madman
Super Moderator
An evaluation of bremelanotide injection for the treatment of hypoactive sexual desire disorder (2022)
Sarah Cipriani, Chiara Alfaroli, Elisa Maseroli & Linda Vignozzi
ABSTRACT
Introduction: 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.
Areas covered: 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 pharmacotherapy with bremelanotide was performed using the PubMed database.
Expert opinion: 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.
1. Introduction
Sexual health is a crucial aspect of quality of life and sexual symptoms are common in women of all ages. Despite the fact that the interest of the medical community in this field of research has spread over the last few decades, at present there is a lack of universally shared protocols for the work-up of female sexual dysfunction (FSD) [1]. These shortcomings are particularly evident when compared to the male counterpart, for which a fair variety of approved etiological treatments is available on the market for at least two of the most common male sexual dysfunctions (SDs), namely erectile dysfunction and premature ejaculation [2]. Such a well-known ‘gender gap’ reflects a major bias in healthcare systems, related to women being underrepresented in clinical trials since they have different susceptibilities and exposures to risk factors (e.g. during pregnancy or after a diagnosis of hormone-dependent cancer), and often face embarrassment, poor awareness and inadequate training in health-care providers when referring for sexual counseling [2].
In this context, female sexual desire stands out as a particularly complex topic, since it represents a domain of a sexual function in which intrapersonal, interpersonal, and social components are deeply intertwined, thus posing a special challenge to our understanding of its biological mechanisms, and consequently to drug discovery in this field. Noteworthy, this last point seems to raise some sensitive issues relating to the emotional and social aspects of sexual desire; namely, a drug treatment for it could be considered inadequate for many reasons, such as unrealistic expectations due to scarce sexual education, pressure from the partner for a more frequent sexual activity and, not least, a history of sexual abuse, that can profoundly influence sexuality, sense of self and interpersonal relationships.
1.1. Hypoactive sexual desire disorder
Hypoactive sexual desire disorder (HSDD) can be considered one of the most common manifestations of FSD, affecting up to 10% of women [3,4]. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV [5] and IV-TR [6], it is substantially determined by the lack of sexual fantasies and desire for sexual activity, associated with distress. Successively, in DSM V [7], it has been collapsed with female sexual arousal disorder (FSAD), generating a new clinical condition labeled as female sexual interest–arousal disorder (FSIAD), although remaining mainly based on sexual desire [3,4]. Such a reclassification has been the topic of considerable scientific debates; however, HSDD is still maintained as an independent diagnostic category in the ICD-11 (International Classification of Diseases, 11th Revision) system [8], as well as in the ISSWSH Nomenclature revision proposal [9]. More in detail, according to the ISSWSH Process of Care (POC), HSDD is defined as a lack/loss of interest in engaging in sexual activity due to both decreased/absent desire linked to sexual stimulation, or maintenance of desire throughout sexual activity, for a minimum of 6 months, that is not dependent on any other medical or psychiatric condition, causing significant personal distress [10].
Although different underpinning factors have been recognized for HSDD, the exact underlying pathophysiological mechanism is not completely understood [3]. As a matter of fact, hormonal, psychological, and relational factors, as well as life situation, culture, ethnicity, menopausal status, and central nervous system (CNS) activity, are deeply intertwined in determining HSDD [11].
Although different underpinning factors have been recognized for HSDD, the exact underlying pathophysiological mechanism is not completely understood [3]. As a matter of fact, hormonal, psychological, and relational factors, as well as life situation, culture, ethnicity, menopausal status, and central nervous system (CNS) activity, are deeply intertwined in determining HSDD [11]. On this background, the 2018 ISSWSH POC for the management of HSDD suggests a ‘biopsychosocial’ approach to patients, including physical examination, laboratory testing as well as elicitation of medical, psychological, sexual, and social history, in order to identify potentially reversible factors of the disorder [10]. For example, sex steroids – in particular, estrogens and androgens – act as key biological determinants of sexual interest in women [12,13]; therefore, conditions leading to alterations of their levels (i.e. amenorrhea, natural and surgical menopause, breastfeeding, use of hormonal contraceptives) should be carefully evaluated in order to exclude secondary forms of HSDD. Consequently, therapeutic strategies entail first effective education, and second, modification of contributing factors thought to be playing a role in HSDD. Sex therapy (i.e. cognitive behavior therapy), hormonal therapy, or CNS agents can be considered only after this careful assessment, and should always be implemented in a patient- and couple-oriented, multidimensional approach [14].
From a neurobiological perspective, the imbalance between excitatory (dopamine, norepinephrine, melanocortins) and inhibitory (serotonin, endocannabinoids) neurotransmission has also been suggested to play a central role in HSDD etiology [15]. The range of therapies based on the modulation of these central pathways has improved in recent years and includes two agents approved by the U.S. Food and Drug Administration (FDA) for the treatment of HSDD in premenopausal women, respectively in 2015 and 2019: flibanserin (Addyi), a multifunctional serotonin agonist/antagonist, and bremelanotide (Vyleesi), a melanocortin receptor agonist in the central nervous system.
Hereby we summarize bremelanotide’s proposed mechanism of action, pharmacokinetics, efficacy, and safety data derived from clinical trials. An intensive literature search of peer-reviewed publications to review the current evidence on pharmacotherapy with bremelanotide was performed using the PubMed database. Articles in English mainly published in the last 10 years have been selected, after the screening of the titles of search results and reviewing abstracts for the removal of unremarkable literature and duplicates.
2. Bremelanotide overview
2.1. Pharmacodynamics
2.2. Pharmacokinetics and metabolism
2.2. Pharmacokinetics and metabolism
2.4. Safety and tolerability
2.5. Company agreements and regulatory affairs
3. Conclusion
It is universally recognized that SD can adversely affect the quality of life and the FDA declared that ‘there is a medical need for the development of drugs with a favorable benefit-risk profile to treat women with sexual dysfunction’ [40]. Particularly, the prevalence of HSDD among women is considerable, as well as the percentage of distress related to it [1]. Within this framework, the availability of bremelanotide, especially in countries outside the U.S. where no drugs indicated for HSDD are on the market, could be of clinical relevance to offer many women access to treatment to improve sexual function. Although its clinical efficacy seems to be modest, its dosages and side effects, including interactions with alcohol and other drugs, have been tested in specific female populations, differently from other drugs currently used ‘off-label’ for the treatment of HSDD. Specifically designed trials are needed to boost bremelanotide’s tolerability (particularly regarding nausea) and to better assess its efficacy, using adequate outcome measures and minimizing biases (see the section below).
4. Expert opinion
Clinical evidence shows that, in premenopausal HSDD women, bremelanotide improves sexual desire with a good safety profile and moderate tolerability (the most common adverse reaction being nausea, up to 40%). The main contraindications are uncontrolled hypertension or known cardiovascular disease, which are not common in young women, and contraception should be advised in case of child-bearing potential. On a positive note, bremelanotide has no key cytochromes or alcohol interactions.
Regarding efficacy, it must be noted that, although data from clinical trials apparently indicate that bremelanotide significantly improved FSFI and FSDS scores, the real clinical benefit appears to be modest. As discussed above, there are some key methodical aspects to consider in the evaluation of the efficacy of the drug. Firstly, the notable rate of symptomatic adverse events, especially of nausea, could lead to an expectation bias, whose extent has not been reported to date, although the study populations of the Phase III trials completed a questionnaire measure of unblinding. Secondly, the aforementioned shift in primary outcomes mainly relies on 4-week recall outcome measures, a period during which women have ineffective drug exposure, due to its pharmacokinetics. Moreover, such questionnaires have been criticized for the unclarity of the instructions and the simplistic idea of ‘more is better’ related to the female sexual desire they convey. Such weaknesses in the field could be solved with the employ of measures of unblinding and more reliable and objectiveable outcome measures in clinical trials, this last point representing a long-lasting challenge of the investigation of female sexuality, however. As a matter of fact, these results should be interpreted in the light of the dramatic challenges in conducting well-designed clinical trials for FSD, due to the significant placebo effect of pharmacotherapy, and the inability to minimize the myriad of potential biases involved in the female sexual response [41].
Concerning the tolerability of bremelanotide, nausea represents a considerable distressing factor, which can lead to drug discontinuation. Specifically designed and larger studies are needed to improve the tolerability of the drug (e.g. with a different route of administration?)
Another relevant aspect to consider is the high costs of bremelanotide, which could preclude access to therapy. It's AWP (average wholesale price) is currently (the year 2022) around $1000 per box, containing 4 disposable prefilled single-dose autoinjectors [42]. In the U.S., these costs may be covered by insurance.
Finally, a major shortcoming is the lack of indication of bremelanotide for postmenopausal women. Only a phase 2 trial, with an intranasal bremelanotide formulation, has been conducted in this population, although postmenopausal women present HSDD more often than women in the fertile age [1]. However, a lower efficacy may be expected in menopausal women due to the decrease in sex steroids, which have been reported to act as positive modulators of the melanocortin systems. Indeed, preclinical studies indicate that not only estrogens but also androgens activate MC4R signaling in the brain [15,17,20].
In conclusion, when prescribing pharmacotherapy for HSDD, physicians should always be aware that, as FSD is multifactorial, so should its treatment. In the context of a biopsychosocial approach to sexual medicine, education of both patients and health care providers is crucial in order to acquire new skills and overcome barriers to an effective workup of sexual difficulties in women and couples. Without forgetting the importance of a general clinical assessment, hormonal evaluation, and psychosexual counseling, only the availability of safe and effective drugs will ultimately allow clinicians to provide a tailored treatment to women with HSDD. In this view, the use and study of bremelanotide can make an important contribution to the knowledge and the preservation of women’s sexual health; nevertheless, future studies are needed to better assess its mechanism of action and improve its efficacy and tolerability for broader use.
Sarah Cipriani, Chiara Alfaroli, Elisa Maseroli & Linda Vignozzi
ABSTRACT
Introduction: 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.
Areas covered: 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 pharmacotherapy with bremelanotide was performed using the PubMed database.
Expert opinion: 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.
1. Introduction
Sexual health is a crucial aspect of quality of life and sexual symptoms are common in women of all ages. Despite the fact that the interest of the medical community in this field of research has spread over the last few decades, at present there is a lack of universally shared protocols for the work-up of female sexual dysfunction (FSD) [1]. These shortcomings are particularly evident when compared to the male counterpart, for which a fair variety of approved etiological treatments is available on the market for at least two of the most common male sexual dysfunctions (SDs), namely erectile dysfunction and premature ejaculation [2]. Such a well-known ‘gender gap’ reflects a major bias in healthcare systems, related to women being underrepresented in clinical trials since they have different susceptibilities and exposures to risk factors (e.g. during pregnancy or after a diagnosis of hormone-dependent cancer), and often face embarrassment, poor awareness and inadequate training in health-care providers when referring for sexual counseling [2].
In this context, female sexual desire stands out as a particularly complex topic, since it represents a domain of a sexual function in which intrapersonal, interpersonal, and social components are deeply intertwined, thus posing a special challenge to our understanding of its biological mechanisms, and consequently to drug discovery in this field. Noteworthy, this last point seems to raise some sensitive issues relating to the emotional and social aspects of sexual desire; namely, a drug treatment for it could be considered inadequate for many reasons, such as unrealistic expectations due to scarce sexual education, pressure from the partner for a more frequent sexual activity and, not least, a history of sexual abuse, that can profoundly influence sexuality, sense of self and interpersonal relationships.
1.1. Hypoactive sexual desire disorder
Hypoactive sexual desire disorder (HSDD) can be considered one of the most common manifestations of FSD, affecting up to 10% of women [3,4]. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM) IV [5] and IV-TR [6], it is substantially determined by the lack of sexual fantasies and desire for sexual activity, associated with distress. Successively, in DSM V [7], it has been collapsed with female sexual arousal disorder (FSAD), generating a new clinical condition labeled as female sexual interest–arousal disorder (FSIAD), although remaining mainly based on sexual desire [3,4]. Such a reclassification has been the topic of considerable scientific debates; however, HSDD is still maintained as an independent diagnostic category in the ICD-11 (International Classification of Diseases, 11th Revision) system [8], as well as in the ISSWSH Nomenclature revision proposal [9]. More in detail, according to the ISSWSH Process of Care (POC), HSDD is defined as a lack/loss of interest in engaging in sexual activity due to both decreased/absent desire linked to sexual stimulation, or maintenance of desire throughout sexual activity, for a minimum of 6 months, that is not dependent on any other medical or psychiatric condition, causing significant personal distress [10].
Although different underpinning factors have been recognized for HSDD, the exact underlying pathophysiological mechanism is not completely understood [3]. As a matter of fact, hormonal, psychological, and relational factors, as well as life situation, culture, ethnicity, menopausal status, and central nervous system (CNS) activity, are deeply intertwined in determining HSDD [11].
Although different underpinning factors have been recognized for HSDD, the exact underlying pathophysiological mechanism is not completely understood [3]. As a matter of fact, hormonal, psychological, and relational factors, as well as life situation, culture, ethnicity, menopausal status, and central nervous system (CNS) activity, are deeply intertwined in determining HSDD [11]. On this background, the 2018 ISSWSH POC for the management of HSDD suggests a ‘biopsychosocial’ approach to patients, including physical examination, laboratory testing as well as elicitation of medical, psychological, sexual, and social history, in order to identify potentially reversible factors of the disorder [10]. For example, sex steroids – in particular, estrogens and androgens – act as key biological determinants of sexual interest in women [12,13]; therefore, conditions leading to alterations of their levels (i.e. amenorrhea, natural and surgical menopause, breastfeeding, use of hormonal contraceptives) should be carefully evaluated in order to exclude secondary forms of HSDD. Consequently, therapeutic strategies entail first effective education, and second, modification of contributing factors thought to be playing a role in HSDD. Sex therapy (i.e. cognitive behavior therapy), hormonal therapy, or CNS agents can be considered only after this careful assessment, and should always be implemented in a patient- and couple-oriented, multidimensional approach [14].
From a neurobiological perspective, the imbalance between excitatory (dopamine, norepinephrine, melanocortins) and inhibitory (serotonin, endocannabinoids) neurotransmission has also been suggested to play a central role in HSDD etiology [15]. The range of therapies based on the modulation of these central pathways has improved in recent years and includes two agents approved by the U.S. Food and Drug Administration (FDA) for the treatment of HSDD in premenopausal women, respectively in 2015 and 2019: flibanserin (Addyi), a multifunctional serotonin agonist/antagonist, and bremelanotide (Vyleesi), a melanocortin receptor agonist in the central nervous system.
Hereby we summarize bremelanotide’s proposed mechanism of action, pharmacokinetics, efficacy, and safety data derived from clinical trials. An intensive literature search of peer-reviewed publications to review the current evidence on pharmacotherapy with bremelanotide was performed using the PubMed database. Articles in English mainly published in the last 10 years have been selected, after the screening of the titles of search results and reviewing abstracts for the removal of unremarkable literature and duplicates.
2. Bremelanotide overview
2.1. Pharmacodynamics
2.2. Pharmacokinetics and metabolism
2.2. Pharmacokinetics and metabolism
2.4. Safety and tolerability
2.5. Company agreements and regulatory affairs
3. Conclusion
It is universally recognized that SD can adversely affect the quality of life and the FDA declared that ‘there is a medical need for the development of drugs with a favorable benefit-risk profile to treat women with sexual dysfunction’ [40]. Particularly, the prevalence of HSDD among women is considerable, as well as the percentage of distress related to it [1]. Within this framework, the availability of bremelanotide, especially in countries outside the U.S. where no drugs indicated for HSDD are on the market, could be of clinical relevance to offer many women access to treatment to improve sexual function. Although its clinical efficacy seems to be modest, its dosages and side effects, including interactions with alcohol and other drugs, have been tested in specific female populations, differently from other drugs currently used ‘off-label’ for the treatment of HSDD. Specifically designed trials are needed to boost bremelanotide’s tolerability (particularly regarding nausea) and to better assess its efficacy, using adequate outcome measures and minimizing biases (see the section below).
4. Expert opinion
Clinical evidence shows that, in premenopausal HSDD women, bremelanotide improves sexual desire with a good safety profile and moderate tolerability (the most common adverse reaction being nausea, up to 40%). The main contraindications are uncontrolled hypertension or known cardiovascular disease, which are not common in young women, and contraception should be advised in case of child-bearing potential. On a positive note, bremelanotide has no key cytochromes or alcohol interactions.
Regarding efficacy, it must be noted that, although data from clinical trials apparently indicate that bremelanotide significantly improved FSFI and FSDS scores, the real clinical benefit appears to be modest. As discussed above, there are some key methodical aspects to consider in the evaluation of the efficacy of the drug. Firstly, the notable rate of symptomatic adverse events, especially of nausea, could lead to an expectation bias, whose extent has not been reported to date, although the study populations of the Phase III trials completed a questionnaire measure of unblinding. Secondly, the aforementioned shift in primary outcomes mainly relies on 4-week recall outcome measures, a period during which women have ineffective drug exposure, due to its pharmacokinetics. Moreover, such questionnaires have been criticized for the unclarity of the instructions and the simplistic idea of ‘more is better’ related to the female sexual desire they convey. Such weaknesses in the field could be solved with the employ of measures of unblinding and more reliable and objectiveable outcome measures in clinical trials, this last point representing a long-lasting challenge of the investigation of female sexuality, however. As a matter of fact, these results should be interpreted in the light of the dramatic challenges in conducting well-designed clinical trials for FSD, due to the significant placebo effect of pharmacotherapy, and the inability to minimize the myriad of potential biases involved in the female sexual response [41].
Concerning the tolerability of bremelanotide, nausea represents a considerable distressing factor, which can lead to drug discontinuation. Specifically designed and larger studies are needed to improve the tolerability of the drug (e.g. with a different route of administration?)
Another relevant aspect to consider is the high costs of bremelanotide, which could preclude access to therapy. It's AWP (average wholesale price) is currently (the year 2022) around $1000 per box, containing 4 disposable prefilled single-dose autoinjectors [42]. In the U.S., these costs may be covered by insurance.
Finally, a major shortcoming is the lack of indication of bremelanotide for postmenopausal women. Only a phase 2 trial, with an intranasal bremelanotide formulation, has been conducted in this population, although postmenopausal women present HSDD more often than women in the fertile age [1]. However, a lower efficacy may be expected in menopausal women due to the decrease in sex steroids, which have been reported to act as positive modulators of the melanocortin systems. Indeed, preclinical studies indicate that not only estrogens but also androgens activate MC4R signaling in the brain [15,17,20].
In conclusion, when prescribing pharmacotherapy for HSDD, physicians should always be aware that, as FSD is multifactorial, so should its treatment. In the context of a biopsychosocial approach to sexual medicine, education of both patients and health care providers is crucial in order to acquire new skills and overcome barriers to an effective workup of sexual difficulties in women and couples. Without forgetting the importance of a general clinical assessment, hormonal evaluation, and psychosexual counseling, only the availability of safe and effective drugs will ultimately allow clinicians to provide a tailored treatment to women with HSDD. In this view, the use and study of bremelanotide can make an important contribution to the knowledge and the preservation of women’s sexual health; nevertheless, future studies are needed to better assess its mechanism of action and improve its efficacy and tolerability for broader use.
