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Home , Bremelanotide, Dihydrotestosterone, Dopamine (medication), Prasterone, Testosterone (patch), Testosterone enanthate

9/23/2015

Disclosures

The Biopsychosocial Perspective: • No financial disclosures to share Pharmacologic Treatment Possibilities

Roya L. Rezaee MD, FACOG Assistant Professor, Department of Reproductive Biology Co-Director, Program for Sexual Health and Vulvovaginal Disorders

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The Neurobiology of Female Sexual Function NeuralA. PET Basis scan – healthy of female HSDD B. PET scan – HSDD female Female sexual function appears to be modulated by specific , structures, and neurohormones

• • Basal ganglia • • Serotonin • Amygdala • Images supplied courtesy of Gert Holstege • Insular cortex • MD PhD • Epinephrine • Neuroimaging studies comparing premenopausal women • Norepinephrine • Caudate nucleus • Endogenous opioids with and without HSDD reveals differences in brain activity a,b,c,d • Hypothalamus • patterns when shown erotic stimuli. • For women with HSDD their prefrontal cortex is unable to • Spinal cord deactivate, frustrating their ability to feel . •Pituitary • The prefrontal cortex is responsible for executive functions • Hippocampus such as coordination of tasks, problem solving and information analysis. Taylor M, et al. J Affect Disord. • 2005;88:241-254. aDifferences in Brain Activity in Premenopausal Women with Hypoactive Sexual Desire Disorder Compared to Women without Basson R. N Engl J Med. bBrain activation patterns in women with acquired hypoactive sexual desire disorder and women with normal sexual 2006;354:1497-1506. function: a cross‐sectional pilot study. Fertility and Sterility 2013. cWomen with hypoactive sexual desire disorder compared to normal females: a functional magnetic resonance imaging study. Neuroscience 2009. dNeural bases of hypoactive sexual desire disorder in women: an event‐related fmri study. Journal of Sexual 2011.

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Role of Role of Steroid Hormones

• • Testosterone and DHT are most potent and • maintains vaginal lubrication, blood flow to , urethra and almost entirely bound by albumin and SHBG • Produced in granulosa cells of the in – Remaing 1-2% of total is freely circulating and premenopausal women available to estrogen and testosterone sensitive • , present have lower numbers and less tissues (including brain and ) affinity for receptors • SHBG synthesized in the • Postmenopause • estrogen deficient state – Estrogen increases, testosterone decreases synthesis • Produced by precursors dehydroepiandosterone (DHEA), dehydroepiandosterone sulphate(DHEAS) • Affected by via first pass and androstenedion (A4) in the adrenal glands and ovary

Role of Steroid Hormones Sex -Binding Globulin • Prohormones: DHEAS, DHEA, A4 converted . SHBG is the carrier protein for estrogen and into testosterone (T) and testosterone (DHT) – SHBG-bound fraction is unavailable for • Ovary via the theca cells produces 25% of T, biological activity 50% of A, and 20% of DHEA . Production regulated by estrogen- • produces 25% of T, 50% of A, testosterone balance 50% of DHEA and 100% of DHEAS – Remaining 30% of DHEA is peripheral conversion of – Estrogen stimulates SHBG production by DHEAS the liver • Testosterone is also produced in the central – Testosterone decreases SHBG synthesis nervous system starting from

– Implications for treatment Selby C. Ann Clin Biochem. 1990;27:532-541.

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CNS Effects of Hormones on Female Role of Neurotransmitters/Signaling Molecules Sexual Function • Exact central neuroendocrine mechanism remains unclear • Involved areas of the brain: brain stem, hypothalamus, forebrain (amygdala) • Excitatory factors • Estrogen, testosterone, , oxytocin, dopamine and norepinephrine • Inhibitory Factors • Serotonin, , endogenous opioids • The Balance is…”the sexual tipping point.”

Perlman MA. The sexual tipping point. J Sex Med 2009 Adapted from: Clayton AH. Psychiatr Clin North Am. 2003;26:673‐682; Ben Zion IZ et al. Mol Psychiatry. 2006;11:782‐786

Physiology of Sexual Function Central Nervous System Role of Neuroendocrine Molecules

- Testosterone 5-HT • On the cellular level it is (NO), vasoactive +/‐ + + + (VIP) and acetylcholine (ACh) that interact for sexual arousal + Estrogen + + • Based upon penile and animal studies Desire Dopamine (DA) - • Sexual stimulation releases NO from vascular + epithelium 5-HT - • Stimulates guanylate cyclase to guanosine Prolactin - Subjective + Norepinephrine (NE) Excitement triphosphate into guanosine monophospate (cGMP) • Stimulates smooth muscle relaxation in the penile arteries and corpora cavernosum causing increased + blood flow Oxytocin Orgasm Berman JR et al. World J Urol 2002

Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338. *slide adapted from website herdesire.net

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Physiology of Sexual Function Peripheral Tissues: effects of neurotransmitters and hormones Role of Neuroendocrine System • Drive is triggered in the hypothalamus and activates the dopamine system Gonads • System is activated early, norepinephrine is released, Adrenals sexual excitation increases and desire to continue 5-HT sexual activity continues - • Estrogen • , increase suggesting the Maintain Genital Structure Nitric Oxide (NO) • Testosterone and Function activation of the noradrenergic system • Progestin + - 5-HT2A + • Neurobiology of the orgasm is unknown although NE includes the mesolimbic dopamine pathway, pudendal, + pelvic and hypogastric nerves Vasocongestion Sensation Clitoral and • Orgasm occurs with the release of contracting agents - Penile oxytocin and serotonin in the tissue 5-HT + + Prostaglandin E • Leads to rhythmic contractions of levator plate, Cholinergic Fibers uterus, vagina Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338. • Resolution varies

*adapted slide from website herdesire.net

Desire in the brain… Excitatory CS-UCS Integrator Inhibitory

Appetitive responses ACC CPu CB1s DA +++ VP NAcc 5-HT

Pir Ctx MSH ++ ArcN How does this translate into DA +++ , 5-HT NE CB1s , pharmacologic treatment options? mPOA VTA GnRH  OT++ NE PVN DA +++ NE , 5-HT Sexual reward Tu VMH LS CS detector UCS detector Olfactory cue MeApd Sexual reward OT

Pfaus J G, Ismail N and Coria-Avila G A (2010) Sexual Motivation. In: Koob G.F., Le Moal M. and Thompson R.F. 16 (eds.) Encyclopedia of Behavioral Neuroscience, volume 3, pp. 201–209 Oxford: Academic Press

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Drugs In Development or Approved for Low Desire :

Biological Approaches for Low Desire Drug Name Drug Pharma Current Developmental Status Category Sponsor

Flibanserin Non-hormonal Sprout Approved 8/2015 for • Increase (locally(DHEA) and CNS agent Pharmaceuticals HSDD in premenopausal women, available 10/17/15

Lybrido (on demand oral + Emotional Brain Phase II completed for HSDD systemically) ) testosterone

Lybridos (on demand oral + Emotional Brain Phase II in progress for HSDD • Increase dopamine tablet) testosterone

DHEA Vaginal Ovules Androgenic EndoCeutics, Inc. Phase III completed for VVA in postmenopausal • Increase norepinephrine () Precursor for VVA Bayer Women;future investigation for HSDD (PT-141) melanocortin Palatin Phase IIB for FSAD completed • Modulate serotonin subq (PL6983) modulator Technologies Phase III underway for HSDD/FSIAD Extended release daily oral and SP-1 Biopharma Phase III set to begin buspirone and bupropion • Melanocortins (LorexysTM) • PDE-5 Inhibitor

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Sexual Desire: Estrogen Testosterone Biological Approaches Excitatory and Inhibitory Pathways Bupropion SR Lorexys Lybrido/Lybridos + Bremelanotide • Increase androgens (locally(DHEA) and

Inhibitory Excitatory systemically) • Increase dopamine 5-HT Testoterone, Prolactin Estrogen, Opioids • Increase norepinephrine Dopamine Endocannabinoids Norepinephrine Oxytocin Melanocortins • Modulate serotonin • Melanocortins • PDE-5 Inhibitor

Adapted from Pfaus J. J Sex Med. 2009;6:1506-1533.

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Published Randomized Studies Demonstrating Efficacy of Testosterone for Low Desire Testosterone in Postmenopausal Women Doses (mcg/d) Subjects (n) Estrogen

- Testosterone Shifren et al, 2000 150/300 SM (75) + 5-HT Progesterone Braunstein, +/‐ + 150/300/450 SM (447) + + + et al 2005 Melanocortins Buster et al, 2005 300 SM (533) + Estrogen + + + Desire Dopamine (DA) Simon et al, 2005 300 SM (562) + - + Davis et al 2006 300 SM (61) + (patch) 5-HT - + ( Prolactin - Subjective + Davis et al, 2006 300 SM (76) Norepinephrine (NE) inhibitors) Excitement Shifren et al, 2006 300 NM (486) + Liu et al, 2008 300 NM (431) + + Oxytocin Orgasm Davis et al, 2008 150/300 NM/SM (814) - Panay et al, 2010 300 NM (272) +/- groups NM= naturally menopausal SM= surgically menopausal Adapted from Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338 slide adapted from herdesire.net.

Off-Label Testosterone Options Davis & Braunstein: Summary of Efficacy & Safety for Low Desire • Randomized, double-blind controlled studies have • Testosterone patches established efficacy of transdermal patch for relieving symptoms of HSDD in naturally and surgically menopausal women with and • Testosterone and patches approved for men without concomitant estrogen or estrogen/ progesterone therapy • Compounded 1% testosterone cream or for • Main side effects: increased hair growth and women • Available safety data, although not conclusive, were reassuring with respect to cardiovascular, breast, and endometrial outcomes • Oral (MT) • Interim data from a long-term phase III safety trial of testosterone • injections gel demonstrate a continued low rate of cardiovascular events and breast in postmenopausal women at increased • Subcutaneous pellets cardiovascular risk • Sublingual testosterone

Davis SR, Braunstein GD. J Sex Med 2012;9:1134‐1148.

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Dopamine for Low Desire Biological Approaches

- Testosterone • Increase androgens (locally(DHEA) and 5-HT Progesterone +/‐ + + + systemically) Melanocortins Estrogen + + + • Increase dopamine Desire Dopamine (DA) - + • Increase norepinephrine 5-HT - Prolactin - Subjective + Norepinephrine (NE) • Modulate serotonin Excitement • Melanocortins + Orgasm • PDE-5 Inhibitor Oxytocin

Adapted from Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-33

25 Slide adapted from herdesire.net.

Drugs In Development or Approved for HSDD :

Drugs Known to Increase Dopamine Drug Name Drug Pharma Current Developmental Status Category Sponsor Transdermal testosterone testosterone Warner Chilcott EMA –Approved for HSDD (surgical ) Medication Indication patch (Intrinsa®) FDA NDA withdrawn US; off the market EU (Parlodel) Hyperprolactinemia/Parkinson’s Flibanserin Non-hormonal Sprout Approved 8/2015 for disease/Restless leg syndrome CNS agent Pharmaceuticals HSDD in premenopausal women, available 10/17/15 Lybrido (on demand oral sildenafil + Emotional Brain Phase II completed for HSDD Cabergolin (Dostinex) tablet) testosterone Lybridos (on demand oral buspirone + Emotional Brain Phase II in progress for HSDD (Mirapex and Sifrol) tablet) testosterone (Norprolac) Parkinson’s disease / Restless leg DHEA Vaginal Ovules Androgenic EndoCeutics, Inc. Phase III completed for VVA in postmenopausal syndrome (Prasterone) Precursor for VVA Bayer Women;future investigation for HSDD Bremelanotide (PT-141) melanocortin Palatin Phase IIB for FSAD completed (Requip) subq injection (PL6983) Technologies Phase III underway for HSDD/FSIAD Extended release daily oral bupropion and SP-1 Biopharma Phase III set to begin (Neupro) buspirone and bupropion trazodone (LorexysTM)

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Bupropion for Low Desire Bupropion

- Testosterone • Norepinephrine and dopamine reuptake inhibitor, prescribed for 5-HT Progesterone +/‐ + and smoking cessation + + Melanocortins • Results in an increase of these neurotransmitters and down stream Estrogen + + + effects Desire Dopamine (DA) - • Prosexual side effects used to treat sexual side effects of SSRIs + 5-HT Buproprion - Prolactin - Subjective + Excitement Norepinephrine (NE)

+ Oxytocin Orgasm

Adapted from Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338

29 Slide adapted from herdesire.net.

SP-1 Biopharma Biological Approaches • IND was filed in early 2012 and a single-patient pilot study of Lorexys (aka SIP-104) completed. • Increase androgens (locally(DHEA) and • The name Lorexys is derived from orgasm and systemically) ecstasy • Increase dopamine • Lorexys combines two FDA-approved in a slow-release formulation. • Increase norepinephrine • Lorexys is a combination of Trazodone • Modulate serotonin (Desyrel®) and Bupropion (Wellbutrin®) • Three Phase III trials with 900 patients will occur • Melanocortins in 2015. • PDE-5 Inhibitor

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Norepinephrine for Low Desire Norepinephrine Increasing Agents

- Testosterone 5-HT Progesterone • for ADHD and Depression +/‐ + + + • Variety of classes Melanocortins – : Adderall, Dexedrine, Dextrostat, Estrogen + + + Vyvanse Desire Dopamine (DA) - – stimulants: Ritalin, Methylin, Concerta + 5-HT – Nonstimulants: Strattera - Prolactin - Subjective + – Antidepressants: Wellbutrin, Tofranil, Pamelor Excitement Norepinephrine (NE) • Benefits: improved focus, concentration, vigilance, presence, increase drive

+ • Side effects: sleep disturbance, , increased BP, elevated Orgasm Oxytocin heart rate, , appetite changes/, suicidal thoughts, decrease drive

Adapted from Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338

Slide adapted from herdesire.net. 34

Serotonin Biological Approaches

• Increase androgens (locally(DHEA) and • Serotonin may have a role in low desire systemically) by acting as a sexual satiety signal. • Increase dopamine • Serotonergic agents (e.g. SSRIs) inhibit • Increase norepinephrine desire, arousal, and orgasm in the brain • Modulate serotonin and in the tissue. • Melanocortins • PDE-5 Inhibitor

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Drugs In Development or Approved for HSDD :

Serotonin Receptors Drug Name Drug Pharma Current Developmental Status Category Sponsor Flibanserin Non-hormonal Sprout Approved 8/2015 for CNS agent Pharmaceuticals HSDD in premenopausal women, available 10/17/15 Lybrido (on demand oral sildenafil + Emotional Brain Phase II completed for HSDD •5-HT (prosexual) tablet) testosterone 1A Lybridos (on demand oral buspirone + Emotional Brain Phase II in progress for HSDD tablet) testosterone •5-HT2A antagonist (prosexual) DHEA Vaginal Ovules Androgenic EndoCeutics, Inc. Phase III completed for VVA in postmenopausal (Prasterone) Precursor for VVA Bayer Women;future investigation for HSDD •5-HT2A agonist (; Anti-sexual) Bremelanotide (PT-141) melanocortin Palatin Phase IIB for FSAD completed subq injection (PL6983) receptor modulator Technologies Phase III underway for HSDD/FSIAD •5-HT agonist (Cardiovascular; Heart valves) Extended release daily oral bupropion and SP-1 Biopharma Phase III set to begin 2B buspirone and bupropion trazodone (LorexysTM) •5-HT2C agonist (Satiety; Weight Loss)

Flibanserin Flibanserin

• Mixed post-synaptic 5HT1A agonist and 5HT2A antagonist. • Submitted to FDA February 2015 –5HT1A could have pro-sexual effects. • Advisory Committee Hearing June 4, 2015 –5HT2A antagonists could have pro-sexual effects. • Approved August 18, 2015 • Has activity at dopamine D4 receptors as well as moderate affinity for 5HT2B

and 5HT2C receptors. • Available October 17, 2015 • Originally studied for depression and precise mechanism for HSDD is • 100mg PO qhs statistically improved sexually satisfying events, unknown desire, and distress when compared with placebo • Thought to produce region-specific elevations in dopamine and • Warning: and syncope due to interaction with , norepinephrine which offset inhibitory serotonergic activity = increased patients with liver impairment or use with CYP3A4 inhibitors desire pathways. • Only available through a restricted program

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Other Serotonin Modulators with Potential Flibanserin for Low Desire • Buspirone (Buspar) Flibanserin – psychotropic drug for generalized anxiety disorder - Testosterone (GAD). It is a weak 5-HT1A partial agonist. 5-HT X Progesterone – appears to produce some oxytocin stimulation, and can partially +/‐ + + + antagonize the sexual side effects of SSRIs. Melanocortins • Trazodone (Desyrel, Oleptro, etc.) Estrogen + + + Desire Dopamine (DA) – antidepressant of the serotonin antagonist and reuptake inhibitor - + X (SARI) class. 5-HT Flibanserin – anxiolytic and sleep-inducing (hypnotic) effects. X - Prolactin - Subjective + – psychosexual side effects in women, including increased , Norepinephrine (NE) Excitement of the clitoris, and spontaneous orgasms. –a 5-HT2A , and a moderate 5-HT1A partial agonist. + Oxytocin Orgasm • Vilazodone (Viibryd) – SSRI for major depressive disorder.

–a 5-HT1A partial agonist.

Adapted from Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338

Slide adapted from herdesire.net.

Biological Approaches PDE5 inhibitors

• Increase androgens (locally(DHEA) and • Alone, no change in • Newer data supports the systemically) desire use of PD5 inhibitors with • If patient complains of women who suffer from • Increase dopamine slow or no arousal, SSRI induced orgasmic • Increase norepinephrine and /or 25-50Mg of Sildenafil one complaints of increased • Modulate serotonin hour before intercourse latency or decreased maybe beneficial intensity or anorgasmia • Melanocortins • Many increase clitoral vasocongestion • PDE-5 Inhibitor

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Drugs In Development or Approved for Low Desire :

Drug Name Drug Pharma Current Developmental Status Lybrido and Lybridos Category Sponsor

Flibanserin Non-hormonal Sprout Approved 8/2015 for CNS agent Pharmaceuticals HSDD in premenopausal women, available 10/17/15 • Testosterone/Sildenafil (Lybrido): increases the brain’s Lybrido (on demand oral sildenafil + Emotional Brain Phase II completed for HSDD response to sexual cues and enhances genital sexual tablet) testosterone

Lybridos (on demand oral buspirone + Emotional Brain Phase II in progress for HSDD response tablet) testosterone

DHEA Vaginal Ovules Androgenic EndoCeutics, Inc. Phase III completed for VVA in postmenopausal • Testosterone/Buspirone (Lybridos): increases the (Prasterone) Precursor for VVA Bayer Women;future investigation for HSDD brain’s response to sexual cues and reduces the Bremelanotide (PT-141) melanocortin Palatin Phase IIB for FSAD completed subq injection (PL6983) receptor modulator Technologies Phase III underway for HSDD/FSIAD inhibitory response to sexual cues. Extended release daily oral bupropion and SP-1 Biopharma Phase III set to begin buspirone and bupropion trazodone (LorexysTM) • Based on the concept of HYPERactive INHIBITORY response, HYPOactive EXCITATORY response or combination of both

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Lybrido, Lybridos – Lybrido/Lybridos for Low Desire

Buspirone - Testosterone 5-HT X Progesterone +/‐ + + + Melanocortins Estrogen + + + Desire Dopamine (DA) - + X 5-HT Buspirone X - Prolactin - Subjective + Excitement Norepinephrine (NE)

PDE-5 inhibitors + Oxytocin Orgasm

Adapted from Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338.

Slide adapted from herdesire.net

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Drugs In Development or Approved for HSDD :

Biological Approaches Drug Name Drug Pharma Current Developmental Status Category Sponsor Flibanserin Non-hormonal Sprout Approved 8/2015 for • Increase androgens (locally(DHEA) and CNS agent Pharmaceuticals HSDD in premenopausal women, available 10/17/15 Lybrido (on demand oral sildenafil + Emotional Brain Phase II completed for HSDD systemically) tablet) testosterone Lybridos (on demand oral buspirone + Emotional Brain Phase II in progress for HSDD tablet) testosterone • Increase dopamine DHEA Vaginal Ovules Androgenic EndoCeutics, Inc. Phase III completed for VVA in postmenopausal (Prasterone) Precursor for VVA Bayer Women;future investigation for HSDD • Increase norepinephrine Bremelanotide (PT-141) melanocortin Palatin Phase IIB for FSAD completed subq injection (PL6983) receptor modulator Technologies Phase III underway for HSDD/FSIAD Extended release daily oral bupropion and SP-1 Biopharma Phase III set to begin • Modulate serotonin buspirone and bupropion trazodone (LorexysTM) • Melanocortins • PDE-5 Inhibitor

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Bremelanotide for Low Desire Bremelanotide Testosterone - receptors • A melanocortin agonist and first-in-class 5-HT Progesterone + +/‐ + + Melanocortins • Activates endogenous pathway that stimulates Estrogen + + + attention and desire Desire Dopamine (DA) - + 5-HT • On-demand use with rapid onset of activity and - Prolactin - Subjective + Norepinephrine (NE) well-tolerated Excitement • Phase 2B studies showed that the 1.75mg dose + to be most effective and is currently undergoing Oxytocin Orgasm Phase 3 trials. Clayton A, Hamilton D. Psychiatr Clin N Am. 2010;33:323-338. *slide adapted from website herdesire.net 51

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Sexual Desire: Estrogen Testosterone Thank you for your kind attention! Excitatory and Inhibitory Pathways Lorexys Bupropion SR Flibanserin Lybrido/Lybridos • [email protected] + Bremelanotide

Inhibitory Excitatory

5-HT Dopamine Prolactin Norepinephrine Opioids Oxytocin Endocannabinoids Melanocortins

Adapted from Pfaus J. J Sex Med. 2009;6:1506-1533.

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