ATC code None Biological half-life 120 minutes PubChem CID 9941379 Molar mass 1,025.2 g/mol | Legal status US: Unscheduled CAS Number 189691-06-3 ChemSpider 8116997 | |
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Bremelanotide (/ˌbrɛmᵻˈlænətaɪd/) (INN, USAN), formerly known as PT-141 and tentative brand name Rekynda, is a peptide drug which has been under development by Palatin Technologies as a treatment for female sexual dysfunction (FSD), hemorrhagic shock, and reperfusion injury. Bremelanotide was originally tested for intranasal administration in treating FSD but this application was temporarily discontinued in 2008 after concerns were raised over increased blood pressure seen with bremelanotide administration in some patients. As of December 2014, Palatin is conducting a human phase III study using a subcutaneous drug delivery system that appears to have little effect on blood pressure.
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Positive results of bremelanotide in the treatment of hypoactive sexual desire disorder (HSDD) in two late-stage phase III clinical trials were announced by Palatin on 1 November 2016. The company is expected to seek approval of bremelanotide for this indication in the United States in the second half of 2017.
Clinical development
Bremelanotide was developed from the peptide hormone melanotan II which underwent testing as a sunless tanning agent. In initial testing, melanotan II did induce the production of darkening dermal pigmentation (melanogenesis) but additionally caused sexual arousal and spontaneous erections as unexpected side effects in nine out of the ten original male volunteer test subjects.
In studies, bremelanotide was shown to induce lordosis in an animal model and was also effective in treating sexual dysfunction in both men (erectile dysfunction or impotence) and women (sexual arousal disorder). Unlike sildenafil (Viagra) and other related medications, it does not act upon the vascular system, but directly increases sexual desire via acting in the brain.
A phase III clinical trial was scheduled to begin in the first half of 2007, but was delayed until August 2007. On August 30, Palatin announced that the U.S. Food and Drug Administration had expressed serious concerns regarding the risk/benefit ratio of bremelanotide with regards to the side effect of increased blood pressure. The FDA stated that it would consider alternate uses for bremelanotide, including as a treatment for individuals who do not respond to more established ED treatments. However, on May 13, 2008, Palatin Technologies announced it had "discontinued development of bremelanotide for the treatment of male and female sexual dysfunction" while concurrently announcing plans to develop it as a treatment for hemorrhagic shock instead. The company additionally announced intentions to focus its attention on another, more selective compound, PL-6983, that was found to produce lower increases in blood pressure in animal models. Palatin has since re-initiated bremelanotide studies for ED and FSD using a subcutaneous delivery method. On August 12, 2009, the company announced that in a double-blind study of 54 volunteers bremelanotide failed to evoke the hypertensive side effects seen with the nasal delivery system used in prior studies, concluding that "variability of uptake" inherent in intranasal administration of the drug resulted in "increases in blood pressure and gastrointestinal events...primarily related to high plasma levels in [only] a subset of patients" and that subcutaneous administration of the drug circumvented the potential for this side effect. Palatin has completed a human phase IIb study utilizing subcutaneous administration and reported positive results.
In Australia, Bremelanotide is being studied to treat Autism in males between the ages of 16-65. The Phase 2 study is sponsored by the University of Sydney and is titled "A Within-Subject Single Dose Trial on the Effects of Bremelanotide on Social Cognition and Behaviour"
Bremelanotide, via the subcutaneous injection route, has been studied in human clinical trials in doses of 0.75, 1.25, and 1.75 mg, with its effectiveness in treating sexual dysfunction increasing with each dosage and side effect rates remaining similar.
Rekynda (bremelanotide), an investigational product, is thought to possess a novel mechanism of action, activating endogenous melanocortin pathways involved in sexual desire and response.
The two Phase 3 studies for HSDD in pre-menopausal women consisted of double-blind placebo-controlled, randomized parallel group studies comparing a single use, subcutaneous dose of 1.75 mg of Rekynda versus placebo, in each case, delivered via an auto-injector. Each trial consisted of more than 600 patients randomized in a 1:1 ratio to either the treatment arm or placebo with a 24 week evaluation period. In both clinical trials, Rekynda met the pre-specified co-primary efficacy endpoints of median improvement in desire and decrease in distress associated with low sexual desire as measured using validated patient-reported outcome instruments.
Women in the trials had the option, after completion of the trial, to continue in an ongoing open-label safety extension study for an additional 52 weeks. Nearly 80% of patients who completed the randomized portion of the study elected to remain in the open-label portion of the study, and all of these patients will continue to receive Rekynda.
In both Phase 2 and Phase 3 clinical trials, the most frequent adverse events were nausea, flushing, and headache, which were generally mild-to-moderate in severity.
Rekynda has no known alcohol interactions.
Pharmacology
Bremelanotide, similarly to its analogues α-MSH and melanotan II, acts as a non-selective agonist of all of the melanocortin receptors except MC2, where it lacks significant affinity. Reported activity of the drug is as follows:
Bremelanotide appears to stimulate sexual desire and arousal completely or mostly via activation of the MC4 receptor (the MC3 receptor may also be involved). It modulates inflammation and limits ischemia via activation of the MC1 and MC4 receptors.
According to Palatin Technologies' original 2003 patent for bremelanotide, it possesses approximately 50 times the potency of melanotan II as an inducer of erection in male rats. In addition, it was stated in the patent that the therapeutic window of bremelanotide in animals (specifically, the range of induction of the desired sexual arousal relative to the induction of side effects including nausea, yawning, stretching, and decreased appetite) was >1,000-fold, whereas that of melanotan II was only 3- to 4-fold. They concluded that bremelanotide would be more tolerable than melanotan II. However, in human clinical trials, bremelanotide has, similarly to melanotan II, been found to produce nausea and vomiting (though yawning, stretching, and loss of appetite do not seem to have been reported). Other side effects reported for bremelanotide in human clinical trials include transient facial flushing, sweating, somnolence, headache, dizziness, dysgeusia (altered sense of taste), hypertension, and skin hyperpigmentation.
Chemistry
Bremelanotide is a cyclic heptapeptide lactam analog of α-melanocyte-stimulating hormone (α-MSH). It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH, 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.