PT-141 Dosing Protocol: Bremelanotide Research Guide

We provide clinically relevant applications for Food and Drug Administration (FDA)-approved medications (flibanserin and bremelanotide) and investigational therapies (Lorexys and testosterone combinations). Detailed study outcomes, safety profiles, and clinical strategies guide clinicians in appropriate diagnosis, patient selection, expectation setting, side effect management, and patient education, improving treatment outcomes and patient satisfaction.

Limitations: No placebo control reported. Review article — no new primary data.

Clinicians must discern important distinctions between flibanserin, bremelanotide, and other agents when managing premenopausal HSDD. Further research with the most suitable clinical endpoints and consideration of patient factors are crucial before widespread adoption of flibanserin and bremelanotide.

Limitations: No placebo control reported. Review article — no new primary data.

Several other continuous and categorical outcomes generated modest apparent benefits, though nearly all of these outcomes were likely derived post-hoc. Across RECONNECT trial data from two prior publications and the current study, bremelanotide's benefits are statistically modest and limited to outcomes for which scant evidence of validity among women with HSDD exists.

Limitations: No placebo control reported. Review article — no new primary data.

Although data from clinical trials demonstrated a significant change in validated questionnaires, the overall clinical benefit appears to be modest. However, these results should be interpreted in the light of the dramatic challenges in conducting well-designed clinical trials for female sexual dysfunction, due to the significant placebo effect of pharmacotherapy, and the frequent use of outcome measures that are likely to be highly susceptible to expectation biases, such as long periods of recall of sexual and emotional response.

Limitations: Review article — no new primary data.

These approvals have also renewed excitement in the development of therapeutics targeting the melanocortin system. Here, we review the anatomy and function of the melanocortin system, discuss progress and challenges in developing melanocortin receptor-based therapeutics, and outline potential metabolic and behavioural disorders that could be addressed using pharmacological agents targeting these receptors.

Limitations: No placebo control reported. Review article — no new primary data.

Because bremelanotide is a cyclic peptide molecule with a molecular weight of 1025, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant's gastrointestinal tract. Until more data become available, bremelanotide should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant.

Limitations: No placebo control reported. Review article — no new primary data.

Studies showed improvements in desire, arousal, and orgasm scores when 1.75 mg of bremelanotide was administered before sexual activity compared to a placebo. Bremelanotide is a promising way to treat HSDD.

Limitations: Animal study only — human translation uncertain. Review article — no new primary data.

Animal studies suggest that bremelanotide may affect female sexual desire by activating presynaptic MC4Rs on neurons in the mPOA of the hypothalamus, leading to increased release of DA, an excitatory neurotransmitter that increases sexual desire. This review presents what is known about the mechanism of action of bremelanotide in the context of treating HSDD.

Limitations: No placebo control reported. Review article — no new primary data.

The clinical development program comprised 3500 subjects in 43 completed studies. In the phase 3 studies, subjects took bremelanotide for up to 18 months.

Limitations: Standard limitations apply. Check original paper for full discussion.

Include delineation of the process of care for pre- and postmenopausal women with HSDD; release of global position statement on testosterone therapy in women; updates on efficacy and safety of vaginal estrogen for genitourinary syndrome of menopause and bremelanotide for HSDD; removal of flibanserin alcohol REMS; and development of new technology to enhance bioavailability and brain delivery of treatments. The DSM-5 revision combining HSDD and FSAD into one diagnostic category is a less accurate characterization of these separate disorders and may hinder access to demonstrated effective treatments for the women with these conditions.

Limitations: No placebo control reported. Review article — no new primary data.

The last decade has seen an increase in the number and type of pharmacologic treatment options for dysfunction primarily associated with menopause and hypoactive sexual desire disorder. Recent publications and systematic reviews have strengthened the safety data of existing FDA-approved medications as well as off-label therapies.

Limitations: No placebo control reported. Review article — no new primary data.

In Study A, 27 of 30 bremelanotide subjects (90.0%) completed the trial and exhibited a significantly greater reduction in body weight after 16&#x2009;days versus placebo [least squares mean difference (95% CI), -1.3 (-1.9 to -0.8) kg; p&#x2009;<&#x2009;.0001]. Mean caloric intake in bremelanotide subjects was decreased versus placebo, with a magnitude of reduction of approximately 400&#x2009;kcal/day throughout Study A (p&#x2009;<&#x2009;.01).

Limitations: Standard limitations apply. Check original paper for full discussion.

Among 1202 patients included in the integrated and subgroup analyses, bremelanotide achieved statistically significant improvements in measures of increased desire and decreased distress associated with low desire across all age, weight, and BMI subgroups, and all baseline bioavailable testosterone quartiles, with few exceptions. Bremelanotide was further associated with statistically significant increases in reported sexual desire (p&#x2009;<&#x2009;0.05) in patients not taking hormonal contraceptives, and with a numerical advantage in those taking hormonal contraceptives.

Limitations: Standard limitations apply. Check original paper for full discussion.

The 2 recently approved medications for HSDD, flibanserin and bremelanotide, are reviewed as well as off-label treatments. Overall, HSDD represents a common yet likely underrecognized disorder that midwives and other health care providers who care for women across the life span are in a unique position to address.

Limitations: No placebo control reported. Review article — no new primary data.

Bremelanotide, with even weaker efficacy, capitalised on the regulatory precedent set by the approval of flibanserin. Reconsideration of regulatory decisions to approve these drugs is in order, as well as a broader examination of how future regulatory decisions can better address conflicts of interest and clinically meaningful benefit.

Limitations: No placebo control reported. Review article — no new primary data.

Bremelanotide's modest benefits on incompletely reported post-hoc measures of questionable validity in combination with participants substantially preferring to take placebo suggest that the drug is generally not useful. Kingsberg et al.'s data reporting and measurement practices were incomplete and lacked transparency.

Limitations: Review article — no new primary data.

Because of the validity of a dilution QC that showed accurate quantification of 10-fold diluted plasma samples (accuracy 99.4 %, precision < 6 %), the assay is suitable for bremelanotide quantification in its effective concentration range up to 100,000&#x2009;pg/mL. The ultra-sensitive assay was applied to the quantification of bremelanotide plasma concentrations after oral administration to beagle dogs, which indicated minimal oral absorption.

Limitations: Animal study only — human translation uncertain.

Bremelanotide is a synthetic peptide analogue of the neuropeptide hormone alpha melanocyte-stimulating hormone (&#x3b1;-MSH) with high affinity for the melanocortin type 4 receptor (thought to be important for sexual function), giving it the potential to modulate brain pathways involved in sexual response. This article summarizes the milestones in the development of bremelanotide leading to this first regulatory approval.

Limitations: No placebo control reported. Review article — no new primary data.

Bremelanotide is a subcutaneous injection that can be administered as needed approximately 45 minutes prior to sexual activity. Bremelanotide is safe and has limited drug-drug interactions, including no clinically significant interactions with ethanol.

Limitations: No placebo control reported. Review article — no new primary data.

Study 301 began on January 7, 2015, and concluded on July 26, 2016. Study 302 began on January 28, 2015, and concluded on August 4, 2016.

Limitations: Standard limitations apply. Check original paper for full discussion.

This review discusses investigations of melanocortin agonists for the treatment of sexual dysfunction with emphasis on proposed sites and mechanisms of action in the central nervous system that appear to be involved in melanocortinergic modulation of sexual function. Current research validates use of melanocortinergic agents for the treatment of both male and female sexual dysfunction.

Limitations: Preliminary/pilot study — needs larger trials. No placebo control reported. Review article — no new primary data.

More women reported moderate or high sexual desire following bremelanotide treatment vs. placebo (P = 0.0114), and a trend toward more positive responses regarding feelings of genital arousal occurred after bremelanotide compared with placebo (P = 0.0833).

Limitations: Preliminary/pilot study — needs larger trials.

Bremelanotide is a parenterally administered melanocortin receptor agonist that is used to treat female hypoactive sexual desire disorder. Bremelanotide has been reported to cause mild serum enzyme elevations during therapy and has been implicated in rare instances of clinically apparent acute liver injury.

Limitations: No placebo control reported. Review article — no new primary data.