Hypoactive Sexual Desire Disorder (HSDD)

9/26/2017

Sharon J. Parish, MD Professor of Medicine in Clinical Psychiatry; 10/07/17 Professor of Clinical Medicine [email protected]

Conflict Of Interest Disclosure Statement

• Advisory board: AMAG, Allergan, Valeant Pharmaceuticals • Speaker: AMAG, Pfizer and Valeant Pharmaceuticals • Writing support: Allergen, Pfizer Pharmaceuticals

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Objectives • Describe epidemiology, associated features, and indications for psychological treatment and pharmacotherapy for HSDD.

• Explain mechanism of action, efficacy, safety, and treatment considerations for flibanserin, a centrally acting, oral daily FDA approved medication for generalized, acquired HSDD in premenopausal women.

• Discuss efficacy and safety of testosterone therapy for HSDD in late reproductive age and postmenopausal women.

• Review published Clinical Guidelines and Position Statements regarding testosterone therapy for women, and discuss practical considerations and applications regarding off‐label, evidenced‐based testosterone therapy.

• Discuss drugs in development for HSDD and future directions. •

1,2 The Sexual Response Cycle

Modified by Kaplan (1974) and Georgiadis et al. (2012)

1. Kaplan HS. The New Sex Therapy: Active Treatment of Sexual Dysfunctions. New York, NY: Psychology Press;1974. 2. Georgiadis JR, et al. Nat Rev Urol. 2012;9(9):486-498.

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Hypoactive Sexual Desire Dysfunction (HSDD): DSM IV‐TR, ICSM (clinical principle)

• Persistent or recurrent deficiency or absence of sexual thoughts, fantasies, and/or desire for sexual activity • Causes marked personal distress or interpersonal difficulties • Not better accounted for by another primary disorder, drug/medication, or general medical condition

McCabe et al. J Sex Med;2016:135‐143. DSM‐IVR. American Psychiatric Association; 2003.

Female Sexual Interest/Arousal Disorder (DSM 5)

Lack of, or significantly reduced, sexual interest/arousal as manifested by 3 of 1. Absent/reduced interest in sexual activity 2. Absent/reduced sexual/erotic thoughts or fantasies 3. No/reduced initiation of sexual activity and unreceptive to partner’s attempts to initiate 4. Absent/reduced sexual excitement/pleasure during sexual activity in almost all or all (75%‐100%) sexual encounters 5. Absent/reduced sexual interest/arousal in response to any internal or external sexual/erotic cues (written, verbal, visual) 6. Absent/reduced genital or nongenital sensations during sexual activity in almost all or all (75%‐100%) sexual encounters

DSM‐5. American Psychiatric Association; 2013.

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Classification: DSM‐IV‐TR vs. DSM‐5 Defined by Onset Defined by Context Characteristics

Lifelong Generalized Clinically significant distress & persistence Present since onset of Not limited to certain types sexual functioning of stimulation, situations, Subtypes: or partners Psychogenic, organic, Acquired Situational mixed, unknown etiology

Develops after period of Limited to certain types of Duration & frequency “normal” functioning stimulation, situations or (6 months, > 75% of partners encounters)

Severity: mild, moderate, severe

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 2013;5:433‐436. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 2000;4

Female Sexual Response Cycle: Circular Model

Emotional Intimacy

Emotional and Physical Satisfaction

Spontaneous Sexual Sexual Drive Stimuli

Arousal and Sexual Desire Sexual Arousal Biologic

Psychological

Basson R. Med Aspects Hum Sex. 2001;1:41‐42.

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Hypoactive Sexual Desire Disorder (HSDD)

Sexual desire is a construct that is not specifically event‐related. Grade B: level of evidence 2‐3 Manifests as any of the following for a minimum of six months: • Lack of motivation for sexual activity as manifested by either: • Reduced or absent spontaneous desire (sexual thoughts or fantasies) • Reduced or absent responsive desire to erotic cues and stimulation or inability to maintain desire or interest through sexual activity • Loss of desire to initiate or participate in sexual activity, including behavioral responses such as avoidance of situations that could lead to sexual activity, that is not secondary to sexual pain disorders • AND is combined with clinically significant personal distress that includes frustration, grief, incompetence, loss, sadness, sorrow, or worry

Parish et al. J Sex. Med. 2016 Dec;13(12):1888‐1906.

Case Scenario – Premenopausal ♀ with HSDD • Julia –age 41, seeks treatment for Hypoactive Sexual Desire Disorder (HSDD) SEXUAL HISTORY • Distressing low sexual desire for 5+ years • Low or no initiation, frequency once monthly or less • Motivation is not endogenous drive • Rare masturbation • Normal arousal & orgasm, no sexual pain • Husband Geoffrey age 46, normal sexual function • Individual and couples therapy have not improved sex life

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Case Scenario – Premenopausal ♀ HSDD (2)

• Marriage as solid and supportive • Alcohol use, 1‐2 glasses of wine, 3‐4 nights/week • Work related social events ‐ alcohol is “part of the job” • OCPs since age 16, discontinued 3 years ago due to low sex drive, nl menses • Depression since age 18, intermittent use of SSRIs • Currently on venlafaxine (SNRI) 75 mg daily for 3 years • Physical exam: general & pelvic normal • Lab: nl TSH, prolactin, FT4, calculated free testosterone 0.4 (nl 0.6‐0.8), SHBG 95 (http://www.issam.ch/freetesto.htm)

Treatment Strategy ?

Referral to sex therapist Bupropion (CBT, mindfulness) Off label testosterone (male or compounded) HSDD

Bremelanotide when FDA‐approved available Flibanserin

Awaiting published CLINICAL GUIDELINES OR INDICATIONS FOR PHARMACOTHERAPY FOR HSDD

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Biopsychosocial Model of Female Sexual Response

(eg, physical health, (eg, performance neurobiology, Biology Psychology anxiety, depression) endocrine function)

(eg, upbringing, cultural (eg, quality of current and Sociocultural Interpersonal past relationships, norms and intervals of abstinence, expectations) life stressors, finances)

Rosen RC, Barsky JL. Obstet Gynecol Clin North Am. 2006;334:515‐526. Althof SE, Leiblum SR, Chevret‐Measson M, et al. J Sex Med. 2005;26:793‐800.

Integrated Model of Sexual Dysfunction

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Contributors to Desire ProblemsTM

Neurotransmitters Past history Sex Hormones of disappointing sex Expectation Illness Biological of negative Fatigue outcome

Lack of privacy Stimulation Lack of Safety Contextual Partner dysfunction appropriate Emotional rapport stimuli Cultural beliefs

Interpersonal Intrapersonal development history Trauma (sexual, physical, medical) Relationship discord Negative emotions (anxiety, fear, Absence of emotional intimacy shame, guilt)

1. TM Created by: Sandra Leiblum, PhD.

Processing of Sexual Cues and Stimuli Impacted by Multiple Factors

Integration of Signals

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The Dual Control Model

− Physiological and + Physiological and Organic Issues Organic Issues

Physiological and Physiological and − + Organic Issues Organic Issues

Sexual Tipping Point® Inhibition Excitation

Variable and Dynamic Process

Etiology of HSDD: Imbalance Between Excitation/Inhibition

• Dopamine • Serotonin • Oxytocin • Opioids • Melanocortin Physiological/ • Endocannabinoids • Vasopressin Organic • Norepinephrine

• Intimacy • Relationship conflict • Shared values • Negative stress • Romance Psychosocial/ • Negative beliefs about sex • Experience/behavior Interpersonal • Experience/behavior

EXCITATION INHIBITION

Bancroft J, et al. J Sex Res. 2009;46:121‐142. Bancroft J,Perelman et al. J Sex MA. Res J. 2009;46:121-142.Sex Med. 2009;6:629‐32. Perelman MA. J Sex Med. 2009;6:629-32.

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Neurotransmitter/Central Regulation of Desire/Arousal

(+)

Estrogen (-) Progesterone Serotonin

Adapted from Clayton AH, Hamilton DV. Obstet Gynecol Clin North Am. 2009;36(4):861‐876. Adapted from Clayton AH, Hamilton DV. Obstet Gynecol Clin North Am. 2009;36(4):861-876.

Key Regions in Brain Regulating Sexual Desire

• Prefrontal cortex (PFC) • Locus coeruleus • Medial preoptic area (mPOA) • Paraventricular nucleus • Reward and attention processing centers of the ventral tegmental area and nucleus accumbens

Slide courtesy of Jim Pfaus Kingsberg SA, Clayton A, Pfaus J. CNS Drugs. 2015;29:915‐933. Pfaus J. J Sex Med 2009;6:1506‐1533.

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PET Scan Changes in Neural Activity in Response to Erotic Video

• Women with HSDD have weaker activation in cerebral cortex in right hemisphere • Possibly representing muted response to sexual cues • Women with HSDD have less deactivation in left hemisphere possibly representing • Inability to deactivate higher order processing and perpetuates inhibitory neural pathways

Holstege G. Sex Med Rev. DOI: http://dx.doi.org/10.1016/j.sxmr.2016.04.002

Arnow et al. (2009) Neuroscience, 158, 484‐502

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Most Prevalent Female Sexual Dysfunction (FSD) is HSDD: Affecting 1 in 10 Women Prevalence of Female Sexual Problems Associated With Distress

50 45 43.1 40 37.7 35 30 25.3 25 21.1 20 15 US Women (%) US Women 9.5 11.5 10 5.1 4.6 5 0 Desire Arousal Orgasm Any

Sexual Problems Distressing Sexual Problems Population: 31,581 US female responders > 18 years of age from 50,002 households

Shifren ShifrenJL, et al. JL,Obstet et al. Gynecol Obstet. Gynecol.2008;112(5):970-978. 2008;112(5):970‐978.

Decreased Sexual Desire With Distress

Prevalence of Sexual Problems Associated With Sexually Related Personal Distress

Any Desire % Prevalence, 5 Arousal Orgasm

0 18-19 20-29 30-39 40-49 50-59 60-69 70-80 >80 Age, y

N=31,581 women Sexual pain not measured in this survey

Shifren JL et al. Obstet Gynecol. 2008;112(5);970‐978.

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HSDD and Personal Distress: WISHeS Study

• Low desire associated with psychological, emotional distress and lower sexual, relationship satisfaction • >80% of women with HSDD concerned, unhappy, letting partner down • Dissatisfaction • 11 times more likely dissatisfied with sex lives • 2.5 times more likely dissatisfied with relationship

Leiblum et al. Menopause. 2006;13:46‐56.

Impact of Low Sexual Desire on Quality of Life

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Prevalence of Sexual Dysfunction: Role of Depression

SEXUAL SEXUAL FSD WITHOUT PROBLEM PLUS DISTRESS COMPLAINT PROBLEM DEPRESSION Desire 38.7% 10% 6.3 –8.8% Arousal 26.1% 5.4% 3.3 –4.7% Orgasm 20.5% 4.7% 2.8 –4.1%

Any Dysfunction 44.2% 12% 7.6 – 10.7%

N=31,581. Definition of depression: Self‐reported depressive sx’s + AD use; AD use without current depressive sx’s; Depressive symptoms without AD use

Shifren J et al. Obstet Gynecol 2008;112:970‐978. Johannes CB et al. J Clin Psychiatry 2009;70(12):1698‐1706. Shifren J et al. Obstet Gynecol 2008;112:970-978. Johannes CB et al. J Clin Psychiatry 2009;70(12):1698-1706.

Diagnosing HSDD in the Clinic Decreased Sexual Desire Screener (DSDS)

• Specifically designed to screen for acquired, Please answer each of the following questions: 1. In the past was your level of sexual desire or interest good and satisfying generalized HSDD □ Yes □ No to you? • Intended for use in practicing clinicians with little to no experience in recognizing HSDD 2. Has there been a decrease in your level of sexual desire or interest? □ Yes □ No • Patient must answer Yes to questions 1‐4 and 3. Are you bothered by your decreased level of sexual desire or interest? □ Yes □ No No to all rule‐outs assessed by question 5 to screen positive for HSDD 4. Would you like your level of sexual desire or interest to increase? □ Yes □ No

5. Please check all the factors that you feel may be contributing to your □ Yes □ No current decrease in sexual desire or interest:

A. An operation, depression, injuries, or other medical condition □ Yes □ No

B. Medication, drugs or alcohol you are currently taking □ Yes □ No

C. Pregnancy, recent childbirth, menopausal symptoms □ Yes □ No D. Other sexual issues you may be having (pain, decreased arousal or □ Yes □ No orgasm) E. Your partner’s sexual problems □ Yes □ No F. Dissatisfaction with your relationship or partner □ Yes □ No G. Stress or fatigue □ Yes □ No When complete, please give this form back to your clinician. Clayton AH, et al. J Sex Med. 2009;6(3):730‐738.

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HSDD: Physical, Medical and Medication Factors

Medical & Psychiatric Conditions Medications Psychosocial Factors Depression Psychopharmacologic  Relationship conflict Urinary Incontinence • Antidepressants • Partner sexual dysfunction Neurological Disease • Antipsychotics • fatigue and stress Cancer • Barbiturates • mood disorder Genitourinary Syndrome of Menopause • Benzodiazepines • poor body image AIDS • Hypnotics Endocrine Hormones • Hypothyroidism/Hyperthyroidism • Oral contraceptives • Hypothalamic amenorrhea • Gonadotropin releasing agonists and • Primary ovarian insufficiency analogs Sexual Factors • Adrenal insufficiency • Anti-androgens (eg, spironolactone ) • Inadequate stimulation • Hypopituitarism • Anti-estrogens • Poor attention focus on stimulation • Pituitary tumors • Other • Poor sexual context • Hyperprolactinemia • Cholesterol-lowering agents • Pain or diminished arousal • Following oophorectomy • Beta-blockers • Diabetes • Chemotherapeutics • Obesity • Metabolic Syndrome Substances of Abuse • Legal • Controlled • Illegal

ParishParish SJ, Hahn SJ, Hahn SR. Hypoactive SR. Sex med Sexual Rev Desi 2016;4:103re Disorder:‐120. A Review of Epidemiology, Biopsychology, Diagnosis, and Treatment. Sex med Rev 2016;4:103-120.

HSDD PROCESS OF CARE Ask/Permission to Discuss: Are you sexually active? What sexual concerns do you have?

Referral Other FSD Low sexual interest/desire No FSD

DSDS and/or Focused Hx

Education/ Counseling/ Lifelong low sexual Acquired, Generalized Acquired, Situational low Education/ Counseling/ Referral interest/ desire HSDD sexual interest/ desire Referral

Focused Medical Assessment

HSDD with potentially modifiable factors HSDD without modifiable factors

Education Education

Modification

HSDD without (remaining) modifiable factors

Peri‐menopause (late reproductive Pre‐menopausal yrs) PreTx labs Post‐menopausal

Sex Therapy / CNS agents Sex Therapy / CNS Agents / Androgens

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Identification of Psychological Factors Contributing to HSDD Helps Determine Appropriate Intervention

Psychological Factor Recommended Approach Depression/anxiety Pharmacotherapy/cognitive behavioral therapy Poor self/body image Psychotherapy Stress/distraction Cognitive behavioral therapy History of abuse (physical, sexual, emotional) Psychotherapy Substance abuse Psychotherapy Self-imposed pressure for sex Office-based counseling or refer for cognitive behavioral therapy Religious, personal, cultural or family values, beliefs Office-based counseling or refer for and taboos cognitive behavioral therapy Relationship factors Office-based counseling or refer for individual/couples therapy Lifestyle factors (e.g., fatigue, sleep deprivation) Office-based counseling Sexual factors (e.g., inadequate stimulation) Office-based counseling

Goldstein I, Kim NN, Clayton AH, DeRogatis LR, Giraldi A, Parish SJ, Pfaus J, Simon JA, Kingsberg SA, Meston C, Stahl SM, Wallen K, Worsley R. Mayo Clinic Proc. 2017 Jan;92(1):114‐128.

Psychotherapy Trials for HSDD

• Mindfulness Meditation Training and CBT trials all small with waitlist or uncontrolled—no placebo • 3 CBT trials and 2 MMT trials superior to wait‐list control1 • Insufficient data to conclude efficacy due to • Lack of hierarchy of endpoints and preplanned primary endpoints • Lack of randomization • Lack of adequate control/placebo

• Nocebo Effect: A negative placebo effect • Waiting list may be a nocebo condition in psychotherapy trials2

1.Pyke R. Clayton A. JSM 2015;12:2451‐2458. 2. Furukawa et al. Acta Psychiatr Scan 2014;130(3):180‐192

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What are the FDA Recognized Measures to Assess HSDD in Clinical Trials?

• Female Sexual Function Index (FSFI)

• Female Sexual Distress Scale-Revised (FSDS-R)

• Item 13: distress related to low sexual desire

• Satisfying Sexual Events (SSEs)

Female Sexual Function Index (FSFI)

• Developed and validated as a “brief self‐report measure of female sexual arousal and other relevant domains of sexual functioning in women” • Full scale consists of 19 questions, 6 domains over 4 weeks – Desire (2 questions) – Arousal (4 questions) – Lubrication (4 questions) – Orgasm (3 questions) – Satisfaction (3 questions) – Pain (3 questions) • Female sexual dysfunction (FSD) = score <26.5 • Limitation: physiologic, genital aspects; current function • www.fsfiquestionnaire.com

Rosen R, et al. J Sex Marital Ther. 2000;26(2):191‐208. Echeverry, BS, et al. J Sex Medicine. 2010; 7:2664.

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Flibanserin (Addyi®) Bupropion/Trazodone (Lorexys) Testosterone/Buspirone (Lybridos)

Hypothalamus and

Bremelanotide Testosterone/Sildenafil (Lybrido)

Kingsberg SA, Clayton AH, Pfaus. CNS Drugs 2015;29:915‐933. Slide courtesy of James Pfaus, PhD.

Flibanserin

• Classified as a multifunctional serotonin agonist and antagonist (MSAA)

• Mixed post‐synaptic 5HT1A agonist and 5HT2A antagonist • Exact mechanism unknown

• 5HT1A agonists 5HT2A antagonists may have pro‐sexual effects

• Activity at dopamine D4 receptors and moderate affinity for 5HT2B and 5HT2C receptors • Region‐specific elevations in dopamine and norepinephrine offset inhibitory serotonergic activity resulting in increased desire pathways

Stahl et al. J Sex Med 2011;8:15‐27.

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Flibanserin • FDA‐approved for acquired, generalized HSDD in premenopausal women not caused by: • Medical or psychiatric condition • Relationship problems • Effects of a medication/drug • 100 mg PO daily at bedtime • REMS program: certification to prescribe (for pharmacies to dispense) • Warnings: • Hypotension and syncope due to interaction with alcohol • Avoid in patients with liver impairment or on CYP3A4 inhibitors

Joffe HV, Chang C, Sewell C, et al. FDA Approval of Flibanserin‐‐Treating Hypoactive Sexual Desire Disorder. NEJM 2016;374:101‐104.

Flibanserin Clinical Program: Inclusion Criteria/Baseline Characteristics

• Premenopausal women : Mean Age 36 • HSDD per DSM‐IV‐TR criteria, generalized acquired type • HSDD duration ≥24 weeks • Comorbid secondary FSAD and/or FOD, only if HSDD commenced prior, and of more importance as assessed by the patient • In a stable, monogamous relationship for at least one year, with a sexually functional partner who was present for at least ½ the time • Willingness to try to engage in sexual activity at least 1/Mo

, per month

Sprout Report: Sprout Briefing Document, June 2015 Flibanserin Advisory Committee (http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/drugsafetyandriskmanagementadvisorycommittee/ucm449090.pdf). Accessed April 20, 2016.

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Flibanserin Trials: Satisfying Sexual Events

Statistically significant separation from placebo in 4‐8 weeks (*p < 0.05)

Katz M et al. J Sex Med 2013;10:1807‐1815. (511.147) Derogatis et al. J Sex Med 2012;9:1074‐1085. (511.71) Thorp et al. J Sex Med 2012;9:793‐804. (511.75)

Flibanserin Improves Sexual Desire (FSFI)

Statistically significant separation from placebo at 4 weeks (p < 0.05)

Katz M et al. J Sex Med 2013;10:1807‐1815. (511.147) Derogatis et al. J Sex Med 2012;9:1074‐1085. (511.71) Thorp et al. J Sex Med 2012;9:793‐804. (511.75)

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Flibanserin Reduces Distressing Low Sexual Desire (FSDS‐R) 25% reduction in distress associated with low desire (p < 0.05)

Reduction in score = improvement

Katz M et al. J Sex Med 2013;10:1807‐1815. (511.147) Derogatis et al. J Sex Med 2012;9:1074‐1085. (511.71) Thorp et al. J Sex Med 2012;9:793‐804. (511.75)

Efficacy Endpoints Phase 3 Pivotal Studies Study 147 Study 71 Study 75 Flibanserin Flibanserin Flibanserin 100 mg qhs 100 mg qhs 100 mg qhs SSE  eDiary Desire - xx FSFI-Desire  FSDS-R13 (Distress)  FSFI-Total Score  FSDS-R Total Score 

1.Derogatis LR, et al. J Sex Med. 2012;9(4):1074‐1085. 2.Thorp J, et al. J Sex Med. 2012;9(3):793‐804. 3.Katz M, et al. J Sex Med. 2013;10(7):1807‐1815. 4.Fisher WA, Pike RE. Sex Med Rev 2017

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Efficacy of Flibanserin in Three Phase 3 Trials* Endpoint Mean baseline Improvement over baseline

Satisfying sexual events 2–3/mo 0.5–1.0/mo (median)

FSFI desire (range, 1.2–6.0) 1.8–1.9 0.3–0.4

Daily desire (range, 0–84) 10–12 1.7–2.3

Distress (range, 0–4) 3.2–3.4 0.3–0.4

*Improvement data represent least‐square means, unless otherwise noted. Improvement in daily desire was not statistically significant. FSFI denotes Female Sexual Function Index. For the FSFI and daily desire scales, the higher the number, the greater the sexual desire. For the distress scale, the higher the number, the greater the distress.

Joffe et al. NEJM 2016;374(2):101‐104. Gao et al. J Sex Med 2015;12: 2095‐2104.

Flibanserin: Magnitude of Response

Responder defined as much improved or very much improved

SSEs FSFI-D FSDS-R13 n = 525 n = 506 n = 302 Baseline in Week 24 Change from n = 521 n = 500n = 239 n = 525 n = 506 n = 259

Placebo Flibanserin 100 mg qhs FAS Flibanserin 100 mg qhs responders

FAS = full analysis set; FSDS‐R13 = Female Sexual Distress Scale‐Revised Item 13; FSFI‐D = Female Sexual Function Index‐Desire domain; SSE = satisfying sexual event; PGI‐I = Patient Global Impression of Improvement Data on file: Sprout Pharmaceuticals, Inc.

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Clinical Relevance PGI of Improvement: PGI‐I Very Much/Much/Minimally Improved How is your condition today –meaning decreased sexual desire and feeling bothered by it – compared with when you started study medication?

**** Flibanserin 100 qhs **** 51.8 50.0 **** Placebo 50 47.0

40 37.7 30.3 30.3 Adjusted 30 P values Responders

*P < 0.05

% **P < 0.01 20 ***P < 0.001 ****P < 0.0001 Week 24 FAS, LOCF 10 511.75 511.71 511.147

Common Adverse Events in ≥1%

Placebo Flibanserin 100 mg qhs N = 1905 N = 1543 Preferred Term N (%) N (%) Dizziness 41 (2.2) 176 (11.4) Somnolence 59 (3.1) 173 (11.2) Nausea 71 (3.7) 161 (10.4) Fatigue 95 (5.0) 142 (9.2) Insomnia 46 (2.4) 75 (4.9) Dry mouth 17 (0.9) 37 (2.4) Anxiety 17 (0.9) 28 (1.8) Constipation 9 (0.5) 25 (1.6) Abdominal pain 15 (0.8) 23 (1.5) Sedation 3 (0.2) 20 (1.3) Vertigo 6 (0.3) 16 (1.0)

Derogatis LR, Komer L, Katz M, et al. J Sex Med 2012;9:1074‐1085. Katz M, DeRogatis LR, Ackerman R, et al. J Sex Med 2013;10:1807‐1815. Thorp J, Simon J, Dattani D, et al. J Sex Med 2012;9:793‐804.

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Adverse Events and Discontinuation

• Hypotension was observed in 0.2% of patients taking flibanserin compared to 0.1% of subjects taking placebo.

• Syncope occurred in 0.4% on flibanserin compared to 0.2% on placebo.

• Discontinuation rates due to adverse effects for women taking 100 mg/day 13.4 vs.10.1% for placebo, 11.4 vs 3.4% & 9.6 vs. 3.7%.

CNS Drugs Have Similar Adverse Event (Aes) Profiles

Flibanserin Bupropion Buspirone

Dizziness 11.4% Tremor 13.5% Dizziness 9% Somnolence 11.2% Agitation 9.7% Nervousness 4% Nausea 10.4% Dry Mouth 9.2% Nausea 3% Fatigue 9.2% Constipation 8.7% Headache 3% Insomnia 4.9% Excessive sweating 7.7%

Dry Mouth 2.4% Dizziness 6.1% Nausea/vomiting 1.0%

Most AEs were transient or episodic, mild to moderate in severity, and mitigated by bedtime dosing

Flibanserin Prescribing Information, 2015. Stahl et al.. J Clin Psychopharmacol. 2004;24(3):339‐342.

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Flibanserin, Depression, SSRI/SNRIs Division Summary, phase 3 placebo‐controlled trials SS/NRIs • Depression more common among flibanserin treated subjects than placebo; incidence is dose‐proportional…no signal of suicidality • Flibanserin did not exacerbate depression or anxiety in patients taking SSRI or SNRI medication. • Combination of flibanserin with SS/NRI exacerbated dizziness and insomnia (in dedicated SSRI study). • Adverse events exacerbated by concomitant use of flibanserin with an SS/NRI were anxiety, somnolence, fatigue, insomnia, and dizziness (pivotal trial). Findings should not preclude concomitant use but consideration should be given...

Phase 1 Alcohol Challenge Study

Study consisted of 5 single dose study periods; subjects received each of the 5 treatments

Study Design Dosing Regimen 0.4 g/kg EtOH is equivalent to • 25 subjects each of the following A. 0.8 g/kg EtOH + in a 70 kg (~154 lb) person: (23 men, 2 women) flibanserin 100 mg • Mean age: 31 years (21-52) Two 12 oz cans of B. 0.8 g/kg EtOH + • Fasted for 10 hours beer containing 5% placebo • Ate a light breakfast alcohol content C. 0.4 g/kg EtOH + • Administered study drug Two 5 oz glasses of flibanserin 100 mg • Given up to 10 minutes to wine containing 12% D. 0.4 g/kg EtOH + ingest liquid solution alcohol content placebo (orange juice or ethanol Two 1.5 oz shots [EtOH] + orange juice) E. Flibanserin 100 mg of 80-proof spirit

ClinicalTrials.gov. September 2017

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Flibanserin and Alcohol

• Results • Participants took 100 mg flibanserin in morning and consumed 2 alcoholic drinks rapidly. • 17% required intervention for symptomatic hypotension ♂ • Orthostatic hypotension in 25% of subjects who consumed 100 mg of flibanserin and equivalent of 4 drinks • Phase 3 trials not regulating alcohol documented no increase in syncope • No difference: 0.4% flibanserin; 0.2% placebo • Safety concerns raised by FDA, including hypotension/syncope rare to infrequent with proper bedtime dosing

Joffe, H. NEJM 2016;374(2): 101‐104.

Effects of Alcohol Administered with Flibanserin in Healthy Premenopausal Women

Results: • In this large, 7‐treatment, 12‐sequence, crossover study, administration of alcohol with flibanserin was not associated with an increased risk of hypotension and syncope • 1 Subject in the ADDYI + 0.4 g/kg EtOH group experienced hypotension • Adverse event profile for concomitant administration of mild (0.2 g/kg) or moderate (0.4 g/kg) quantities of ethanol with flibanserin was similar to that of flibanserin alone • Increased drowsiness following administration of flibanserin (with or without ethanol) in this study supports the recommended (bedtime) dosing

Sicard, E; Effects of Alcohol Administered with Flibanserin on Dizziness, Syncope, and Hypotension in Healthy Premenopausal Women

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Flibanserin Prescribing • Due to alcohol interaction with flibanserin • Patients must abstain from alcohol • Prescribers evaluate patient’s ability to do this • Contraindications: • Use of alcohol • Use of moderate or strong CYP‐3A4 inhibitors • HIV drugs, antifungals, antibiotics (cipro, macrolides), diltiazem, verapamil, conivaptan, nefazodone • Hepatic impairment

Oral Contraceptives and Flibanserin

• Oral contraceptives (OC) are classified as weak CYP3A4 inhibitors • Meta‐analysis results from phase 1 studies showed exposure to flibanserin was slightly increased when co‐administered with OC • Concomitant use of flibanserin and OC (30 mcg ethinyl estradiol/150 mcg levonorgestrel) may increase risk of AEs • Dizziness, somnolence, and fatigue

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Fluconazole and Flibanserin

Flibanserin [prescribing information]. Bridgewater, NJ: Valeant Women’s Health; 2015.

Flibanserin‐REMS program • Must become a certified prescriber • Providers/pharmacies MUST participate in Risk Evaluation and Mitigation Strategy (REMS) • To mitigate the increased risk of hypotension and syncope due to alcohol use • To become a certified prescriber go to www.AddyiREMS.com • Read the prescribing information and complete training program • Complete an assessment • Enroll

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Relationship Between Age and Androgens in Women

35 TT (ng/dl)

30 FT (pmol/L)

DHEA-S (mol/L) 25 Androstenedione (nmol/L) 20

0 18-24 (n=22) 25-34 (n=97) 35-44 (n=153) 45-54 (n=140) 55-64 (n=74) 65-75 (n=109)

Davison, S. L. et al. J Clin Endocrinol Metab 2005;90:3847-3853 Davison et al. J of Clin Endocrinology & Metabolism, 2005

Systemic Testosterone for Treatment of Low Libido

Randomized, placebo controlled trials consistently show benefits of transdermal testosterone vs. placebo for sexual desire and arousal, orgasm, pleasure, satisfaction, and pain. •Surgically postmenopausal women on E (A) •Naturally postmenopausal women on E & P (A) •Postmenopausal women on no other HT (A) •Premenopausal women in late reproductive years (B) •Treatment emergent SSRI/SNRI antidepressant induced SD (B) •POF/POI with HSDD (expert opinion, clinical principle) •No RCT data: Premenopausal women on COCs •Lack of RCT data supporting use of systemic DHEA

Davis SR, Wahlin‐Jacobsen S. Lancet Diabetes Endocrinol 2015; 3:980–92.

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Published Randomized Studies Demonstrating Efficacy of Testosterone (Patch) in Postmenopausal Women

Doses (mcg/d) Subjects (n) Estrogen Shifren et al, 2000 150/300 SM (75) + Braunstein, 150/300/450 SM (447) + et al 2005 Buster et al, 2005 300 SM (533) + Simon et al, 2005 300 SM (562) + Davis et al 2006 300 SM (61) + (patch) Davis et al, 2006 300 SM (76) + (aromatase inhibitors) Shifren et al, 2006 300 NM (486) + Liu et al, 2008 300 NM (431) + Davis et al, 2008 150/300 NM/SM (814) - Panay et al, 2010 300 NM (272) +/- groups

NM= naturally menopausal SM= surgically menopausal

Summary of Efficacy & Safety

• Randomized, double‐blind placebo controlled studies have established efficacy of transdermal patch for relieving symptoms of HSDD in naturally and surgically menopausal women with and without concomitant estrogen or estrogen/ progesterone therapy • Main side effects: increased hair growth and acne • Available safety data, although not conclusive, were reassuring with respect to cardiovascular, breast, and endometrial outcomes. • Long term safety data demonstrate no significant impact on intermediate metabolic endpoints and a low rate of cardiovascular events and breast cancer in postmenopausal women at increased cardiovascular risk. • No clinically relevant changes in lipids, liver function, hematology, carbohydrate metabolism • Small weight gain of 1.7 kg (p<0.05) • Small increase in blood pressure (<2 mm Hg) (p>0.05) • Rate of invasive breast cancer consistent with age appropriate expected rates Davis SR, Braunstein GD. J Sex Med 2012;9:1134‐1148. Khera M. Sex Med Rev 2015;3:137‐144 Nachtigall L, Casson P, Lucas J, Schofield V, Melson C, Simon JA. Gynecol Endocrinol. 2011 Jan;27(1):39‐48.

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Testosterone Therapy: Who to Treat • Primary indication for testosterone therapy: treatment of persistent low libido that profoundly impairs quality of life • Women late reproductive years and beyond who have experienced distinct change and are distressed • Women with the following conditions & distressing loss of libido: • Surgical menopause • Premature ovarian failure • Adrenal insufficiency (including glucocorticosteroid)

Davis SR. Menopause 2013;20(7):795‐797.

Testosterone Therapy: 2009‐2016

• ICSM 2009, 2015; ACOG Practice Bulletin 2011, reaffirmed 2017 • NAMS Recommendation for Clinical Care 2014, IMS 2016 • Decision to use T individualized, informed consent • No pretreatment T level defines androgen deficiency • Long term safety data lacking to support use > 6 months • Current data do not support T in pre and peri‐menopausal ♀ • Achieving physiological free T levels by transdermal delivery decreases adverse effects • Relative contraindications: androgenic alopecia, seborrhea, acne, hirsuitism • Contraindications: hyperlipidemia, liver dysfunction • Contraindicated with or high risk: breast & endometrial cancer, CVD, veno‐thromobotic events pending additional safety data

Wierman et al. J Sex Med 2010:7:561‐585. Shiffren JL, Gass MLS. Menopause 2014;21:1038‐1062. Davis et. al. J Sex Med 2016;13:168‐178. Baber et al. Climacteric 2016;19:109‐150.

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Clinical Guidelines ‐ UpToDate

•Topical compounded 1 percent testosterone cream or gel (0.5 grams Available daily) applied daily (no regulation) preparations for • Intrinsa 300 mg patch (2x/week) no Postmenopausal longer in Europe (consistent blood Women not levels) responding to • Transdermal patches and gels for men nonpharmacological (supraphysiologic dosing, 1/10th dose; therapy arms, legs, abdomen, risk to children) Not FDA approved •Oral: methyltestosterone, micronized testosterone (compounded), DHEA Long term safety data lacking •Intramuscular injections or implants (supra‐physiologic dosing)

Off‐Label Non‐Hormonal Pharmacologic Therapy for HSDD Bupropion Buspirone

• Norepinephrine‐dopamine reuptake inhibitor • Presynaptic serotonin 5‐HT1A partial agonist (NDRI) – Greater presynaptic than postsynaptic effects, – Inhibits dopamine transporter and resulting in a reduction in serotonergic tone norepinephrine transporter • Post hoc analysis of add‐on buspirone to selective • Investigated in several clinical trials for the serotonin reuptake inhibitors (SSRI) for the treatment treatment of HSDD of depression – Bupropion improved sexual function (as – 58% of subjects treated with buspirone reported an measured by CSFQ and BISF‐W), but had no effect improvement in sexual function, compared with 30% treated with placebo on frequency

Loane C, Politis M. Brain Res. 2012;1461:111‐118. Landén M, et al. J Clin Psychopharmacol. 1999;19:268‐271. BISF‐W, Brief Index of Sexual Functioning in Women; CSFQ ‐ Changes in Sexual Functioning Questionnaire

Stahl SM, et al. Prim Care Companion J Clin Psychiatry. 2004;6:159‐166. Segraves RT, et al. J Sex Marital Ther. 2001;27:303‐316. Segraves RT, et al. J Clin Psychopharmacol. 2004;24:339‐342.

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Drugs in Development for HSDD

Drug Name Drug Category Pharma Sponsor Current Developmental Status Lybrido (on demand oral tablet) sildenafil + Emotional Brain Phase II completed for HSDD testosterone No activity in ClinTrials.gov Lybridos (on demand oral tablet) buspirone + Emotional Brain Phase II in completed for HSDD testosterone No activity in ClinTrials.gov Bremelanotide (PT‐141) melanocortin AMAG Pharmaceuticals Phase IIB for FSAD completed subq injection (PL6983) receptor 4 agonist Phase III completed for HSDD; extension ongoing. NDA planned 1Q19 Topical testosterone gel testosterone BioSante Pharmaceuticals Phase III efficacy (failed) (Libigel) Phase III safety (stopped early) Intranasal testosterone gel testosterone Trimel Pharmaceuticals Phase II completed for anorgasmia (TefinaTM) No activity in ClinTrials.gov Extended release daily oral bupropion and SP‐1 Biopharma Phase II completed bupropion and trazodone trazodone No activity in ClinTrials.gov (LorexysTM) Transdermal sildenafil delivery sildenafil Strategic Science & Phase II for FSAD system (SST 6007) Technologies, LLC No activity in ClinTrials.gov

ClinTrials.Gov 9/17

Key Points: HSDD Treatment Approaches

• HSDD is a prevalent condition affecting 1 in 10 women. • Current standard of non‐pharmacological care includes CBT, mindfulness, and psychotherapy; also office based counseling. • Flibanserin is moderately effective for pre‐menopausal women with generalized, acquired HSDD. • Flibanserin must be prescribed in conjunction with the REMS and is contraindicated with strong CYP‐3A4 inhibitors. • Testosterone is effective for late reproductive and post‐menopausal women with distressing low libido. • Barriers exist related prescribing, patient eligibility and access. • Drugs with combined CNS and peripheral mechanisms are in development.

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ARS Question 1

Flibanserin, indicated for generalized acquired HSDD in premenopausal women, is contraindicated with all of the following except: • a. Fluconazole • b. Oral contraceptives • c. Alcohol • d. Clinically advanced hepatitis C • e. SSRIs in patient with daytime sedation

ARS Question 2

Regarding testosterone therapy in women, which of the following is true: a. Testosterone is effective for both pre and postmenopausal women with HSDD. b. Main adverse events include increase rates of breast cancer. c. Pretreatment blood levels predict treatment response. d. Achieving physiological free T levels by transdermal delivery decreases adverse effects. e. Women receiving testosterone therapy should be prescribed 1/5th of the standard male dose.