PT-141

Bremelanotide: First Approval.

Bremelanotide (Vyleesi™) is a melanocortin receptor agonist recently approved in the USA for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty. It is a self-administered, on-demand subcutaneous therapy. Initially developed by Palatin Technologies who sponsored the Phase 3 clinical trials, bremelanotide was subsequently out-licensed to AMAG Pharmaceuticals Inc. for exclusive North American rights to develop and commercialize the drug, including submitting the New Drug Application to the US FDA. Bremelanotide is a synthetic peptide analogue of the neuropeptide hormone alpha melanocyte-stimulating hormone (α-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.

PT-141 Palatin.

Palatin, under license from Competitive Technology, is developing the peptide PT-141, a synthetically modified analog of PT-14, as a nasal spray for the potential treatment of erectile dysfunction (ED) and female sexual dysfunction. In September 2003, Palatin had completed a phase IIb trial in patients with ED and in February 2004, Palatin planned to start phase III trials in early 2005.

Hypoactive Sexual Desire Disorder in Women: Physiology, Assessment, Diagnosis, and Treatment.

Nearly half of women in the United States report problems with sexual function. Many health care providers do not ask about sexual concerns during routine clinical encounters because of personal discomfort, lack of familiarity with treatment, or the belief that they lack adequate time to address this complex issue. This may be especially true for hypoactive sexual desire disorder (HSDD), the most commonly identified sexual problem among women. HSDD is characterized by a deficiency of sexual thoughts, feelings, or receptiveness to sexual stimulation that has been present for at least 6 months, causes personal distress, and is not due to another medical condition. This is an up-to-date overview of HSDD for clinicians, discussing its physiology, assessment, diagnosis, and treatment strategies. Although a definitive physiology of HSDD is still unknown, multiple hormones and neurotransmitters likely participate in a dual-control model to balance excitation and inhibition of sexual desire. For assessment and diagnosis, validated screening tools are discussed, and the importance of a biopsychosocial assessment is emphasized, with guidance on how this can be implemented in clinical encounters. 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.

Safety Profile of Bremelanotide Across the Clinical Development Program.

Background: Bremelanotide, a melanocortin receptor agonist, is Food and Drug Administration (FDA)-approved for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. Methods: Review of bremelanotide's safety profile from the clinical development program (phases 1 through 3). Results: The clinical development program comprised 3500 subjects in 43 completed studies. In the phase 3 studies, subjects took bremelanotide for up to 18 months. The most common adverse events (AEs) were nausea (40.0% vs. 1.3%), flushing (20.3% vs. 1.3%), headache (11.3% vs. 1.9%), and injection site reactions (5.4 vs. 0.5), bremelanotide versus placebo groups, respectively, in the integrated double-blind portion of the phase 3 studies (N = 1247). Nausea was the most common reason for bremelanotide discontinuation. There were no deaths; a few subjects experienced serious AEs. Focal hyperpigmentation was rare when bremelanotide was dosed in accordance with label recommendations, but it occurred in more than one-third of subjects following up to 16 consecutive daily dosings. Small and transient but statistically significant blood pressure increases were observed during ambulatory blood pressure monitoring. Most drug-drug interactions were not clinically significant, except for interactions that lowered plasma concentrations of indomethacin and naltrexone. In the double-blind portion of the integrated phase 3 studies, 70% of the bremelanotide group proceeded to the open-label phase of the studies versus 87% of those on placebo. Conclusions: The AEs associated with bremelanotide are mostly mild to moderate. Although not deemed clinically important, bremelanotide should be used with caution in patients at risk of cardiovascular disease, and blood pressure should be well controlled during treatment. Clinical Trial Registration number: NCT02333071 [Study 301] and NCT02338960 [Study 302].

Bremelanotide for Treatment of Female Hypoactive Sexual Desire.

Hypoactive sexual desire disorder (HSDD) is a persistent deficiency or absence of sexual fantasies and desire resulting in significant distress or interpersonal difficulty. Women with this disorder may display a lack of motivation for sexual activity, reduced responsiveness to erotic cues, a loss of interest during sexual activity, and avoidance of situations that could lead to sexual activity. The pathophysiology of HSDD is thought to be centered around inhibitory and excitatory hormones, neurotransmitters, and specific brain anatomy. Due to the multifactorial nature of HSDD, treatment can be complex and must attempt to target the biological and psychosocial aspects of the disorder. Bremelanotide is a melanocortin receptor agonist and has been recently approved by the FDA to treat HSDD. Bremelanotide is administered intranasally or as a subcutaneous injection. The recommended dosage of bremelanotide is 1.75 mg injected subcutaneously in the abdomen or thigh at least 45 min before sexual activity. 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.

Targeting the central melanocortin system for the treatment of metabolic disorders.

A large body of preclinical and clinical data shows that the central melanocortin system is a promising therapeutic target for treating various metabolic disorders such as obesity and cachexia, as well as anorexia nervosa. Setmelanotide, which functions by engaging the central melanocortin circuitry, was approved by the FDA in 2020 for use in certain forms of syndromic obesity. Furthermore, the FDA approvals in 2019 of two peptide drugs targeting melanocortin receptors for the treatment of generalized hypoactive sexual desire disorder (bremelanotide) and erythropoietic protoporphyria-associated phototoxicity (afamelanotide) demonstrate the safety of this class of peptides. 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.

Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder.

Objective: To review data regarding bremelanotide, a recently approved therapy for hypoactive sexual desire disorder (HSDD). Data Sources: Literature search of Medline, SCOPUS, and EMBASE was performed using the search terms bremelanotide, bremelanotide injection, Vyleesi, and melanocortin 4 receptor agonist between January 1, 1996, and December 15, 2019. Reference lists from included articles were also reviewed for pertinent citations. Study Selection/Data Extraction: We included phase 2 and 3 trials of bremelanotide. There were 2 reports of phase 3 trials and 2 reports of phase 2 trials. Additional information from supplementary analyses was also referenced. Data Synthesis: Bremelanotide demonstrates significant improvement in desire and a significant decrease in distress related to lack of desire. The most common adverse effects include nausea (39.9%), facial flushing (20.4%), and headache (11%). Relevance to Patient Care and Clinical Practice: Bremelanotide is the second Food and Drug Administration-approved medication for the treatment of HSDD. Bremelanotide's place in therapy is unknown, as the HSDD guidelines were last updated in 2017. Although the trials met statistical significance for change in sexual desire elements and distress related to sexual desire, the clinical benefit may only be modest. Conclusion: 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. Prescribing guidelines recommend no more than 1 dose in 24 hours and no more than 8 doses per month. Individuals should discontinue use after 8 weeks without benefit.

An evaluation of bremelanotide injection for the treatment of hypoactive sexual desire disorder.

Female sexual response implies a deep intertwining between psychosocial and neurobiological mediators. Regulation of central melanocortin signaling may enhance sexual desire. In premenopausal women with hypoactive sexual desire disorder (HSDD), melanocortin receptor agonist bremelanotide (Vyleesi) has been hypothesized to trigger excitatory brain pathways. Hereby we summarize bremelanotide's proposed mechanism of action, pharmacokinetics, efficacy and safety data derived from clinical trials. A literature search of peer-reviewed publications on the current evidence on the pharmacotherapy with bremelanotide was performed using the PubMed database. Bremelanotide appears to be moderately safe and well-tolerated; the most common adverse reaction is nausea (40%). 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.

Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials.

To evaluate the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder. Two identical phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trials (RECONNECT) evaluated the safety and efficacy of bremelanotide 1.75 mg administered subcutaneously as needed in premenopausal women with hypoactive sexual desire disorder. Patients were randomized 1:1 to 24 weeks of treatment with bremelanotide or placebo. Sample size was estimated based on simulations from key endpoints in patients with hypoactive sexual desire disorder from a prior trial. Coprimary efficacy endpoints were change from baseline to end-of-study in the Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13. 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. Of the 1,267 women randomized, 1,247 and 1,202 were in the safety and efficacy (modified intent-to-treat) populations, respectively. Most participants were white (85.6%), from U.S. sites (96.6%), and had a mean age of 39 years. From baseline to end-of-study, women taking bremelanotide had statistically significant increases in sexual desire (study 301: 0.30, P<.001; study 302: 0.42, P<.001; integrated studies 0.35, P<.001) and statistically significant reductions in distress related to low sexual desire (study 301: -0.37, P<.001; study 302: -0.29, P=.005; integrated studies -0.33, P<.001) compared with placebo. Patients taking bremelanotide experienced more nausea, flushing, and headache (10% or more in both studies) compared with placebo. Both studies demonstrated that bremelanotide significantly improved sexual desire and related distress in premenopausal women with hypoactive sexual desire disorder. The safety profile was favorable. Most treatment-emergent adverse events were related to tolerability and the majority were mild or moderate in intensity. ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302). Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Novel Pharmacologic Treatments of Female Sexual Dysfunction.

This review evaluates pharmacologic treatments for female sexual dysfunction (FSD), focusing on hypoactive sexual desire disorder (HSDD). 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.

Bremelanotide (Vyleesi) for hypoactive sexual desire disorder.

Medical Treatment of Female Sexual Dysfunction.

Female sexual dysfunction (FSD) comprises multiple overlapping sexual disorders with a multifaceted cause within the frame of the biopsychosocial model. Health care providers can screen for FSD according to their level of expertise and deliver at least basic counseling before eventually referring to sexual medicine specialists for specific care. The therapeutic algorithm comprises a multidisciplinary approach, including pharmacologic and nonpharmacologic management. Flibanserin and bremelanotide are psychoactive agents indicated for the treatment of generalized acquired hypoactive sexual desire disorder (HSDD) in premenopausal women, whereas transdermal testosterone is effective on HSDD in postmenopausal women. Menopause hormone therapy (systemic and local) is the mainstay for individualized management of women at midlife.

Re-Analyzing Phase III Bremelanotide Trials for "Hypoactive Sexual Desire Disorder" in Women.

Kingsberg et al. described results from two 24-week Phase III trials of bremelanotide for treating hypoactive sexual desire disorder (HSDD) in women. 72.72% of protocol-listed outcomes were not reported by Kingsberg et al., who provided results of 15 secondary measures which were not listed in the study protocols. None of their efficacy outcomes were reported in line with CONSORT data reporting standards and no secondary outcome had a stated rationale or cited evidence of validity. My meta-analysis of the trials' data, based on the FDA New Drug Application, found similar results to Kingsberg et al. However, Kingsberg et al. did not report that a) adverse event-induced study discontinuation was substantially higher on bremelanotide: OR&#xa0;= 11.98, 95% CI&#xa0;= 3.74-38.37, NNH: 6 or b) participants preferred placebo, measured by the combination of both 1) completing a clinical trial and 2) electing to participate in the follow-up open-label study (OR&#xa0;= 0.30, 95% CI&#xa0;= .24-.38, NNH: 4). 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.

Pharmacotherapy for Sexual Dysfunction in Women.

This review article discusses the controversy in the DSM-5 conceptualization and diagnostic criteria for female sexual dysfunction (FSD). An overview of recent studies on available treatments for hypoactive sexual desire disorder (HSDD), female sexual arousal disorder (FSAD), and genitopelvic pain/penetration disorder (GPPD) is provided. 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. There are a wide range of pharmacological, other physiological, and psychological treatment options available for women with FSD, which can be offered based on their specific symptoms, potential benefits/risks, and preferences.

Prespecified and Integrated Subgroup Analyses from the RECONNECT Phase 3 Studies of Bremelanotide.

Background: Hypoactive sexual desire disorder (HSDD), the most prevalent female sexual dysfunction, is characterized as persistent diminished desire for sexual activity accompanied by distress. The efficacy and safety of bremelanotide, a melanocortin receptor agonist approved by the U.S. Food and Drug Administration for treatment of acquired generalized HSDD in premenopausal women, were established in the phase 3 RECONNECT studies, two identically designed double-blind randomized placebo-controlled studies with an optional 52-week open-label extension. This report investigates efficacy of bremelanotide versus placebo according to prespecified subgroups (age, weight, body mass index [BMI], and bioavailable testosterone) in the RECONNECT studies. Materials and Methods: Patients self-administered bremelanotide 1.75&#x2009;mg or placebo subcutaneously using an autoinjector, as needed, before sexual activity for 24 weeks. Efficacy was assessed using change from baseline to end-of-study for Female Sexual Function Index desire domain and Female Sexual Distress Scale-Desire/Arousal/Orgasm Item 13 for bremelanotide versus placebo. Results: 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. Patients treated with bremelanotide experienced decreased distress compared with those in the placebo group at levels of statistical significance (p&#x2009;<&#x2009;0.05) regardless of hormonal contraceptive use. Statistically significant improvements were observed in the presence or absence of decreased arousal, and regardless of HSDD duration. Conclusions: Bremelanotide was associated with statistically significant improvements in sexual desire and reduced distress across several prespecified subgroups, with few exceptions.

Bremelanotide and flibanserin for low sexual desire in women: the fallacy of regulatory precedent.

The US Food and Drug Administration (FDA) has approved two drugs for 'hypoactive sexual desire disorder' in women, flibanserin (Addyi) in 2015 and bremelanotide (Vyleesi) in 2019. In this paper we examine the outcome measures and clinical trial data upon which regulatory approval was based. In clinical trials, flibanserin led to an average of only one additional enjoyable sexual experience every two months, bremelanotide to none. Trials for both drugs feature shifts in primary outcomes and a contested indication. A politicised industry-sponsored advocacy campaign and conflicted patient and expert testimony likely influenced flibanserin's approval at its third attempt. 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.

Pharmacologic therapeutic options for sexual dysfunction.

Sexual problems are reported by up to 45% of individuals assigned female at birth. Although sexual function is a complex biopsychosocial construct, there are a number of pharmacologic treatment options aimed at addressing the changing vaginal hormonal milieu in postmenopausal individuals and moderating the excitatory and inhibitory aspects of the central nervous system in those with hypoactive sexual desire disorder. 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. Pharmacologic treatment with local estrogen and testosterone replacement in postmenopausal individuals and with centrally-acting therapies such as flibanserin, bremelanotide, and testosterone in premenopausal individuals assigned female at birth are safe and can be used to improve sexual desire and sexual satisfaction.

The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women.

Hypoactive sexual desire disorder (HSDD) is a common female sexual dysfunction and is estimated to affect approximately 10% of women in the United States. It has been suggested that HSDD is associated with an imbalance of hormone and neurotransmitter levels in the brain, resulting in decreased excitation, increased inhibition, or a combination of both. Evidence suggests neurotransmitters, including dopamine (DA), norepinephrine, and serotonin, as well as hormones such as estradiol and testosterone, contribute to female sexual desire and response. Current treatments for HSDD include psychotherapy, and two US Food and Drug Administration-approved medications for premenopausal women: flibanserin, a serotonin mixed agonist and antagonist, and bremelanotide, a melanocortin receptor (MCR) agonist. Melanocortins are endogenous neuropeptides associated with the excitatory pathway of the female sexual response system. MCRs are found throughout the body, including the brain. Bremelanotide is an MCR agonist that nonselectively activates several of the receptor subtypes, of which subtype 4 (MC4R) is the most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area (mPOA) of the hypothalamus in the brain, and is important for female sexual function. 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.

Therapeutic Peptides in Aesthetic, Metabolic and Endocrine Conditions: Effects, Safety, Clinical Applications, and Future Perspectives.

Therapeutic peptides are short chains of amino acids used to treat metabolic and endocrine conditions such as obesity and type 2 diabetes. While several peptide drugs have undergone rigorous approval processes that evaluate both safety and efficacy, novel, unapproved compounds have emerged and are rapidly expanding into preventive medicine and performance enhancement. Our objective is to present the effects, clinical applications, safety profiles, and regulatory status of prominent peptides used to treat several conditions. We reviewed 106 articles, prioritizing systematic reviews, meta-analyses, and randomized controlled trials in the PubMed, ScienceDirect, and SciELO databases. Our results suggest that therapeutic peptides are a promising tool for treating type 2 diabetes and obesity, for skin rejuvenation, and as hormone analogs for specific diseases and conditions. Although these are strategic and innovative options that can improve health, performance, and longevity, further studies are needed before most new peptides can be used safely in humans.

Bremelanotide: the female Viagra?

Effect of bremelanotide on body weight of obese women: Data from two phase 1 randomized controlled trials.

The melanocortin 4 receptor (MC4R) plays a central role in appetite regulation, and agonistic activity at this receptor promotes satiety. Results from two randomized controlled clinical trials examine the effects of bremelanotide's agonism at MC4R on caloric intake and body weight. Premenopausal women with a body mass index >30&#x2009;kg/m2 were studied in two phase 1, single-centre, randomized, double-blind, placebo-controlled trials. Study A matched subjects 1:1 to receive subcutaneous placebo or bremelanotide three times daily for days 1-15. Study B was a crossover trial with six distinct treatment sequences consisting of three 4-day treatment periods, investigating once-a-day and twice-a-day exposure to bremelanotide versus placebo. Subjects received one of the three treatments twice-daily during each period: 0&#xa0;mg/0&#xa0;mg, 2.5&#xa0;mg/0&#xa0;mg or 2.5&#xa0;mg/2.0&#xa0;mg bremelanotide. Body weight and food intake were recorded in detail daily. Adverse events were recorded throughout both studies. 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). In Study B, 15 of 27 subjects (55.6%) completed all three phases. Significantly greater reduction of mean body weight occurred in twice-daily bremelanotide subjects versus placebo (1.7 vs. 0.9&#xa0;kg, respectively, p&#x2009;<&#x2009;.001). Total caloric intake reduction was significantly greater in the bremelanotide groups versus placebo (mean difference range: 398-469&#x2009;kcal; p&#x2009;<&#x2009;.0001). Agonist activity at the MC4R may aid in reducing caloric intake and weight loss in obese women.

Melanocortins in the treatment of male and female sexual dysfunction.

Melanocortinergic agents are currently being investigated for a possible therapeutic role in male and female sexual dysfunction. These investigations were sparked by findings that systemic administration of a synthetic analog of alpha-MSH, MT-II, causes penile erections in a variety of species, including humans. Several other melanocortinergic agents including HP-228, THIQ, and bremelanotide (PT-141) have since been shown to have erectogenic properties thought to be due to binding to melanocortin receptors in the central nervous system, particularly the hypothalamus. Bremelanotide, a nasally administered synthetic peptide, is the only melanocortinergic agent that has been clinically studied in both males and females. Data from Phase II clinical trials of bremelanotide support the use of melanocortin-based therapy for erectile dysfunction. Studies using animal models have demonstrated that pre-copulatory behaviors in female rats analogous to sexual arousal are evoked, and preliminary clinical data also suggest a role in promoting sexual desire and arousal in women. Based on bremelanotide clinical experience, administration of a melanocortin agonist is well tolerated and not associated the hypotension observed with phosphodiesterase-5 inhibitors currently used to treat erectile dysfunction. 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.

An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist.

Melanocortins affect multiple physiological responses, including sexual behaviors. Bremelanotide is a synthetic peptide melanocortin analog of alpha-melanocyte-stimulating hormone that is an agonist at melanocortin receptors MC3R and MC4R. To evaluate a single intranasal dose of bremelanotide for potential effects on physiological and subjective measurements of sexual arousal and desire in premenopausal women with sexual arousal disorder. Change in vaginal pulse amplitude during neutral and erotic videos after treatment with bremelanotide or placebo and subjects' perceptions of physiological and sexual response within 24 hours of treatment with bremelanotide or placebo. Eighteen premenopausal women with a primary diagnosis of female sexual arousal disorder were randomly assigned to receive a single intranasal dose of 20 mg bremelanotide or matching placebo in a double-blind manner during the first in-clinic treatment session, and the alternate medication during the second in-clinic treatment session. During each session, subjects viewed a 20-minute neutral video followed by a 20-minute sexually explicit video. Vaginal photoplethysmography was used to monitor vaginal vasocongestion and questionnaires were used to evaluate perceptions of sexual response within the following 24-hour period. 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). Among women who attempted sexual intercourse within 24 hours after treatment, significantly more were satisfied with their level of sexual arousal following bremelanotide, compared with placebo (P = 0.0256). Vaginal vasocongestion did not change significantly while viewing erotic videos following bremelanotide administration compared with placebo. This preliminary evaluation suggests the potential for bremelanotide to positively affect desire and arousal in women with female sexual arousal disorder and indicates that bremelanotide is a promising candidate for further evaluation in an at-home study.

Small Effects, Questionable Outcomes: Bremelanotide for Hypoactive Sexual Desire Disorder.

Efficacy outcomes are only informative to the extent that they are validated. We examined the measurement properties of efficacy measures from the phase III ("RECONNECT") bremelanotide trials for hypoactive sexual desire disorder (HSDD) in women. Continuous efficacy outcomes, including a) the Female Sexual Function Index (FSFI) and its Desire domain (FSFI-D) and b) the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) and its item assessing distress due to low desire (FSDS-DAO #13) have questionable, at best, validity evidence for women with HSDD. We found no validity evidence for previously published categorical treatment response outcomes from the RECONNECT trials. All efficacy results should be reported, but results on 8 of the 11 clinicaltrials.gov-specified efficacy outcomes were heretofore unpublished (including FSDS-DAO total score, FSFI total score, FSFI arousal domain, and items from the Female Sexual Encounter Profile-Revised). We analyzed these outcomes, upon which effect sizes ranged from nil to small. 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.

Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide.

Responder analyses are used to determine whether changes that occur during a clinical trial are clinically meaningful; for subjective endpoints such as those based on patient-reported outcomes (PROs), responder analyses are particularly useful. To identify the minimal clinically important difference (MCID) for selected scores on questionnaires assessing female sexual functioning and to use these differences to analyze the response in a large, controlled, phase 2b, dose-finding study of bremelanotide in premenopausal women with hypoactive sexual desire disorder (HSDD) and mixed HSDD/female sexual arousal disorder (FSAD). The responder analyses were performed for the change from baseline to end of study for a total of 7 endpoints. Each PRO endpoint was assessed using at least 1 of 4 types of responder analyses: a planned analysis anchored to MCIDs based on expert estimates (historical anchors); post hoc analyses based on self-reported global benefit; receiver operating characteristic (ROC) curves; and cumulative distribution function. The prespecified analysis groups were all female sexual dysfunction (FSD)-based diagnoses (all study participants), those with HSDD alone, and a combined group of those with FSAD alone plus those with mixed HSDD/FSAD. Post hoc analyses were also performed for subjects with mixed HSDD/FSAD with a primary diagnosis of HSDD. MCIDs based on the ROC curves for changes in Female Sexual Function Index-desire domain, Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO) total score, FSDS-DAO item 13 and 14 scores, and number of satisfying sexual events. Outcomes matched those based on input from clinical experts. For all 7 endpoints, responder rates at the 1.75 mg dose in the overall modified intention-to-treat population achieved statistical significance compared with placebo (P &#x2264; .03). These responder definitions were subsequently used in the bremelanotide phase 3 registration studies (RECONNECT) that evaluated the safety and efficacy of the bremelanotide 1.75 mg subcutaneous dose in premenopausal women with HSDD. MCIDs for this study were based on changes from a single-blind phase to account for changes due to the placebo effect. These analyses were restricted to a study population composed only of premenopausal women with a clinical diagnosis of HSDD and/or FSAD and were based on data from the same clinical trial. Bremelanotide was safe and well tolerated and demonstrated significant improvement in efficacy vs placebo in the phase 2b trial. The multiple responder analyses offer a valuable approach for determining clinically important effects of bremelanotide for HSDD and FSAD. Althof S, Derogatis LR, Greenberg S, et&#xa0;al. Responder Analyses from a Phase 2b Dose-Ranging Study of Bremelanotide. J Sex Med 2019;16:1226-1235.

Melanocortin Receptor Agonist Bremelanotide Induces Cell Death and Growth Inhibition in Glioblastoma Cells via Suppression of Survivin Expression.

Glioblastoma is the most aggressive form of brain tumor and has a dismal prognosis; therefore, novel therapeutic approaches based on the mechanisms underlying its aggressive nature are urgently required. A growing body of evidence suggests that neurotransmitters play a key role in modulating the biology of glioblastoma; however, the role of melanocortins remains unclear. The effects of bremelanotide, a melanocortin receptor agonist, alone or in combination with chemotherapeutic agents, on survivin expression and cell viability were investigated in human glioblastoma cell lines. Bremelanotide reduced survivin expression and induced cell death in glioblastoma cells at concentrations that were not toxic to normal human cells, and both of these effects were canceled in the presence of an antagonist of melanocortin receptors 3 and 4. Bremelanotide-induced cell death was prevented by the forced over-expression of survivin in glioblastoma cells, suggesting that bremelanotide induces glioblastoma cell death by inhibiting the expression of survivin. Bremelanotide also promoted cell death induced by chemotherapeutic agents, such as temozolomide and osimertinib. The present results identified melanocortin receptors 3 and 4 as novel and viable therapeutic targets for glioblastoma. Activation of these receptors by bremelanotide may inhibit the expression of survivin, thereby sensitizing glioblastoma cells to cell death.

Management of Hypertension with Female Sexual Dysfunction.

Female sexual dysfunction (FSD) in hypertension has been less studied than male sexual dysfunction, and antihypertensive agents' impact on female sexual function is not defined. In this review, randomized double-blind clinical trials and cross-sectional studies related to female sexual function in hypertension were analyzed from 1991 to 2021. FSD appeared to be higher in hypertensive women than in normotensive women. Beta-blockers are the only antihypertensive agents with relatively strong evidence of damaging the female sexual function. Angiotensin receptor blockers (ARB) are relatively beneficial to female sexual function. To treat FSD in the presence of hypertension, controlling blood pressure is key, and the administration of angiotensin receptor blockers is preferred. In addition to controlling blood pressure, for premenopausal women, flibanserin and bremelanotide can be tried, while ospemifene and hormone supplements are preferred for postmenopausal women.

Structural insights into ligand recognition and activation of the melanocortin-4 receptor.

Melanocortin-4 receptor (MC4R) plays a central role in the regulation of energy homeostasis. Its high sequence similarity to other MC receptor family members, low agonist selectivity and the lack of structural information concerning MC4R-specific activation have hampered the development of MC4R-seletive therapeutics to treat obesity. Here, we report four high-resolution structures of full-length MC4R in complex with the heterotrimeric Gs protein stimulated by the endogenous peptide ligand &#x3b1;-MSH, FDA-approved drugs afamelanotide (Scenesse&#x2122;) and bremelanotide (Vyleesi&#x2122;), and a selective small-molecule ligand THIQ, respectively. Together with pharmacological studies, our results reveal the conserved binding mode of peptidic agonists, the distinctive molecular details of small-molecule agonist recognition underlying receptor subtype selectivity, and a distinct activation mechanism for MC4R, thereby offering new insights into G protein coupling. Our work may facilitate the discovery of selective therapeutic agents targeting MC4R.

2019 FDA TIDES (Peptides and Oligonucleotides) Harvest.

2019 has been an excellent year in terms of peptides and oligonucleotides (TIDES) approved by the FDA. Despite the drop in the number of total drugs approved by the FDA in 2019 in comparison with 2018 (48 vs. 59), the total number of TIDES authorized increased (seven vs. three). Year after year, TIDES are increasingly present in therapy, as imaging agents, theragnostic and constituent moieties of other complex drugs, such as antibody drug conjugates. This means a consolidation of these kinds of drugs in the pharmaceutical arena, paving the way in the coming years for the approval of others for diverse medical indications. Here the TIDES approved in 2019 are analyzed in terms of chemical structure, medical target, mode of action, and adverse effects.

Intravenous peptides and amino acids for erectile dysfunction: a narrative review of current applications and future directions.

Erectile dysfunction (ED) pathophysiology involves complex interactions between vasculogenic, hormonal, and neurological mechanisms, with endothelial dysfunction and oxidative stress playing crucial roles. There is growing interest in intravenous (IV) peptides and amino acids as potential therapeutic options for ED treatment. This narrative review examines recent developments in peptide and amino acid therapies for ED, focusing on PT-141, PnPP-19, L-arginine, and L-citrulline. The literature search utilized PubMed to identify relevant English-language publications up to October 2024, emphasizing studies from the past decade. IV peptides and amino acids offer promising therapeutic options for ED through mechanisms of action distinct from PED5 inhibitors. PT-141 and PnPP-19 show efficacy through central nervous system activation and nitric oxide regulation, while L-arginine and L-citrulline enhance endothelial function. Although evidence suggests potential benefits, large-scale clinical trials are needed to establish safety profiles, optimal dosing regimens, and possible synergistic effects with existing ED treatments.

Female Syrian hamster analyses of bremelanotide, a US FDA approved drug for the treatment of female hypoactive sexual desire disorder.

Hypoactive sexual desire disorder (HSDD) is the most reported sexual dysfunction among premenopausal women worldwide. Bremelanotide, trade name Vyleesi, has been approved by the United States Food and Drug Administration to treat HSDD. However, despite approval, very little is known about its neurobiological mechanism of action. In this study, we utilized a female Syrian hamster model to investigate the effects of bremelanotide on melanocortin receptor expression in the mesolimbic dopamine system and sexual reward. We found that the majority of melanocortin 3 and 4 (MC4R) receptor mRNA is expressed in dopamine neurons in the ventral tegmental area (VTA). Fewer neurons express MC4R in the nucleus accumbens (NAc) or dorsal striatum, where they rarely colocalize with neurons expressing dopamine D1 or D2 receptors. Instead, MC4R mRNA is expressed in nucleus accumbens interneurons. Neither the low nor the high dose of bremelanotide had an effect on the expression of melanocortin receptor mRNA in the mesolimbic dopamine system. Finally, sexual experience resulted in a conditioned place preference (CPP) in female Syrian hamsters, though bremelanotide treatment failed to enhance sexual reward in this test. The results of this study are discussed in conjunction with similar studies in rats, with the conclusion that bremelanotide does not act on the VTA-NAc reward circuit and does not enhance the rewarding effects of sexual interactions.

Bremelanotide: an overview of preclinical CNS effects on female sexual function.

Bremelanotide is an analogue of the naturally occurring peptide alpha-melanocyte-stimulating hormone (alpha-MSH). It stimulates erection in men and male rats, and is currently in clinical trials for the treatment of erectile dysfunction. To review the effects of bremelanotide, an analogue of the naturally occurring peptide alpha-MSH, on the preclinical indices of sexual desire in female rats, and where in the brain these actions may occur. Appetitive sexual behaviors, such as solicitations, hops and darts, and pacing, were assessed along with consummatory behaviors such as lordosis. The involvement of brain regions was assessed following direct administration to the region, by the stimulation of molecular markers of neural activation, and using microdialysis to examine extracellular fluid for different neurotransmitters. Using a model that allows ovariectomized, hormone-primed female rats to control the timing of sexual encounters with males, we tested the ability of bremelanotide to increase appetitive (proceptive) and/or consummatory sexual behaviors. Bremelanotide dramatically and selectively increased measures of solicitation in female rats, without altering pacing or lordosis, following both peripheral (subcutaneous) administration or infusions directly into the lateral ventricles or medial preoptic area (mPOA), but not the ventromedial hypothalamus. The mPOA is critical for the display of appetitive sexual behaviors in females and males of a variety of species. Peripheral administration of bremelanotide activates the mPOA and other hypothalamic and limbic regions of the brain involved in sexual behavior, and may work by activating dopamine terminals in the mPOA. To the extent that solicitations indicate the desire of female rats to engage in sexual activity, bremelanotide appears to possess the behavioral, pharmacological, and neuroanatomical specificity required of a drug in the treatment of hypoactive sexual desire disorders.

Polymorphism of Melanocortin Receptor Genes-Association with Inflammatory Traits and Diseases.

Melanocortin receptors (MCRs) are responsible for various functions ranging from skin pigmentation, regulation of appetite, stress response and cognition, steroid synthesis, and energy balance to cellular regeneration and immunomodulation. The genetic polymorphism with tissue distribution ranging from the brain, limbic system, and adrenal cortex to neutrophils, monocytes, and macrophages is evident in MCRs. The mutations in MC1R, MC2R, MC3R, and MC4R genes are associated with risk of melanoma, familial glucocorticoid deficiency, obesity, and type 2 diabetes mellitus, respectively. Meanwhile, MC1R, MC2R, and MC5R genes are involved in the risk of major depressive disorder. Melanocortin receptors are involved in different inflammatory disorders, i.e., atopic dermatitis, autoimmune uveitis, sarcoidosis, respiratory diseases, multiple sclerosis, scleroderma, inflammatory bowel disease, amyotrophic lateral sclerosis, Alzheimer's disease, arthritis, and reperfusion injury. Several newer therapeutic agents related to MCRs have numerous advantages over the current anti-inflammatory drugs, demonstrating therapeutic relevance. Among them, &#x3b1;-MSH analogs play a role in atopic dermatitis and scleroderma, and MC1R agonist Dersimelagon has shown effectiveness in systemic sclerosis. The FDA has recently approved the repository corticotropin injection (RCI) to treat sarcoidosis. The FDA has also approved various melanocortin agonists, i.e., Bremelanotide, Afamelanotide, and Setmelanotide, for the treatment of hypoactive sexual desire disorder, Erythropoietic protoporphyria, and obesity, due to pro-opiomelanocortin and leptin receptor deficiency, respectively. Therefore, this review aims to summarize the function and genetic polymorphism of melanocortin receptors, regulatory pathways involving MCRs, and the existing evidence of the prime effect of MCRs on inflammatory responses via different mechanisms and their potential therapeutic use in inflammatory diseases.

A biodegradable suction patch for sustainable transbuccal peptide delivery.

Despite considerable advances in the systemic delivery of peptides, their susceptibility to gastrointestinal degradation and high molecular weight, which restricts permeability across biological barriers, remain obstacles to oral administration. As a result, most peptide therapies rely on injections to achieve therapeutic effects. Recent studies on a bioinspired suction patch demonstrated positive effects in vivo with three peptides - desmopressin, semaglutide, and teriparatide - yet materials used for patch fabrication were non-degradable. In this work, a more sustainable patch alternative is introduced by replacing previously used materials with biodegradable polymers, aiming for degradation of the patch after removal to reduce environmental impact. A scalable mold casting process was employed to thermally crosslink synthesized and functionalized copolyesters, yielding the desired devices. Mechanical testing across various materials and shapes identified the best-performing polymer, while its degradation was confirmed in both aqueous medium and simulated waste. An ex vivo model using porcine buccal tissue validated the functionality of biodegradable patches, showing enhanced permeation of a poorly permeable dye when combined with a chemical permeation enhancer. In beagle dogs, the bioavailability of semaglutide (4.11&#xa0;kDa) was substantially improved compared to the commercially available tablet, with an application time of only 10&#xa0;min. Additionally, the patch achieved a relative bioavailability of 26% for bremelanotide (1.03&#xa0;kDa) compared to subcutaneous administration. This work underscores the potential of replacing silicone devices with biodegradable alternatives, providing a more sustainable approach for peptide delivery via the buccal suction patch.

Ultra-sensitive quantification of the therapeutic cyclic peptide bremelanotide utilizing UHPLC-MS/MS for evaluation of its oral plasma pharmacokinetics.

Bremelanotide (Vyleesi&#xae;), a cyclic heptapeptide, was recently approved for the subcutaneous treatment of premenopausal hypoactive sexual desire disorder. To foster the development of alternative routes of administration, we aimed at determining the oral plasma pharmacokinetics of bremelanotide in beagle dogs. Therefore, we established a UHPLC-MS/MS assay with an LLOQ of 10&#x2009;pg/mL (9.8&#x2009;pM) using 100&#x2009;&#x3bc;L of plasma and validated it according to the guidelines of the US Food and Drug Administration and the European Medicines Agency. Bremelanotide was isolated from plasma by protein precipitation and quantification was performed with positive heated ESI MS/MS in the SRM mode. The calibrated concentration range of 10-10,000&#x2009;pg/mL was linear showing correlation coefficients > 0.99. In the calibrated range, interday and intraday accuracy ranged from 88.9-100.0 % with corresponding precision < 8 %. Accuracy at the LLOQ ranged from 93.6-100.8 % with corresponding precision < 11 %. 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.

Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin.

The discovery of melanocortins in 1916 has resulted in more than 100 years of research focused on these peptides. Extensive studies have elucidated well-established functions of melanocortins mediated by cell surface receptors, including MSHR (melanocyte-stimulating hormone receptor) and ACTHR (adrenocorticotropin receptor). Subsequently, three additional melanocortin receptors (MCRs) were identified. Among these five MCRs, MC3R and MC4R are expressed primarily in the central nervous system, and are therefore referred to as the neural MCRs. Since the central melanocortin system plays important roles in regulating energy homeostasis, targeting neural MCRs is emerging as a therapeutic approach for treating metabolic conditions such as obesity and cachexia. Early efforts modifying endogenous ligands resulted in the development of many potent and selective ligands. This review focuses on the ligands for neural MCRs, including classical ligands (MSH and agouti-related peptide), nonclassical ligands (lipocalin 2, &#x3b2;-defensin, small molecules, and pharmacoperones), and clinically approved ligands (ACTH, setmelanotide, bremelanotide, and several repurposed drugs).

Pharmacotherapy of Hypoactive Sexual Desire Disorder in Premenopausal Women.

This review aims to provide an overview of pharmacologic management for hypoactive sexual desire disorder (HSDD) in premenopausal women, with a focus on available agents. Through a literature search on PubMed, Google Scholar, and ClinicalTrials.gov from 1999 to 2024, studies were selected using the following MeSH search terms: hypoactive sexual desire disorder, premenopause, pharmacologic management, flibanserin, bremelanotide, buspirone, bupropion, and testosterone, excluding those involving postmenopausal women or other sexual disorders. Product monographs were also reviewed. Relevant English-language studies or those conducted in humans were considered. Hypoactive sexual desire disorder, characterized by a lack of motivation for sexual activity, predominantly affects women aged 45 years and older. Treatment involves a multimodal approach, including nonpharmacologic interventions such as psychotherapy and lifestyle adjustments, alongside pharmacologic options. Although bupropion and buspirone may be considered off-label treatments, flibanserin and bremelanotide are the sole medications approved by the Food and Drug Administration for generalized acquired HSDD in premenopausal women. However, caution is advised due to their limited efficacy, potential adverse effects, and transparency issues in reporting. Hypoactive sexual desire disorder, while not life-threatening, significantly impacts well-being and relationships. Pharmacotherapy, including options like flibanserin and bremelanotide, is essential within a multidisciplinary approach. Validated tools and objective measures inform tailored premenopausal HSDD care plans and aid in striking a balance between potential risks and adverse effects while maximizing meaningful clinical benefits, including for transgender individuals. 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. Pharmacists are encouraged to embrace this opportunity to provide premenopausal HSDD care in ambulatory and community practice settings.

Therapeutic peptides in gerontology: mechanisms and applications for healthy aging.

Peptide therapeutics represent an emerging frontier in gerontological medicine, targeting fundamental hallmarks of aging including metabolic dysfunction, telomere attrition, tissue repair impairment, and hormonal decline. To comprehensively review the mechanisms, clinical applications, evidence base, and safety profiles of therapeutic peptides with demonstrated or potential applications in healthy aging and age-related conditions. A comprehensive narrative review was conducted through systematic searches of PubMed, Scopus, and regulatory databases (FDA, WADA) from inception through January 2026. Search terms included "peptide therapeutics," "aging," "gerontology," "healthspan," combined with specific peptide names (tirzepatide, epitalon, GHK-Cu, BPC-157, TB-500, Semax, CJC-1295, ipamorelin, bremelanotide). Peer-reviewed articles, clinical trials, regulatory documents, and preclinical studies were evaluated. A total of 20 primary sources were selected based on relevance, methodological quality, and contribution to understanding peptide mechanisms and clinical outcomes in aging populations. Nine peptides were identified spanning diverse aging interventions: metabolic restoration (tirzepatide), telomere biology (epitalon), dermal regeneration (GHK-Cu), tissue repair (BPC-157, TB-500), neuroprotection (Semax), growth hormone modulation (CJC-1295, ipamorelin), and sexual function (bremelanotide). FDA-approved agents demonstrated robust safety profiles from large-scale trials. Non-approved peptides showed promising preclinical and limited clinical evidence but lack long-term safety data and systematic validation. Significant knowledge gaps include optimal dosing regimens, combination therapy effects, and biomarkers for monitoring efficacy. Therapeutic peptides offer mechanistically diverse approaches to multiple aging hallmarks. While FDA-approved agents demonstrate clinical potential, investigational peptides require rigorous validation through well-designed clinical trials to establish safety and efficacy for healthspan extension.