Bremelanotide
Template:Short description Template:Use dmy dates Template:Cs1 config Template:Drugbox
Bremelanotide, sold under the brand name Vyleesi, is a medication used to treat low sexual desire in women.<ref name=AHFS2019/> 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.<ref name=FDA2019 /><ref name="FDA Snapshot">{{#invoke:citation/CS1|citation |CitationClass=web }}Template:PD-notice</ref><ref name=AHFS2019/> It is given by an injection just under the skin of the thigh or abdomen.<ref name=AHFS2019/><ref name="FDA Snapshot" />
Common side effects include nausea, pain at the site of injection, and headache.<ref name=AHFS2019>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="FDA Snapshot" /> The medication is a peptide and acts by activating the melanocortin receptors.<ref name="Vyleesi-Label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Kingsberg2015rev">Template:Cite journal</ref>
Bremelanotide was approved for medical use in the United States in 2019.<ref name=AHFS2019/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It was developed by Palatin Technologies.<ref name="AdisInsight">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The US Food and Drug Administration (FDA) considers it to be a first-in-class medication.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Medical usesEdit
Bremelanotide is used for the treatment of generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.<ref name=FDA2019 /><ref name="Frellick">{{#invoke:citation/CS1|citation |CitationClass=web }}</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/>
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>Template:Cite press releaseTemplate:PD-notice</ref>
ContraindicationsEdit
Due to its effects on blood pressure (generally a transient increase in systolic blood pressure by 6Template:NbspmmHg, and diastolic blood pressure by 3Template:NbspmmHg), bremelanotide is considered contraindicated in people with uncontrolled high blood pressure 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 effectsEdit
The most frequently encountered side effect of bremelanotide is nausea (40.0%), which may be intolerable to some people.<ref name="Vyleesi-Label" /> The use of anti-nausea medications (e.g., ondansetron) prior to administration of bremelanotide may help to reduce the nausea.<ref name="Vyleesi-Label" /> 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%).<ref name="Vyleesi-Label" /><ref name=Gelman2017rev>Template:Cite journal</ref><ref name=Belkin2015rev/> Discoloration of the skin, specifically hyperpigmentation, 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 (setmelanotide) is approved for weight loss in rare types of obesity.<ref>Template:Cite journal</ref> Template:Side effects of bremelanotide in phase 3 clinical trials
InteractionsEdit
Bremelanotide does not meaningfully interact with alcohol, unlike flibanserin (for which the interaction with alcohol is a major barrier to its use).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Clayton et al">Template:Cite journal</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 (bioavailability) of certain medications, such as naltrexone and indomethacin.<ref name="Vyleesi-Label" />
PharmacologyEdit
PharmacodynamicsEdit
Bremelanotide is a non-selective agonist of the melanocortin receptors, MC1 through MC5 (with the exception of MC2, the receptor of Template:Abbrlink), but acting primarily as an MC3 and MC4 receptor agonist.<ref name=King2007rev>Template:Cite journal</ref><ref name=Gelman2017rev/><ref name=Kingsberg2015rev/>
PharmacokineticsEdit
The bioavailability of bremelanotide with subcutaneous injection is about 100%.<ref name="Vyleesi-Label" /> Following a subcutaneous injection of bremelanotide, maximal levels occur after about one hour, with a range of 0.5 to 1.0 hours.<ref name="Vyleesi-Label" /> The plasma protein binding of bremelanotide is 21%.<ref name="Vyleesi-Label" /> Bremelanotide is metabolized via hydrolysis of its peptide bonds.<ref name="Vyleesi-Label" /> The elimination half-life of bremelanotide is 2.7 hours, with a range of 1.9 to 4.0 hours.<ref name="Vyleesi-Label" /> Bremelanotide is excreted 64.8% in urine and 22.8% in feces.<ref name="Vyleesi-Label" />
ChemistryEdit
Bremelanotide is a cyclic heptapeptide lactam analogue of α-melanocyte-stimulating hormone (α-MSH).<ref name=Belkin2015rev>Template:Cite journal</ref> It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH,<ref name=INN>Template:Cite journal</ref> and is also known as Template:Chem name (a substitutional name). Bremelanotide is an active metabolite of melanotan II that lacks the C-terminal amide group.<ref name=Hadley2005/>
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 peptides they subsequently named, melanotan-I and melanotan II.<ref name=King2007rev/><ref name=Hadley2005>Template:Cite journal</ref>
Very early in the process one of the scientists, Mac Hadley,<ref name=Hadley2005/> 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.<ref name=King2007rev/>
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,<ref>Template:Cite news</ref><ref name=HadleyDorr2006>Template:Cite journal</ref> which changed its name to Clinuvel in 2006.<ref>Template:Cite news</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>Template:Cite press release</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>Template:Cite press release</ref>
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 blood pressure in clinical trial subjects; Palatin stopped development of the intranasal formulation in 2008.<ref name=Lodise2013rev>Template:Cite journal</ref><ref name=Gelman2017rev/><ref name=Ückert2014rev>Template:Cite journal</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>Template:Cite news</ref>
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.<ref name=Kingsberg2015rev/><ref name=Belkin2015rev/> Palatin launched the Phase III trials with bremelanotide administered via an autoinjector.<ref name=10K2015/>
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.<ref name=10K2015>{{#invoke:citation/CS1|citation |CitationClass=web }}</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>Template:Cite news</ref> 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.<ref>Template:Cite news</ref>
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It was approved for use in the United States in June 2019.<ref name=FDA2019 /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=WP-FDA>Template:Cite news</ref>
ReferencesEdit
Template:Sexual dysfunction pharmacotherapies Template:Melanocortin receptor modulators Template:Portal bar