, one trial aimed to assess its role in preventing actinic keratosis in organ transplant recipients.[19] Further trials were pursued for the first two conditions, while results for the latter three were not published.[20][21][22] Following the initial trials, research efforts centered on erythropoietic protoporphyria, and due to the epidemiology of the condition. Clinuvel secured orphan drug for afamelanotide in both the US and the EU by 2010.[23]

The first approval of afamelanotide came in May 2010 from the Italian Medicines Agency (AIFA, or Agenzia Italiana del Farmaco), followed by the European Medicines Agency (EMA) in January 2015. Both approvals were for the treatment of erythropoietic protoporphyria.[24][4]

The US Food and Drug Administration (FDA) granted approval in October 2019 for the use of afamelanotide as a medication to alleviate pain caused by sun exposure in individuals with erythropoietic protoporphyria. This decision was largely based on three trials involving 244 adults aged 18–74 across 22 sites in the US and Europe, which had a focus on pain-free hours in sunlight, outdoor hours under varying light conditions, and side effects.[3][25]

Between 2022 and 2023, trials were outlined to study the effects of afamelanotide on xeroderma pigmentosum and variegate porphyria, along with two additional trials exploring its impact on vitiligo. According to the register, as of April 2025, most of these trials are currently in the recruitment phase.

Society and culture

Usage in general public

A number of products are sold online and in gyms and beauty salons as "melanotan" or "melanotan-1" which discuss afamelanotide in their marketing.[26][27][28]

Without a prescription, these drugs are not legally sold in many jurisdictions and are potentially dangerous.[29][30][31][32]

Starting in 2007, health agencies in various countries began issuing warnings against their use.[33][34][35][36][37][38]

References

  1. ↑ 1.0 1.1 1.2 1.3 Cite error: Invalid <ref> tag; no text was provided for refs named Scenesse FDA label
  2. ↑ 2.0 2.1 "Scenesse EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/scenesse. 
  3. ↑ 3.0 3.1 "Drug Trials Snapshots: Scenesse". 8 October 2019. http://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-scenesse.  Public Domain This article incorporates text from this source, which is in the public domain.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "Scenesse: Summary of Product Characteristics". European Medicines Agency (EMA). 27 January 2016. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002548/WC500182307.pdf. 
  5. ↑ "New Drug Therapy Approvals 2019". 31 December 2019. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019. 
  6. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN)". World Health Organization (WHO). 2009. https://www.who.int/medicines/publications/druginformation/innlists/PL100prepubli.pdf. 
  7. ↑ "The role of melanin-concentrating hormone in color change". Annals of the New York Academy of Sciences 680 (1): 279–289. May 1993. doi:10.1111/j.1749-6632.1993.tb19690.x. PMID 8390154. Bibcode: 1993NYASA.680..279B. 
  8. ↑ "4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity". Proceedings of the National Academy of Sciences of the United States of America 77 (10): 5754–5758. October 1980. doi:10.1073/pnas.77.10.5754. PMID 6777774. Bibcode: 1980PNAS...77.5754S. 
  9. ↑ Lan EL (1992). Preformulation studies of melanotan-II (PDF) (Ph.D. thesis). University of Arizona. Archived (PDF) from the original on 16 April 2021. Retrieved 16 April 2021.
  10. ↑ "Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics". Journal of Medicinal Chemistry 32 (12): 2555–2561. December 1989. doi:10.1021/jm00132a010. PMID 2555512. 
  11. ↑ 11.0 11.1 "Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization". Peptides 27 (4): 921–930. April 2006. doi:10.1016/j.peptides.2005.01.029. PMID 16412534. 
  12. ↑ 12.0 12.1 "EpiTan focuses on Melanotan, a potential blockbuster". The Pharma Letter. 1 November 2004. https://www.thepharmaletter.com/article/epitan-focuses-on-melanotan-a-potential-blockbuster. 
  13. ↑ "Epitan changes name to Clinuvel, announces new clinical program". LabOnline. 27 February 2006. http://www.labonline.com.au/content/life-scientist/news/epitan-changes-name-to-clinuvel-announces-new-clinical-program-161764385. 
  14. ↑ "Risks of unregulated use of alpha-melanocyte-stimulating hormone analogues: a review". International Journal of Dermatology 56 (10): 975–980. October 2017. doi:10.1111/ijd.13585. PMID 28266027. 
  15. ↑ "Melanotropic peptides: more than just 'Barbie drugs' and 'sun-tan jabs'?". The British Journal of Dermatology 163 (3): 451–455. September 2010. doi:10.1111/j.1365-2133.2010.09891.x. PMID 20545686. 
  16. ↑ Clinuvel Pharmaceuticals Limited (2021-02-25). A Phase III, Randomised, Double Blind, Placebo Controlled, Parallel Group Study, to Evaluate the Safety and Efficacy of Subcutaneous Implants of Afamelanotide (16 mg) in Patients Suffering From Polymorphic Light Eruption (PLE) (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04704713. 
  17. ↑ Wright, Dr Dennis (2009-09-13). A Phase II, Open Label Pilot Study to Evaluate the Safety and Efficacy of A Bioresorbable Subcutaneous Implant of CUV1647 in Patients With Solar Urticaria (SU) (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT00859534?intr=Afamelanotide&rank=9. 
  18. ↑ Clinuvel Pharmaceuticals Limited (2021-09-28). A Phase II, Randomised, Open Label Pilot Study to Evaluate the Efficacy and Safety of Two Dosage Regimens of Subcutaneous Bioresorbable Afamelanotide Implants in Patients With Mild to Moderate Acne Vulgaris (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04943159. 
  19. ↑ A Multicentre, Randomised, Double-Blind, Placebo Controlled, Phase II Study to Evaluate the Safety and Efficacy of Subcutaneous Bioresorbable Implants of Afamelanotide (CUV1647) for the Prophylactic Treatment of Pre-Cancerous Skin Lesions of the Head, Forearms and Hands in Immune Compromised, Organ Transplant Patients. (Report). clinicaltrials.gov. 2010-12-03. https://clinicaltrials.gov/study/NCT00829192?intr=Afamelanotide&limit=100&page=1&rank=18&tab=table. 
  20. ↑ Clinuvel Pharmaceuticals Limited (2019-10-08). A Phase III, Multicentre, Randomised, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Subcutanenous Bioresorbable CUV1647 Implants in Patients With Erythropoietic Protoporphyria (EPP) (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04053270. 
  21. ↑ Clinuvel Pharmaceuticals Limited (2013-03-21). Proof of Concept Study to Compare Efficacy and Safety of Subcutaneous, Bioresorbable Afamelanotide Implants and Narrow-Band Ultraviolet B (NB-UVB) Light Versus NB-UVB Light Alone in the Treatment of Nonsegmental Vitiligo (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT01430195. 
  22. ↑ Clinuvel Pharmaceuticals Limited (2013-03-21). A Phase II Randomised Pilot Study to Compare the Efficacy and Safety of Subcutaneous, Bioresorbable Afamelanotide Implants and Narrow-Band Ultraviolet B (NB-UVB) Light in the Treatment of Nonsegmental Vitiligo (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT01382589. 
  23. ↑ "Biotechnology profile: Bright future for Clinuvel (ASX:CUV)" (in en). https://www.labonline.com.au/content/life-scientist/news/biotechnology-profile-bright-future-for-clinuvel-asx-cuv--837406981. 
  24. ↑ "Gazzetta Ufficiale: Sommario". Agenzia Nazionale Stampa Associata. 2010. http://www.ansa.it/web/notizie/rubriche/gazzettaufficiale/2010/05/17/visualizza_new.html_1793113900.html. 
  25. ↑ "FDA approves first treatment to increase pain-free light exposure in patients with a rare disorder" (Press release). 8 October 2019. Archived from the original on 9 October 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  26. ↑ "Believe It Or Not 'Tanorexia' A Very Real Problem". WCBS-TV, CBS. 20 May 2009. http://wcbstv.com/topstories/tanorexia.melanotan.self.2.1013828.html. 
  27. ↑ "Fools Gold". Cosmopolitan (Australia). 14 June 2009. http://www.cosmopolitan.com.au/fool_gold.htm. 
  28. ↑ "Suntan Drug Greenlighted for Trials". Wired. 29 January 2009. https://www.wired.com/wiredscience/2009/01/tan/. Retrieved 11 April 2009. 
  29. ↑ "Tanning drug a health risk". Herald Sun. 31 October 2009. http://www.heraldsun.com.au/news/tanning-drug-a-health-risk/story-e6frf7jo-1225792923321. 
  30. ↑ "Melanotropic peptides: more than just 'Barbie drugs' and 'sun-tan jabs'?". The British Journal of Dermatology 163 (3): 451–455. September 2010. doi:10.1111/j.1365-2133.2010.09891.x. PMID 20545686. 
  31. ↑ "Change in moles linked to use of unlicensed "sun tan jab"". BMJ 338: b277. January 2009. doi:10.1136/bmj.b277. PMID 19174439. 
  32. ↑ "Risky tan jab warnings 'ignored'". BBC News Online. 18 February 2009. https://news.bbc.co.uk/2/hi/health/7895366.stm. 
  33. ↑ "Warning against the product Melanotan". Danish Medicines Agency. 2008. http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=13865. 
  34. ↑ ""Tan jab" is an unlicensed medicine and may not be safe" (Press release). Medicines and Healthcare products Regulatory Agency (MHRA). 2008. Archived from the original on 5 December 2014. Retrieved 17 November 2008.
  35. ↑ "US Lab Research Inc Warning letter". U.S. Food and Drug Administration (FDA). 29 January 2009. https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm152426.htm. 
  36. ↑ "Melanotan Powder for Injection". Notice Information: – Warning – 27 February 2009. Irish Medicines Board. 2009. http://www.imb.ie/EN/Safety--Quality/Advisory-Warning--Recall-Notices/Human-Medicines/Melanotan-Powder-for-Injection-.aspx. 
  37. ↑ "Legemiddelverket advarer mot bruk av Melanotan" (in no). Norwegian Medicines Agency. 13 December 2007. http://www.slk.no/templates/InterPage____65110.aspx. 
  38. ↑ "Melanotan – farlig og ulovlig brunfarge" (in no). Norwegian Medicines Agency. 23 January 2009. http://www.slk.no/templates/InterPage____80434.aspx. 



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