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Revision as of 05:31, 14 November 2006 edit69.22.233.172 (talk) I introduced many points of caution consistent with the fact that this drug has not been approved by the US or any other governmental body,. This article itself is an example of public relations.← Previous edit Latest revision as of 21:13, 29 November 2024 edit undoSlothwizard (talk | contribs)Extended confirmed users1,239 edits Drug classTags: Visual edit Mobile edit Mobile web edit 
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{{Short description|Chemical compound}}
]
{{Use dmy dates|date=November 2019}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Drugbox
| Verifiedfields = verified
| Watchedfields = verified
| verifiedrevid = 445399889
| image = Bremelanotide structure.svg
| width = 250
| alt = <!--Clinical data-->
| pronounce = {{IPAc-en|audio=bremelanotide-pronunciation.ogg|ˌ|b|r|ɛ|m|ᵻ|ˈ|l|æ|n|ə|t|aɪ|d}}
| tradename = Vyleesi
| Drugs.com = {{drugs.com|monograph|bremelanotide-acetate}}
| MedlinePlus = a619054
| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| licence_EU = <!-- EMEA requires brand name -->
| DailyMedID = Bremelanotide
| licence_US = <!-- FDA may use generic name -->
| pregnancy_AU = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU_comment =
| pregnancy_category =
| routes_of_administration = ]<ref name="Vyleesi-Label" />
| class = ] ]
| ATCvet =
| ATC_prefix = G02
| ATC_suffix = CX05
| ATC_supplemental = <!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment =
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->


<!--Pharmacokinetic data-->| bioavailability = {{abbrlink|SC|Subcutaneous injection}}: ~100%<ref name="Vyleesi-Label" />
'''Bremelanotide''' (formerly PT-141) is the generic term for a new ] that has been tested with rats and is currently proposed as useful in treating some aspects of ] in some men (] or ]) as well as possible sexual dysfunctions in some women (]). The promoters think of it as a ] ], but doubt has been cast on this category in general and there is no reliable evidence for the existence of this class of chemicals. Unlike ] and other related medications, Bremelanotide does not act upon the vascular system, but is alleged to affect the central nervous system, raising new questions about safety and efficacy. Side effects, long term effects, and efficacy in different populations are all open to question and further study at the moment. Bremelanotide is being tested not as a pill or injection, but as a nasal spray.
| protein_bound = 21%<ref name="Vyleesi-Label" />
| metabolism = ] of ]s<ref name="Vyleesi-Label" />
| metabolites =
| onset =
| elimination_half-life = 2.7 hours<ref name="Vyleesi-Label" />
| duration_of_action =
| excretion = ]: 64.8%<br />]: 22.8%


<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|CAS}}
The manufacturers have said that originally, the ] ] that bremelanotide was developed from was tested as a sunless tanning agent. In initial testing, they report, Melanotan II did induce tanning but additionally caused sexual arousal and spontaneous erections as unexpected side effects in eight out of the ten original male volunteer test subjects. Further information about the subjective aspects of the response or the long term impact is missing. In unpublished clinical studies that the manufacturer reports through press releases and at non-peer-reviewed conferences, bremelanotide has been shown to be effective in treating male sexual and erectile dysfunction as well as female sexual dysfunction in highly selected participants. It is currently being tested by ] who have not offered any indication of how they plan to market this product and prevent its abuse.
| CAS_number = 189691-06-3
| CAS_supplemental =
| PubChem = 9941379
| PubChemSubstance =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB11653
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 8116997
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 6Y24O4F92S
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D06569
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 2070241
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = PT-141; Rekynda
| USAN = bremelanotide acetate


<!-- Chemical and physical data -->| IUPAC_name = (3''S'',6''S'',9''R'',12''S'',15''S'',23''S'')-15--9-benzyl-6-{3-propyl}-12-(1''H''-imidazol-5-ylmethyl)-3-(1''H''-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaazacyclotricosane-23-carboxylic acid
Bremelanotide is a cyclic hepta-] ] analog of ] (alpha-MSH) that activates the ]s ] and ] in the ]. It has the ] Ac-Nle-''cyclo''-OH or ''cyclo''-alpha-MSH-(4-10). PT-141 is a ] of ] that lacks the ] ] ]. Its molecular forumla is C<sub>50</sub>H<sub>68</sub>N<sub>14</sub>O<sub>10</sub> with a molecular weight of 1025.2.
| C = 50
| H = 68
| N = 14
| O = 10
| SMILES = O=C(C)N(CCCC)C(N1C(N(CC2=CNC=N2)C(N(CC3=CC=CC=C3)C(N(CCC/N=C(N)\N)C(N(CC4=CNC5C=CC=CC45)C(N(CCCCNC(C1)=O)C(O)=O)=O)=O)=O)=O)=O)=O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C50H68N14O10/c1-3-4-16-35(58-29(2)65)43(67)64-41-25-42(66)54-20-11-10-18-37(49(73)74)60-46(70)39(23-31-26-56-34-17-9-8-15-33(31)34)62-44(68)36(19-12-21-55-50(51)52)59-45(69)38(22-30-13-6-5-7-14-30)61-47(71)40(63-48(41)72)24-32-27-53-28-57-32/h5-9,13-15,17,26-28,35-41,56H,3-4,10-12,16,18-25H2,1-2H3,(H,53,57)(H,54,66)(H,58,65)(H,59,69)(H,60,70)(H,61,71)(H,62,68)(H,63,72)(H,64,67)(H,73,74)(H4,51,52,55)/t35-,36-,37-,38+,39-,40-,41-/m0/s1
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FFHBJDQSGDNCIV-MFVUMRCOSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}
<!-- Definition and medical uses -->


'''Bremelanotide''', sold under the brand name '''Vyleesi''', is a medication used to treat ].<ref name=AHFS2019/> Specifically it is used for low sexual desire which occurs before ] and is not due to medical problems, psychiatric problems, or problems within the relationship.<ref name=FDA2019 /><ref name="FDA Snapshot">{{cite web | title=Drug Trials Snapshots: Vyleesi | website=U.S. ] (FDA) | date=12 July 2019 | url=https://www.fda.gov/drugs/drug-safety-and-availability/drug-trials-snapshots-vyleesi | archive-url=https://web.archive.org/web/20191120184724/https://www.fda.gov/drugs/drug-safety-and-availability/drug-trials-snapshots-vyleesi | archive-date=20 November 2019 | url-status=live | access-date=20 November 2019}}{{PD-notice}}</ref><ref name=AHFS2019/> It is given by an ] of the ] or ].<ref name=AHFS2019/><ref name="FDA Snapshot" />
In the ] it is currently in a ] ]. The utlimate usefulness of this drug cannot be predicted at the moment, since it has not been approved by the U.S. or any other government, nor is approval scheduled. The drug has received widespread publicity, indicating the strength of the public relations available to the manufacturer.


<!-- Side effects and mechanism -->
== External links ==
Common side effects include ], ], and ].<ref name=AHFS2019>{{cite web |title=Bremelanotide Acetate Monograph for Professionals |url=https://www.drugs.com/monograph/bremelanotide-acetate.html |website=Drugs.com |access-date=24 October 2019 }}</ref> It may also cause a temporary increase in ] and decrease in ] after each dose, and ].<ref name="FDA Snapshot" /> The medication is a ] and acts by ] the ]s.<ref name="Vyleesi-Label">{{cite web | title=Vyleesi- bremelanotide injection | website=] | date=10 September 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=9146ae05-918b-483e-b86d-933485ce36eb | access-date=20 November 2019}}</ref><ref name="Kingsberg2015rev">{{cite journal | vauthors = Kingsberg SA, Clayton AH, Pfaus JG | title = The Female Sexual Response: Current Models, Neurobiological Underpinnings and Agents Currently Approved or Under Investigation for the Treatment of Hypoactive Sexual Desire Disorder | journal = CNS Drugs | volume = 29 | issue = 11 | pages = 915–933 | date = November 2015 | pmid = 26519340 | doi = 10.1007/s40263-015-0288-1 | s2cid = 7437096 }}</ref>
* The company that has developed bremelanotide.
* bremelanotide (PT-141) patent (Appl. No.:040547)
* bremelanotide (PT-141) patent (Appl. No.:066501)
*
* A scientific study with female rats.
* (in German).
* The June 2006 release of summarized Phase IIa test results for women, which indicated significantly increased sexual desire and arousal (67% and 72% respectively) in women diagnosed with ].
* Norman Levine, MD; researcherss on Melanotan at University of Arizona Dermatology
* (]; cached HTML version is )


<!-- History and culture -->
]
Bremelanotide was approved for medical use in the United States in 2019.<ref name=AHFS2019/><ref>{{cite web | title=Drug Approval Package: Vyleesi | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210557Orig1s000TOC.cfm }}</ref> It was developed by Palatin Technologies.<ref name="AdisInsight">{{cite web|title=Bremelanotide|url=http://adisinsight.springer.com/drugs/800014146|publisher=AdisInsight|access-date=6 April 2017}}</ref> The US ] (FDA) considers it to be a ].<ref>{{cite web | title=New Drug Therapy Approvals 2019 | website=U.S. Food and Drug Administration | date=31 December 2019 | url=https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2019 | access-date=15 September 2020}}</ref>
]

]
==Medical uses==
]
Bremelanotide is used for the treatment of generalized ] (HSDD) in premenopausal women.<ref name=FDA2019 /><ref name="Frellick">{{cite web | vauthors = Frellick M |title=FDA Approves New Libido-Boosting Drug for Premenopausal Women |url=https://www.medscape.com/viewarticle/914779?nlid=130327_3901&src=wnl_newsalrt_190621_MSCPEDIT&uac=194606CT&impID=2003265&faf=1 |website=Medscape |publisher=WebMD LLC |access-date=22 June 2019 }}</ref> Specifically it is only recommended in those who have the condition without an underlying cause, such as medical, psychiatric, or relationship problems.<ref name=FDA2019/><ref name=AHFS2019/>
]

<!-- The wikilinks below are interlanguage links. -->
It should be used at least 45 minutes before anticipated sexual activity.<ref name=FDA2019/> Only one dose per 24 hours or no more than eight doses per month is recommended.<ref name=FDA2019/> It should be stopped after eight weeks if there is no improvement in sexual desire and associated distress.<ref name=FDA2019>{{cite press release | title=FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women | website=U.S. ] (FDA) | date=21 June 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hypoactive-sexual-desire-disorder-premenopausal-women | archive-url=https://web.archive.org/web/20191120183329/https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-hypoactive-sexual-desire-disorder-premenopausal-women | archive-date=20 November 2019 | url-status=live | access-date=24 October 2019}}{{PD-notice}}</ref>
]

==Contraindications==
Due to its effects on blood pressure (generally a transient increase in systolic blood pressure by 6{{nbsp}}mmHg, and diastolic blood pressure by 3{{nbsp}}mmHg), bremelanotide is considered contraindicated in people with uncontrolled ] or cardiovascular disease.<ref name="Vyleesi-Label" /> 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.<ref name="Vyleesi-Label" />

==Side effects==
The most frequently encountered side effect of bremelanotide is ] (40.0%), which may be intolerable to some people.<ref name="Vyleesi-Label" /> The use of ] medications (e.g., ]) prior to administration of bremelanotide may help to reduce the nausea.<ref name="Vyleesi-Label" /> Other side effects may include ] (20.3%), ]s (13.2%), ] (11.3%), ] (4.8%), ] (3.3%), ] (3.2%), ]es (2.7%), ] (2.6%), ] (2.2%), and ] (2.1%).<ref name="Vyleesi-Label" /><ref name=Gelman2017rev>{{cite journal | vauthors = Gelman F, Atrio J | title = Flibanserin for hypoactive sexual desire disorder: place in therapy | journal = Therapeutic Advances in Chronic Disease | volume = 8 | issue = 1 | pages = 16–25 | date = January 2017 | pmid = 28203348 | pmc = 5298357 | doi = 10.1177/2040622316679933 }}</ref><ref name=Belkin2015rev/> Discoloration of the skin, specifically ], may occur—especially if bremelanotide is used more than eight times in one month.<ref name="Vyleesi-Label" /> The discoloration may not resolve upon stopping use of bremelanotide, and may occur on the face, gums, or breasts.<ref name="Vyleesi-Label" /> Experiments in animals, even at high doses, failed to find any negative consequence of bremelanotide on fertility.<ref name="Vyleesi-Label" />

An analysis of clinical trials found that obese women reduced their calorie intake and lost weight. Another drug with a similar mechanism of action (]) is approved for weight loss in rare types of obesity.<ref>{{cite journal | vauthors = Spana C, Jordan R, Fischkoff S | title = Effect of bremelanotide on body weight of obese women: Data from two phase 1 randomized controlled trials | journal = Diabetes, Obesity & Metabolism | volume = 24 | issue = 6 | pages = 1084–1093 | date = June 2022 | pmid = 35170192 | pmc = 9314948 | doi = 10.1111/dom.14672 }}</ref>
{{Side effects of bremelanotide in phase 3 clinical trials}}

== Interactions ==
Bremelanotide does not meaningfully interact with ], unlike ] (for which the interaction with alcohol is a major barrier to its use).<ref>{{cite web | vauthors = Garde D |title=Experimental drug for women revives an intense debate on sexual desire |url=https://www.statnews.com/2019/06/20/women-sex-drive-experimental-drug-bremelanotide/ |website=STAT |access-date=23 June 2019 |date=20 June 2019 }}</ref><ref name="Clayton et al">{{cite journal | vauthors = Clayton AH, Kingsberg SA, Goldstein I | title = Evaluation and Management of Hypoactive Sexual Desire Disorder | journal = Sexual Medicine | volume = 6 | issue = 2 | pages = 59–74 | date = June 2018 | pmid = 29523488 | pmc = 5960024 | doi = 10.1016/j.esxm.2018.01.004 }}</ref> However, bremelanotide does interact with certain medications that people take by mouth. By slowing gastric motility, bremelanotide is thought to reduce the oral absorption (]) of certain medications, such as ] and ].<ref name="Vyleesi-Label" />

==Pharmacology==

===Pharmacodynamics===
Bremelanotide is a ] ] of the ]s, ] through ] (with the exception of ], the receptor of {{abbrlink|ACTH|adrenocorticotropic hormone}}), but acting primarily as an ] and ] agonist.<ref name=King2007rev>{{cite journal | vauthors = King SH, Mayorov AV, Balse-Srinivasan P, Hruby VJ, Vanderah TW, Wessells H | title = Melanocortin receptors, melanotropic peptides and penile erection | journal = Current Topics in Medicinal Chemistry | volume = 7 | issue = 11 | pages = 1098–1106 | year = 2007 | pmid = 17584130 | pmc = 2694735 | doi = 10.2174/1568026610707011111 | author6-link = Hunter Wessells }}</ref><ref name=Gelman2017rev/><ref name=Kingsberg2015rev/>

===Pharmacokinetics===
The ] of bremelanotide with ] is about 100%.<ref name="Vyleesi-Label" /> Following a subcutaneous injection of bremelanotide, ] occur after about one hour, with a range of 0.5 to 1.0&nbsp;hours.<ref name="Vyleesi-Label" /> The ] of bremelanotide is 21%.<ref name="Vyleesi-Label" /> Bremelanotide is ] via ] of its ]s.<ref name="Vyleesi-Label" /> The ] of bremelanotide is 2.7&nbsp;hours, with a range of 1.9 to 4.0&nbsp;hours.<ref name="Vyleesi-Label" /> Bremelanotide is ] 64.8% in ] and 22.8% in ].<ref name="Vyleesi-Label" />

==Chemistry==
Bremelanotide is a ] ] ] ] of ] (α-MSH).<ref name=Belkin2015rev>{{cite journal | vauthors = Belkin ZR, Krapf JM, Goldstein AT | title = Drugs in early clinical development for the treatment of female sexual dysfunction | journal = Expert Opinion on Investigational Drugs | volume = 24 | issue = 2 | pages = 159–167 | date = February 2015 | pmid = 25376023 | doi = 10.1517/13543784.2015.978283 | s2cid = 207477620 }}</ref> It has the ] Ac-Nle-''cyclo''-OH,<ref name=INN>{{cite journal|title=Proposed INN List 95|journal=WHO Drug Information|date=2006|volume=20|issue=2|page=124|url=https://www.who.int/medicines/publications/druginformation/innlists/PL95.pdf?ua=1}}</ref> and is also known as {{Chem name|''cyclo''-Ac-α-MSH-(4-10)}} (a substitutional name). Bremelanotide is an ] of ] that lacks the ] ] ].<ref name=Hadley2005/>

Aside from melanotan II and endogenous ]s like α-MSH, other peptide analogues of the same family as bremelanotide include ] (NDP-α-MSH), ], and ].

==History==
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 ] agents. They synthesized and tested several ]s, including peptides they subsequently named, ] and ].<ref name=King2007rev/><ref name=Hadley2005>{{cite journal | vauthors = Hadley ME | title = Discovery that a melanocortin regulates sexual functions in male and female humans | journal = Peptides | volume = 26 | issue = 10 | pages = 1687–1689 | date = October 2005 | pmid = 15996790 | doi = 10.1016/j.peptides.2005.01.023 | s2cid = 22559801 }}</ref>

Very early in the process one of the scientists, Mac Hadley,<ref name=Hadley2005/> who was conducting experiments on himself with the peptide ], injected himself with twice the dose he intended and experienced an ], along with nausea and vomiting.<ref name=King2007rev/>

To pursue the tanning agent, melanotan-I was licensed by Competitive Technologies, a ] company operating on behalf of University of Arizona, to an Australian startup called Epitan,<ref>{{cite news|title=EpiTan focuses on Melanotan, a potential blockbuster|url=https://www.thepharmaletter.com/article/epitan-focuses-on-melanotan-a-potential-blockbuster|work=The Pharma Letter|date=1 November 2004}}</ref><ref name=HadleyDorr2006>{{cite journal | vauthors = Hadley ME, Dorr RT | title = Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization | journal = Peptides | volume = 27 | issue = 4 | pages = 921–930 | date = April 2006 | pmid = 16412534 | doi = 10.1016/j.peptides.2005.01.029 | s2cid = 21025287 }}</ref> which changed its name to Clinuvel in 2006.<ref>{{cite news|title=Epitan changes name to Clinuvel, announces new clinical program|url=http://www.labonline.com.au/content/life-scientist/news/epitan-changes-name-to-clinuvel-announces-new-clinical-program-161764385|work=LabOnline|date=27 February 2006}}</ref>

To pursue the sexual dysfunction agent, melanotan II was licensed by Competitive Technologies to Palatin Technologies.<ref name=Hadley2005/> 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.<ref name=King2007rev/><ref name=Litigation/> Competitive Technologies sued Palatin for breach of contract and to try to claim ownership of bremelanotide;<ref name=Litigation>{{cite press release|title=Palatin Technologies Refutes Competitive Technologies Contention of Material Breach|url=http://www.prnewswire.com/news-releases/palatin-technologies-refutes-competitive-technologies-contention-of-material-breach-58006787.html|publisher=Palatin Technologies|date=12 September 2007|access-date=6 April 2017|archive-url=https://web.archive.org/web/20170407055315/http://www.prnewswire.com/news-releases/palatin-technologies-refutes-competitive-technologies-contention-of-material-breach-58006787.html|archive-date=7 April 2017|url-status=dead}}</ref> the parties settled in 2008, with Palatin retaining rights to bremelanotide, returning rights to melanotan-II to Competitive Technologies, and paying $800,000.<ref>{{cite press release|title=Palatin Technologies Announces Litigation Settlement With Competitive Technologies|url=http://www.prnewswire.com/news-releases/palatin-technologies-announces-litigation-settlement-with-competitive-technologies-57107302.html|publisher=Palatin Technologies|date=22 January 2008|access-date=6 April 2017|archive-url=https://web.archive.org/web/20170406204527/http://www.prnewswire.com/news-releases/palatin-technologies-announces-litigation-settlement-with-competitive-technologies-57107302.html|archive-date=6 April 2017|url-status=dead}}</ref>

In August 2004, Palatin signed an agreement with ] to co-develop bremelanotide in the US and jointly license it outside the US; King paid Palatin $20M upfront.<ref>{{cite web|title=Form 10-K for the year ended June 30, 2004|url=https://www.sec.gov/Archives/edgar/data/911216/000108802004000046/form10-k_063004.htm|publisher=Palatin via SEC EDGAR|date=13 September 2004}}</ref>

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 ] in clinical trial subjects; Palatin stopped development of the intranasal formulation in 2008.<ref name=Lodise2013rev>{{cite journal | vauthors = Lodise NM | title = Hypoactive sexual desire disorder in women: treatment options beyond testosterone and approaches to communicating with patients on sexual health | journal = Pharmacotherapy | volume = 33 | issue = 4 | pages = 411–421 | date = April 2013 | pmid = 23553810 | doi = 10.1002/phar.1209 | s2cid = 206357650 }}</ref><ref name=Gelman2017rev/><ref name=Ückert2014rev>{{cite journal | vauthors = Ückert S, Bannowsky A, Albrecht K, Kuczyk MA | title = Melanocortin receptor agonists in the treatment of male and female sexual dysfunctions: results from basic research and clinical studies | journal = Expert Opinion on Investigational Drugs | volume = 23 | issue = 11 | pages = 1477–1483 | date = November 2014 | pmid = 25096243 | doi = 10.1517/13543784.2014.934805 | s2cid = 22665242 }}</ref> Four trials were conducted in ED, the last being a Phase IIb published in 2008.<ref name=Ückert2014rev/> King terminated the co-development agreement shortly after the FDA halted the trials.<ref>{{cite news| vauthors = Nagle M |title=Erectile dysfunction drug deemed a flop|url=http://www.outsourcing-pharma.com/Preclinical-Research/Erectile-dysfunction-drug-deemed-a-flop|work=Outsourcing Pharma|date=10 September 2007 }}</ref>

The drug was then ] 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.<ref name=Kingsberg2015rev/><ref name=Belkin2015rev/> Palatin launched the Phase III trials with bremelanotide administered via an ].<ref name=10K2015/>

In 2014, Palatin licensed European rights to bremelanotide to ] 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.<ref name=10K2015>{{cite web|title=Palatin 10K for the fiscal year ended June 30, 2015|url=https://www.sec.gov/Archives/edgar/data/911216/000135448815004334/ptn_10k.htm|publisher=Palatin via SEC EDGAR|date=18 September 2015}}</ref>

In November 2016, Palatin announced results of the Phase III trials, and shortly thereafter began seeking a partner to complete development in the US.<ref>{{cite news|agency=Reuters|title=Female Viagra: Drugmaker Palatin Is Looking for a Buyer|url=http://fortune.com/2016/11/02/female-viagra-addyi-palatin/|work=]|date=2 November 2016}}</ref> In January 2017, Palatin and ] 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.<ref>{{cite news|title=AMAG Pharma closes deal for North America rights to Rekynda|url=https://www.thepharmaletter.com/article/amag-pharma-closes-deal-for-north-america-rights-to-rekynda|work=The Pharma Letter|date=2 February 2017}}</ref>

A ] of bremelanotide for female sexual dysfunction was accepted by the US ] (FDA) in June 2018, with a ] (PDUFA) goal date set for 23 March 2019.<ref>{{Cite web|url=http://www.mdmag.com/medical-news/fda-accepts-bremelanotide-nda-for-treatment-of-hypoactive-sexual-desire-disorder|title=Press release: FDA Accepts Bremelanotide NDA for Treatment of Hypoactive Sexual Desire Disorder|website=MD Magazine|access-date=2018-06-27}}</ref> It was approved for use in the United States in June 2019.<ref name=FDA2019 /><ref>{{cite web | vauthors = Nedelman M |title=FDA approves new drug for women with low sexual desire disorder |url=https://www.cnn.com/2019/06/21/health/women-sexual-desire-drug-bremelanotide-vyleesi-bn/index.html |publisher=] |date=21 June 2019 |access-date=23 June 2019 }}</ref><ref name=WP-FDA>{{Cite news| vauthors = Cha AE, McGinley L | title=A new 'female Viagra' approved by FDA despite skepticism| newspaper=]| url=https://www.washingtonpost.com/health/2019/06/21/new-female-viagra-approved-by-fda-despite-skepticism/ | date=21 June 2019| access-date=21 June 2019 }}</ref>

== References ==
{{Reflist}}

{{Sexual dysfunction pharmacotherapies}}
{{Melanocortin receptor modulators}}
{{Portal bar | Medicine}}

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Latest revision as of 21:13, 29 November 2024

Chemical compound

Pharmaceutical compound
Bremelanotide
Clinical data
Pronunciation/ˌbrɛmɪˈlænətaɪd/
Trade namesVyleesi
Other namesPT-141; Rekynda, bremelanotide acetate (USAN US)
AHFS/Drugs.comMonograph
MedlinePlusa619054
License data
Routes of
administration		Subcutaneous
Drug classMelanocortin receptor agonist
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilitySCTooltip Subcutaneous injection: ~100%
Protein binding21%
MetabolismHydrolysis of peptide bonds
Elimination half-life2.7 hours
ExcretionUrine: 64.8%
Feces: 22.8%
Identifiers
IUPAC name
  • (3S,6S,9R,12S,15S,23S)-15--9-benzyl-6-{3-propyl}-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexaazacyclotricosane-23-carboxylic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC50H68N14O10
Molar mass1025.182 g·mol
3D model (JSmol)
SMILES
  • O=C(C)N(CCCC)C(N1C(N(CC2=CNC=N2)C(N(CC3=CC=CC=C3)C(N(CCC/N=C(N)\N)C(N(CC4=CNC5C=CC=CC45)C(N(CCCCNC(C1)=O)C(O)=O)=O)=O)=O)=O)=O)=O
InChI
  • InChI=1S/C50H68N14O10/c1-3-4-16-35(58-29(2)65)43(67)64-41-25-42(66)54-20-11-10-18-37(49(73)74)60-46(70)39(23-31-26-56-34-17-9-8-15-33(31)34)62-44(68)36(19-12-21-55-50(51)52)59-45(69)38(22-30-13-6-5-7-14-30)61-47(71)40(63-48(41)72)24-32-27-53-28-57-32/h5-9,13-15,17,26-28,35-41,56H,3-4,10-12,16,18-25H2,1-2H3,(H,53,57)(H,54,66)(H,58,65)(H,59,69)(H,60,70)(H,61,71)(H,62,68)(H,63,72)(H,64,67)(H,73,74)(H4,51,52,55)/t35-,36-,37-,38+,39-,40-,41-/m0/s1
  • Key:FFHBJDQSGDNCIV-MFVUMRCOSA-N
  (verify)

Bremelanotide, sold under the brand name Vyleesi, is a medication used to treat low sexual desire in women. Specifically it is used for low sexual desire which occurs before menopause and is not due to medical problems, psychiatric problems, or problems within the relationship. It is given by an injection just under the skin of the thigh or abdomen.

Common side effects include nausea, pain at the site of injection, and headache. It may also cause a temporary increase in blood pressure and decrease in heart rate after each dose, and darkening of the gums, face, and breasts. The medication is a peptide and acts by activating the melanocortin receptors.

Bremelanotide was approved for medical use in the United States in 2019. It was developed by Palatin Technologies. The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses

Bremelanotide is used for the treatment of generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Specifically it is only recommended in those who have the condition without an underlying cause, such as medical, psychiatric, or relationship problems.

It should be used at least 45 minutes before anticipated sexual activity. Only one dose per 24 hours or no more than eight doses per month is recommended. It should be stopped after eight weeks if there is no improvement in sexual desire and associated distress.

Contraindications

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. 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.

Side effects

The most frequently encountered side effect of bremelanotide is nausea (40.0%), which may be intolerable to some people. The use of anti-nausea medications (e.g., ondansetron) prior to administration of bremelanotide may help to reduce the nausea. 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 flashes (2.7%), paresthesia (2.6%), dizziness (2.2%), and nasal congestion (2.1%). Discoloration of the skin, specifically hyperpigmentation, may occur—especially if bremelanotide is used more than eight times in one month. The discoloration may not resolve upon stopping use of bremelanotide, and may occur on the face, gums, or breasts. Experiments in animals, even at high doses, failed to find any negative consequence of bremelanotide on fertility.

An analysis of clinical trials found that obese women reduced their calorie intake and lost weight. Another drug with a similar mechanism of action (setmelanotide) is approved for weight loss in rare types of obesity.

Side effects of bremelanotide in phase 3 clinical trials
Side effect Placebo (n = 620) Bremelanotide 1.75 mg (n = 627)
n % n %
Nausea 8 1.3 251 40.0
FlushingTooltip Flushing_(physiology) 2 0.3 127 20.3
Headache 12 1.9 71 11.3
Injection site reaction 3 0.5 34 5.4
Vomiting 1 0.2 30 4.8
Cough 8 1.3 21 3.3
Fatigue 3 0.5 20 3.2
Injection site erythema 1 0.2 18 2.9
Hot flush 1 0.2 17 2.7
Paresthesia 0 0.0 16 2.6
Dizziness 3 0.5 14 2.2
Injection site pruritus 1 0.2 13 2.1
Abdominal pain 4 0.6 12 1.9
Myalgia 1 0.2 11 1.8
Summary: Side effects of bremelanotide with a ≥1% incidence in a combined analysis of two phase 3, double-blind, placebo controlled-clinical trials evaluating safety and efficacy at a daily dosage of 1.75 mg. Nausea was very common and occurred after a median time of 30 minutes for a median duration of 2.4 hours. "Across both studies, seven patients who received bremelanotide reported 10 treatment-emergent serious adverse events, and three patients who received placebo reported four treatment-emergent serious adverse events." Most side effects were reported to be transient and were "mild or moderate in intensity". Bremelanotide had a "favourable" safety profile. Sources: See template.

Interactions

Bremelanotide does not meaningfully interact with alcohol, unlike flibanserin (for which the interaction with alcohol is a major barrier to its use). 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.

Pharmacology

Pharmacodynamics

Bremelanotide is a non-selective agonist of the melanocortin receptors, MC1 through MC5 (with the exception of MC2, the receptor of ACTHTooltip adrenocorticotropic hormone), but acting primarily as an MC3 and MC4 receptor agonist.

Pharmacokinetics

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

Chemistry

Bremelanotide is a cyclic heptapeptide lactam analogue of α-melanocyte-stimulating hormone (α-MSH). It has the amino acid sequence Ac-Nle-cyclo-OH, and is also known as cyclo-Ac-α-MSH-(4-10) (a substitutional name). Bremelanotide is an active metabolite of melanotan II that lacks the C-terminal amide group.

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.

History

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 peptides they subsequently named, melanotan-I and melanotan II.

Very early in the process one of the scientists, Mac Hadley, 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.

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, which changed its name to Clinuvel in 2006.

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

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.

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

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. Palatin launched the Phase III trials with bremelanotide administered via an autoinjector.

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.

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

A New Drug Application of bremelanotide for female sexual dysfunction was accepted by the US Food and Drug Administration (FDA) in June 2018, with a Prescription Drug User Fee Act (PDUFA) goal date set for 23 March 2019. It was approved for use in the United States in June 2019.

References

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  2. ^ "Bremelanotide Acetate Monograph for Professionals". Drugs.com. Retrieved 24 October 2019.
  3. ^ "FDA approves new treatment for hypoactive sexual desire disorder in premenopausal women". U.S. Food and Drug Administration (FDA) (Press release). 21 June 2019. Archived from the original on 20 November 2019. Retrieved 24 October 2019.Public Domain This article incorporates text from this source, which is in the public domain.
  4. ^ "Drug Trials Snapshots: Vyleesi". U.S. Food and Drug Administration (FDA). 12 July 2019. Archived from the original on 20 November 2019. Retrieved 20 November 2019.Public Domain This article incorporates text from this source, which is in the public domain.
  5. ^ 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): 915–933. doi:10.1007/s40263-015-0288-1. PMID 26519340. S2CID 7437096.
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Sexual dysfunction pharmacotherapies
Dopamine agonists
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PDE5 inhibitors
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