Bremelanotide

Bremelanotide
Clinical data
Pronunciation /ˌbrɛmɪˈlænətaɪd/ ( listen)
Trade names Rekynda (tentative)
Synonyms PT-141
ATC code
  • None
Legal status
Legal status
  • US: Unscheduled
Pharmacokinetic data
Elimination half-life 120 minutes[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C50H68N14O10
Molar mass 1025.2 g/mol
3D model (JSmol)
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Bremelanotide (tentative brand name Rekynda; former developmental code name PT-141) is a peptide melanocortin receptor agonist which is under development by Palatin Technologies as a treatment for female sexual dysfunction.[2][3]

Pharmacology

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.[1][4][5]

Chemistry

Bremelanotide is a cyclic heptapeptide lactam analogue of α-melanocyte-stimulating hormone (α-MSH).[6] It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH,[7] 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.[8]

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

History

Research in the early 1960s showed that in rats, administration of α-MSH caused sexual arousal, and work on this continued in many labs up through the 1980s, when scientists at University of Arizona began attempting to develop α-MSH and analogs as potential sunless tanning agents, and synthesized and tested several analogs, including melanotan-I and melanotan II.[1][8]

Very early in the process one of the scientists, Mac Hadley[8], who was conducting experiments on himself with an early tool compound, melanotan II, injected himself with twice the dose he intended and experienced an eight-hour erection, along with nausea and vomiting.[1]

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,[9][10] which changed its name to Clinuvel in 2006.[11]

To pursue the sexual dysfunction agent, melanotan-II was licensed by Competitive Technologies to Palatin Technologies.[8] 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.[1][12] Competitive Technologies sued Palatin for breach of contract and to try to claim ownership of bremelanotide;[12] the parties settled in 2008 with Palatin retaining rights to bremelanotide, returning rights to melanotan-II to Competitive Technologies, and paying $800,000.[13]

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.[14]

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.[15][4][16] Four trials were conducted in ED, the last being a Phase IIb published in 2008.[16] King terminated the co-development agreement shortly after the FDA halted the trials.[17]

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.[5][6] Palatin launched the Phase III trials with bremelanotide administered via an autoinjector.[18]

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.[18]

In November 2016 Palatin announced results of the Phase III trials, and shortly thereafter began seeking a partner to complete development in the US.[19] 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.[20]

A New Drug Application of bremelanotide for female sexual dysfunction was accepted by the FDA in June 2018 with a PDUFA date set for March 23, 2019.[21]

Adverse effects described in the medical literature as of 2017 included nausea, flushing, headache, injection-site pain and itchiness, and upper respiratory tract infections.[4][6]

See also

References

  1. 1 2 3 4 5 King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H (2007). "Melanocortin receptors, melanotropic peptides and penile erection". Curr Top Med Chem. 7 (11): 1098–1106. doi:10.2174/1568026610707011111. PMC 2694735. PMID 17584130.
  2. ↑ "Bremelanotide". AdisInsight. Retrieved 6 April 2017.
  3. ↑ Kingsberg SA, Clayton AH, Pfaus JG (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. 1 2 3 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. 1 2 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.
  6. 1 2 3 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.
  7. ↑ "Proposed INN List 95" (PDF). WHO Drug Information. 20 (2): 124. 2006.
  8. 1 2 3 4 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.
  9. ↑ "EpiTan focuses on Melanotan, a potential blockbuster". The Pharma Letter. 1 November 2004.
  10. ↑ 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.
  11. ↑ "Epitan changes name to Clinuvel, announces new clinical program". LabOnline. 27 February 2006.
  12. 1 2 "Press Release: Palatin Technologies Refutes Competitive Technologies Contention of Material Breach". Palatin Technologies via PR Newswire. September 12, 2007.
  13. ↑ "Press Release: Palatin Technologies Announces Litigation Settlement With Competitive Technologies". Palatin Technologies via PR Newswire. January 22, 2008.
  14. ↑ "Form 10-K for the year ended June 30, 2004". Palatin via SEC EDGAR. 13 September 2004.
  15. ↑ 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.
  16. 1 2 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.
  17. ↑ Nagle, Mike (10 September 2007). "Erectile dysfunction drug deemed a flop". Outsourcing Pharma.
  18. 1 2 "Palatin 10K for the fiscal year ended June 30, 2015". Palatin via SEC EDGAR. September 18, 2015.
  19. ↑ Reuters (November 2, 2016). "Female Viagra: Drugmaker Palatin Is Looking for a Buyer". Fortune.
  20. ↑ "AMAG Pharma closes deal for North America rights to Rekynda". The Pharma Letter. February 2, 2017.
  21. ↑ "Press release: FDA Accepts Bremelanotide NDA for Treatment of Hypoactive Sexual Desire Disorder". MD Magazine. Retrieved 2018-06-27.


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