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Bremelanotide, sold under the brand name Vyleesi, is a medication used to treat low sexual desire in women.[1][2][3] It is given by an injection into the fat of the thigh or abdomen.[1]

Bremelanotide
Bremelanotide structure.svg
Clinical data
Pronunciation/ˌbrɛmɪˈlænətd/ (About this soundlisten)
Trade namesVyleesi
SynonymsPT-141; Rekynda
Routes of
administration
Subcutaneous injection[1]
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
BioavailabilitySC: ~100%[1]
Protein binding21%[1]
MetabolismHydrolysis of peptide bonds[1]
Elimination half-life2.7 hours[1]
ExcretionUrine: 64.8%
Feces: 22.8%
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC50H68N14O10
Molar mass1025.2 g/mol g·mol−1
3D model (JSmol)
  (verify)

The medication is a peptide and acts as an agonist of the melanocortin receptors.[1][3]

Bremelanotide was developed by Palatin Technologies and was approved for use in the United States by the Food and Drug Administration (FDA) in June 2019.[2]

Contents

Medical usesEdit

Bremelanotide is used to treat hypoactive sexual desire disorder (HSDD).[1]

ContraindicationsEdit

Due to its effects on blood pressure (generally a transient increase in systolic blood pressure by 6 mmHg, and diastolic blood pressure by 3 mmHg), bremelanotide is considered contraindicated in people with uncontrolled high blood pressure or cardiovascular disease.[1] As long as bremelanotide is not used more than once in one day, it is not expected to cause more severe increases in blood pressure.[1]

Side effectsEdit

The most frequently encountered side effect of bremelanotide is nausea (40.0%), which may be intolerable to some people.[1] The use of anti-nausea medications (e.g. ondansetron) prior to administration of bremelanotide may help to reduce the nausea.[1] Other side effects may include flushing (20.3%), injection site reactions (13.2%), headache (11.3%), vomiting (4.8%), cough (3.3%), fatigue (3.2%), hot flushes (2.7%), paresthesia (2.6%), dizziness (2.2%), and nasal congestion (2.1%).[1][4][5] Discoloration of the skin, specifically hyperpigmentation, may occur—especially if bremelanotide is used more than 8 times in one month.[1] The discoloration may not resolve upon stopping use of bremelanotide, and may occur on the face, gums, or breasts.[1] Experiments in animals, even at high doses, failed to find any negative consequence of bremelanotide on fertility.[1]

InteractionsEdit

Bremelanotide does not meaningfully interact with alcohol, unlike flibanserin (for which the interaction with alcohol is a major barrier to its use).[6][7] However, bremelanotide does interact with certain medications that people take by mouth. By slowing gastric motility, bremelanotide is thought to reduce the oral absorption (bioavailability) of certain medications, such as naltrexone and indomethacin.[1]

PharmacologyEdit

PharmacodynamicsEdit

Bremelanotide is a non-selective agonist of the melanocortin receptors, MC1 through MC5 (with the exception of MC2, the receptor of ACTH), but acting primarily as an MC3 and MC4 receptor agonist.[8][4][9]

PharmacokineticsEdit

The bioavailability of bremelanotide with subcutaneous injection is about 100%.[1] Following a subcutaneous injection of bremelanotide, maximal levels occur after about one hour, with a range of 0.5 to 1.0 hours.[1] The plasma protein binding of bremelanotide is 21%.[1] Bremelanotide is metabolized via hydrolysis of its peptide bonds.[1] The elimination half-life of bremelanotide is 2.7 hours, with a range of 1.9 to 4.0 hours.[1] Bremelanotide is excreted 64.8% in urine and 22.8% in feces.[1]

ChemistryEdit

Bremelanotide is a cyclic heptapeptide lactam analogue of α-melanocyte-stimulating hormone (α-MSH).[5] It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH,[10] and is also known as cyclo-[Nle4,Asp5,D-Phe7,Lys10]α-MSH-(4-10). Bremelanotide is an active metabolite of melanotan II that lacks the C-terminal amide group.[11]

Aside from melanotan II and endogenous melanocyte-stimulating hormones like α-MSH, other peptide analogues of the same family as bremelanotide include afamelanotide (NDP-α-MSH), modimelanotide, and setmelanotide.

HistoryEdit

Studies in the early 1960s showed that administration of α-MSH caused sexual arousal in rats, sparking interest in α-MSH. In the 1980s, scientists at University of Arizona began developing α-MSH and analogs as potential sunless tanning agents. They synthesized and tested several analogs, including melanotan-I and melanotan II.[8][11]

Very early in the process one of the scientists, Mac Hadley[11], who was conducting experiments on himself with the peptide melanotan II, injected himself with twice the dose he intended and experienced an eight-hour erection, along with nausea and vomiting.[8]

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][13] which changed its name to Clinuvel in 2006.[14]

To pursue the sexual dysfunction agent, melanotan II was licensed by Competitive Technologies to Palatin Technologies.[11] Palatin ceased development of melanotan-II in 2000 and synthesized, patented, and began to develop bremelanotide, a likely metabolite of melanotan-II that differs from melanotan-II in that it has a hydroxyl group where melanotan-II has an amide.[8][15] Competitive Technologies sued Palatin for breach of contract and to try to claim ownership of bremelanotide;[15] the parties settled in 2008 with Palatin retaining rights to bremelanotide, returning rights to melanotan-II to Competitive Technologies, and paying $800,000.[16]

In August 2004 Palatin signed an agreement with King Pharmaceuticals to co-develop bremelanotide in the US and jointly license it outside the US; King paid Palatin $20M upfront.[17]

Palatin conducted Phase II trials of intranasal bremelanotide in both female sexual dysfunction (FSD) and male erectile dysfunction (ED) but these trials were halted by the FDA in 2007 due to increased blood pressure in clinical trial subjects; Palatin stopped development of the intranasal formulation in 2008.[18][4][19] Four trials were conducted in ED, the last being a Phase IIb published in 2008.[19] King terminated the co-development agreement shortly after the FDA halted the trials.[20]

The drug was then reformulated to be delivered by injection and trials continued in FSD. A phase II dose-finding trial in FSD in which the drug was administered 45 minutes before sex showed promise at the highest dose and only transient signs of high blood pressure; two Phase III trials were launched at the end of 2014.[9][5] Palatin launched the Phase III trials with bremelanotide administered via an autoinjector.[21]

In 2014, Palatin licensed European rights to bremelanotide to Gedeon Richter Plc. for around $10 million, and Palatin received a milestone payment of around $3 million when it started the Phase III trials in the US. In September 2016, Palatin and Gedeon RIchter terminated that agreement.[21]

In November 2016, Palatin announced results of the Phase III trials, and shortly thereafter began seeking a partner to complete development in the US.[22] In January 2017 Palatin and AMAG Pharmaceuticals agreed that AMAG exclusively would complete development and market bremelanotide in North America and the two would work together to license it in other territories; AMAG agreed to pay $60 million upfront, up to $80 million in regulatory milestones, up to $300 million in sales milestones, and tiered royalties ranging from high single digit to low double digit percentages.[23]

A New Drug Application of bremelanotide for female sexual dysfunction was accepted by the Food and Drug Administration (FDA) in June 2018 with a PDUFA date set for March 23, 2019.[24] The drug was approved for sale in June 2019.[25] It was approved for use in the United States by the FDA on June 21, 2019.[26]

See alsoEdit

ReferencesEdit

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x "VYLEESI (bremelanotide injection), for subcutaneous use" (PDF). AMAG Pharmaceuticals, Inc.
  2. ^ a b "Bremelanotide". AdisInsight. Retrieved 6 April 2017.
  3. ^ a b Kingsberg SA, Clayton AH, Pfaus JG (November 2015). "The Female Sexual Response: Current Models, Neurobiological Underpinnings and Agents Currently Approved or Under Investigation for the Treatment of Hypoactive Sexual Desire Disorder". CNS Drugs. 29 (11): 915–33. doi:10.1007/s40263-015-0288-1. PMID 26519340.
  4. ^ a b c Gelman F, Atrio J (January 2017). "Flibanserin for hypoactive sexual desire disorder: place in therapy". Therapeutic Advances in Chronic Disease. 8 (1): 16–25. doi:10.1177/2040622316679933. PMC 5298357. PMID 28203348.
  5. ^ a b c Belkin ZR, Krapf JM, Goldstein AT (February 2015). "Drugs in early clinical development for the treatment of female sexual dysfunction". Expert Opinion on Investigational Drugs. 24 (2): 159–67. doi:10.1517/13543784.2015.978283. PMID 25376023.
  6. ^ Garde, Damian (20 June 2019). "Experimental drug for women revives an intense debate on sexual desire". STAT. Retrieved 23 June 2019.
  7. ^ Clayton AH, Kingsberg SA, Goldstein I (June 2018). "Evaluation and Management of Hypoactive Sexual Desire Disorder". Sexual Medicine. 6 (2): 59–74. doi:10.1016/j.esxm.2018.01.004. PMC 5960024. PMID 29523488.
  8. ^ a b c d King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H (2007). "Melanocortin receptors, melanotropic peptides and penile erection". Current Topics in Medicinal Chemistry. 7 (11): 1098–1106. doi:10.2174/1568026610707011111. PMC 2694735. PMID 17584130.
  9. ^ a b Kingsberg SA, Clayton AH, Pfaus JG (November 2015). "The Female Sexual Response: Current Models, Neurobiological Underpinnings and Agents Currently Approved or Under Investigation for the Treatment of Hypoactive Sexual Desire Disorder". CNS Drugs. 29 (11): 915–33. doi:10.1007/s40263-015-0288-1. PMID 26519340.
  10. ^ "Proposed INN List 95" (PDF). WHO Drug Information. 20 (2): 124. 2006.
  11. ^ a b c d Hadley ME (October 2005). "Discovery that a melanocortin regulates sexual functions in male and female humans". Peptides. 26 (10): 1687–9. doi:10.1016/j.peptides.2005.01.023. PMID 15996790.
  12. ^ "EpiTan focuses on Melanotan, a potential blockbuster". The Pharma Letter. 1 November 2004.
  13. ^ Hadley ME, Dorr RT (April 2006). "Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization". Peptides. 27 (4): 921–30. doi:10.1016/j.peptides.2005.01.029. PMID 16412534.
  14. ^ "Epitan changes name to Clinuvel, announces new clinical program". LabOnline. 27 February 2006.
  15. ^ a b "Palatin Technologies Refutes Competitive Technologies Contention of Material Breach" (Press release). Palatin Technologies. September 12, 2007.[dead link]
  16. ^ "Palatin Technologies Announces Litigation Settlement With Competitive Technologies" (Press release). Palatin Technologies. January 22, 2008.[dead link]
  17. ^ "Form 10-K for the year ended June 30, 2004". Palatin via SEC EDGAR. 13 September 2004.
  18. ^ Lodise NM (April 2013). "Hypoactive sexual desire disorder in women: treatment options beyond testosterone and approaches to communicating with patients on sexual health". Pharmacotherapy. 33 (4): 411–21. doi:10.1002/phar.1209. PMID 23553810.
  19. ^ a b Ückert S, Bannowsky A, Albrecht K, Kuczyk MA (November 2014). "Melanocortin receptor agonists in the treatment of male and female sexual dysfunctions: results from basic research and clinical studies". Expert Opinion on Investigational Drugs. 23 (11): 1477–83. doi:10.1517/13543784.2014.934805. PMID 25096243.
  20. ^ Nagle, Mike (10 September 2007). "Erectile dysfunction drug deemed a flop". Outsourcing Pharma.
  21. ^ a b "Palatin 10K for the fiscal year ended June 30, 2015". Palatin via SEC EDGAR. September 18, 2015.
  22. ^ Reuters (November 2, 2016). "Female Viagra: Drugmaker Palatin Is Looking for a Buyer". Fortune.
  23. ^ "AMAG Pharma closes deal for North America rights to Rekynda". The Pharma Letter. February 2, 2017.
  24. ^ "Press release: FDA Accepts Bremelanotide NDA for Treatment of Hypoactive Sexual Desire Disorder". MD Magazine. Retrieved 2018-06-27.
  25. ^ Nedelman, Michael (June 21, 2019). "FDA approves new drug for women with low sexual desire disorder". CNN. Retrieved 23 June 2019.
  26. ^ Ariana Eunjung Cha; Laurie McGinley (June 21, 2019). "A new 'female Viagra' approved by FDA despite skepticism". The Washington Post. Retrieved June 21, 2019.

External linksEdit