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

ABSTRACT: OBJECTIVE:To evaluate the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder. METHODS: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. RESULTS: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. CONCLUSIONS: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. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302). FUNDING SOURCE:Palatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

SUBMITTER: Kingsberg SA

PROVIDER: S-EPMC6819021 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Kingsberg Sheryl A SA Clayton Anita H AH Portman David D Williams Laura A LA Krop Julie J Jordan Robert R Lucas Johna J Simon James A JA

Obstetrics and gynecology 20191101 5

<h4>Objective</h4>To evaluate the safety and efficacy of bremelanotide for the treatment of premenopausal women with hypoactive sexual desire disorder.<h4>Methods</h4>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 breme ...[more]

PMID: 31599840

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Project description:ObjectiveTo evaluate the long-term safety and efficacy of bremelanotide as treatment for hypoactive sexual desire disorder in premenopausal women.MethodsWomen who completed the 24-week double-blind core phase of RECONNECT, composed of two parallel phase 3 trials (301 and 302) examining the safety and efficacy of bremelanotide compared with placebo in premenopausal women with hypoactive sexual desire disorder, could enroll in the 52-week open-label extension, provided they had not experienced serious adverse events during the core phase. Efficacy was assessed using the coprimary endpoints from the core phase, and all adverse events were collected during the open-label extension. All statistical analyses were descriptive.ResultsThe study 301 open-label extension began on July 17, 2015, and concluded on July 13, 2017; the study 302 open-label extension began on October 5, 2015, and concluded on June 29, 2017. Of the 856 eligible patients who completed the core phase, 684 elected to participate in the open-label extension, and 272 completed it. The most common treatment-emergent adverse events considered related to study drug were nausea (40.4%), flushing (20.6%), and headache (12.0%), and the only severe treatment-emergent adverse event experienced by more than one participant in both studies was nausea during the open-label extension. The change in Female Sexual Function Index-desire domain score and Female Sexual Distress Scale-Desire/Arousal/Orgasm item 13 from baseline to end of the open-label extension ranged from 1.25 to 1.30 and -1.4 to -1.7, respectively, for patients who received bremelanotide during the core phase, and 0.70-0.77 and -0.9, respectively, for patients who received placebo during the core phase.ConclusionDuring the 52-week open-label extension of RECONNECT, no new safety signals were observed, and premenopausal women treated with bremelanotide exhibited sustained improvements in hypoactive sexual desire disorder symptoms.Clinical trial registrationClinicalTrials.gov, NCT02333071 (study 301) and NCT02338960 (study 302).Funding sourcePalatin Technologies, Inc., and AMAG Pharmaceuticals, Inc.

Project description:IntroductionCounts of satisfying sexual events (SSEs) per month have been criticized as an end point in treatment trials of women with hypoactive sexual desire disorder (HSDD) but grounding improvement in sexual desire by assessing changes in sexual behavior remains of some importance.MethodsWe conducted a literature review to find validated measurements that are specific sexual behavioral correlates of low sexual desire. We compared expert-proposed criteria for dysfunctional desire, expert-developed sets of scale items, and self-rated scales developed before issuance of, or in accordance with, the Food and Drug Administration's guidance on developing patient-reported outcomes. Behavioral measurements of HSDD were isolated from these sets of criteria or scales.Main outcome measuresWe outline a plan to evaluate such behavioral measurements of HSDD with reference to SSEs.ResultsEleven rating scales, four expert-originated and seven self-rated scales mainly derived from patient input were identified as well validated and relevant to HSDD. Three recent sets of diagnostic criteria for conditions such as HSDD were compared with the scales. Twenty-four different symptoms were found in the scales. Content found relevant to HSDD during development of the rating scales varied highly among measurements, including the self-rated scales developed in conformity with current recommendations for patient-reported outcome measurements. The only item on all sets was desire for sexual activity. Four other items were in approximately at least half the sets: sexual thoughts or fantasies, frequency of sexual activity, receptivity, and initiations. Sexual thoughts or fantasies were in every expert-derived set but in only three of the seven patient-derived sets. Receptivity was in five of the seven expert-derived sets vs two of the seven patient-derived sets. Frequency of sexual activity was in one of the seven expert-derived sets but in five of the patient-derived sets. Initiation was in approximately half the two sets. All other items were on one to three sets each. We identified three sexual behaviors of validated specificity for female HSDD: frequency of sexual activity, receptivity, and initiations. Six or seven items are relevant and informative. The item on frequency of sexual activity in the Changes in Sexual Functioning-Female scale is the only item that covers frequency of dyadic and solitary sexual activity. An item in the Female Sexual Desire Questionnaire (FSDQ) covers the intuitively relevant topic of frequency of sexual activity motivated by the woman's desire. Three FSDQ items on initiations and two items on receptivity reflect expert opinion on the sexual behaviors of most relevance to HSDD, but the FSDQ has not been validated in women with HSDD.ConclusionsSSEs have been discredited as the primary measurement in clinical trials of women with HSDD, but it would be meaningful to include at least one sexual behavioral symptom specific to HSDD as an end point. Expert-recommended sexual behaviors specifically related to HSDD are irregularly represented in self-rating scales whether developed as in the Food and Drug Administration guidance on patient-reported outcomes or not. Six or seven items on sexual behavior in self-rated scales can be recommended for relevance to women with HSDD in clinical trials. Items on female sexual behavior should be tested in comparison with SSEs in women with HSDD for relevance and for treatment sensitivity, and responder and functional and dysfunctional cutoffs should be determined before incorporation into large-scale clinical trials. Pyke R and Clayton A. What Sexual Behaviors Relate to Decreased Sexual Desire in Women? A Review and Proposal for End Points in Treatment Trials for Hypoactive Sexual Desire Disorder. Sex Med 2017;5:e73-e83.

Project description:ImportanceDespite being the most common female sexual health complaint worldwide, current treatment options for hypoactive sexual desire disorder (HSDD) are limited in their safety and effectiveness. The hormone kisspeptin is a key endogenous activator of the reproductive hormonal axis with additional emerging roles in sexual and emotional behavior; however, its effects in women with HSDD are unknown.ObjectiveTo test the hypothesis that kisspeptin enhances sexual and attraction brain processing in women with HSDD.Design, setting, and participantsThis randomized clinical trial was double-masked and placebo controlled with a 2-way crossover. The trial was conducted in a university research setting in the UK from October 2020 to April 2021. Eligible participants were premenopausal women with HSDD. Functional neuroimaging, psychometric, and hormonal analyses were employed to investigate the effects of kisspeptin administration on brain processing, in response to erotic stimuli (erotic videos) and facial attraction (face images of varying attractiveness). Data were analyzed from May to December 2021.InterventionsA 75-minute intravenous infusion of kisspeptin-54 (1 nmol/kg/h) vs equivalent-rate placebo infusion.Main outcomes and measuresBlood oxygen level-dependent responses across the whole brain and regions of interest during kisspeptin vs placebo administration in response to erotic and facial attraction stimuli.ResultsOf the 40 participants who were randomized, 32 women completed both kisspeptin and placebo visits, with a mean (SE) age of 29.2 (1.2) years. Kisspeptin administration resulted in modulations in sexual and facial attraction brain processing (deactivation of the left inferior frontal gyrus: Z max, 3.76; P = .01; activation of the right postcentral and supramarginal gyrus: Z max, 3.73; P < .001; deactivation of the right temporoparietal junction: Z max 4.08; P = .02). Furthermore, positive correlations were observed between kisspeptin-enhanced hippocampal activity in response to erotic videos, and baseline distress relating to sexual function (r = 0.469; P = .007). Kisspeptin's enhancement of posterior cingulate cortex activity in response to attractive male faces also correlated with reduced sexual aversion, providing additional functional significance (r = 0.476, P = .005). Kisspeptin was well-tolerated with no reported adverse effects.Conclusions and relevanceThese findings lay the foundations for clinical applications for kisspeptin in women with HSDD.Trial registrationISRCTN trial registry identifier: ISRCTN17271094.

Project description:BACKGROUNDHypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress and interpersonal difficulty. It is the most prevalent female sexual health problem globally, affecting approximately 10% of women, but has limited treatment options. Melanocortin 4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, through unknown mechanisms. Studying the pathways involved is crucial for our understanding of normal and abnormal sexual behavior.METHODSUsing psychometric, functional neuroimaging, and hormonal analyses, we conducted a randomized, double-blinded, placebo-controlled, crossover clinical study to assess the effects of MC4R agonism compared with placebo on sexual brain processing in 31 premenopausal heterosexual women with HSDD.RESULTSMC4R agonism significantly increased sexual desire for up to 24 hours after administration compared with placebo. During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity and deactivated the secondary somatosensory cortex, specifically in response to visual erotic stimuli, compared with placebo. In addition, MC4R agonism enhanced functional connectivity between the amygdala and the insula during visual erotic stimuli compared with placebo.CONCLUSIONThese data suggest that MC4R agonism enhanced sexual brain processing by reducing self-consciousness, increasing sexual imagery, and sensitizing women with HSDD to erotic stimuli. These findings provide mechanistic insight into the action of MC4R agonism in sexual behavior and are relevant to the ongoing development of HSDD therapies and MC4R agonist development more widely.TRIAL REGISTRATIONClinicalTrials.gov NCT04179734.FUNDINGThis is an investigator-sponsored study funded by AMAG Pharmaceuticals Inc., the Medical Research Council (MRC) (MR/T006242/1), and the National Institute for Health Research (NIHR) (CS-2018-18-ST2-002 and RP-2014-05-001).

Project description:Abstract Introduction Hypoactive sexual desire disorder (HSDD) is characterized by a persistent deficiency of sexual fantasies and desire for sexual activity, causing marked distress or interpersonal difficulty. It is the most prevalent female sexual health problem worldwide, affecting approximately 1 in 10 women, but has limited treatment options despite its substantial health, social, and economic burden. Melanocortin-4 receptor (MC4R) agonists have emerged as a promising therapy for women with HSDD, although, to date, their mechanism of action is unknown. This study aims to use functional MRI to delineate the reproductive neuroendocrine pathways involved and elucidate how MC4R agonists treat HSDD in women. Methods We conducted a randomized, double-blinded, placebo-controlled, crossover clinical study, using psychometric, functional neuroimaging and hormonal analyses, to assess the effects of MC4R agonism on sexual brain processing in 31 premenopausal women with HSDD. Participants attended on two occasions, receiving either a subcutaneous injection of an MC4R agonist (Bremelanotide 1.75 mg), or placebo, at each study visit, thereby acting as their own controls. Results 31 randomized women were included (mean age 32 years, mean duration of HSDD 41 months). MC4R agonism significantly increased self-reported sexual desire for up to 24-hours post administration, compared to placebo (P=0.007). During functional neuroimaging, MC4R agonism enhanced cerebellar and supplementary motor area activity, as well as deactivating the secondary somatosensory cortex, specifically in response to visual erotic videos, compared to placebo (Z=2.3, P<0.05). In addition, MC4R agonism enhanced functional connectivity between the amygdala-insula and amygdala-thalamus during prolonged visual erotic stimuli, compared to placebo (P=0.025). MC4R agonism resulted in a mean increase in LH of 1.1 iU/L (F [1,58] = 13.38, P=0.0005), and FSH of 0.35 iU/L (F [1,60] = 10.97, P=0.0016) across the 300-minute duration of the study, with no effect observed on circulating estradiol or progesterone levels. Interpretation of results and conclusions:We demonstrate that MC4R agonism deactivates the secondary somatosensory cortex which can reduce the detrimental self-monitoring process often observed in HSDD, thereby increasing sexual desire. Furthermore, cerebellar and supplementary motor area activation by MC4R agonism are associated with increased sexual arousal and sexual motor imagery respectively. Finally, MC4R agonism enhanced functional connectivity between key limbic structures which can be disrupted in HSDD. In summary, these data identify the previously undescribed neural substrates and connections through which MC4R agonism modulates sexual brain processing to increase sexual desire. These findings provide mechanistic insight for the action of MC4R agonism in sexual behaviour and are relevant to ongoing therapeutic development for HSDD and for MC4R agonist development more widely. Trial registration: ClinicalTrials.gov identifier NCT04179734.Funding: Investigator-sponsored study funded by AMAG Pharmaceuticals Inc, MRC and NIHR. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

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

Publications

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

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