Desire for Desire. Michael L Krychman MD

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1 Desire for Desire Michael L Krychman MD Executive Director of the Southern California Center for Sexual Health and Survivorship Medicine AASECT Certified Sexual Counselor Associate Clinical Professor UCI Newport Beach, CA 1 1

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6 What s New Outside the Medicine Cabinet 16 < Michael Krychman TX paradigm 2015 Treatment Pathways: Sexual Complaints Treatment of systemic illness Undiagnosed chronic medical illnesses: Hypertension Diabetes Thyroid dysfunction Identification of medications Many patients are on poly pharmacy Screen for unnecessary SSRI Sexual Pharmacology 6

Lifestyle Factors and Sexual Activity Increased Physically active women Social support Healthy diet Decreased Sleep difficulties Inactivity Depression Obesity Greendale et al.

19 Medications and Sexuality Andrenergic function CNS depression Anticholinergics Antihistamines Antihypertensives Antipsychotics Barbituates Histamine H2 receptor blockers Promotility agents

7 Lifestyle Factors and Sexual Activity Increased Physically active women Social support Healthy diet Decreased Sleep difficulties Inactivity Depression Obesity Greendale et al. Journal of Women s Health 1996;5: Medications and Sexuality Andrenergic function CNS depression Anticholinergics Antihistamines Antihypertensives Antipsychotics Barbituates Histamine H2 receptor blockers Promotility agents Barbiturates Benzodiazepines Selective serotonin reuptake inhibitors Lithium Tricyclic antidepressants Indomethacin (Indocin) Ketoconazole (Nizoral) Phenytoin sodium (Dilantin Structured Sexual Tasks Sensate focusing Guided imagery Relaxation exercise Fantasy exploration Skilled exercises Tantra Sexual Awakening Sexual Devices/Accessories Self stimulator/vibrators Dilator therapy Sexy lingere Attachable nipples 7

Mindfulness Relationship exercises Assess

Activities Bring vacation time home again

the living room Ride a roller coaster Boost

8 Psychoeducational Treatments Cognitive therapy Education Behaviour therapy Mindfulness Relationship exercises Assess the Couples Communication 23 Focus on Novel Activities Bring vacation time home again Do something novel and exciting Dance in the living room Ride a roller coaster Boost adrenaline and increases oxytocin hormones the love hormone 8

Nhat Hahn, 1976 Acupuncture Acupuncture and herbal medicine have been incorporated for over 4000 years into treatment of all sexual complaints Multiple studies demonstrate that when acupuncture

9 Mindfulness vs. Mind FULL the miracle by which we master and restore ourselves it is the miracle which cancallbackinaflashourdispersedmind and restore it to wholeness so that we can live each minute of life Thich Nhat Hahn, 1976 Acupuncture Acupuncture and herbal medicine have been incorporated for over 4000 years into treatment of all sexual complaints Multiple studies demonstrate that when acupuncture needles are placed in key strategic locations many processes are activated Hormonal release Nervous system regulation Increased blood flow Acupuncture has a profound calming effect on mental and emotional states thus enhancing well being and sexual desire Testosterone IS ALL Off Label 1% testosterone gels Male dose: 5 cc per day 1/20 th to 1/10 th dose: cc per day mg gel applied Measure free T/calc free T/ FAI in 3 4 wks 9

PDE5 Inhibitors (Off Label) If patient complains of slow or no arousal vaginal estrogen and /or 25 50Mg of Sildenafil one hour before

10 Safety of Androgen Replacement Fluid retention Breast cancer risk Virilization Lipid profile changes Drug interactions Hepatocelluar damage Male Sexual Therapeutics? For Women? PDE5 Inhibitors (Off Label) If patient complains of slow or no arousal vaginal estrogen and /or 25 50Mg of Sildenafil one hour before intercourse maybe beneficial Many increase clitoral vasocongestion No change in desire Newer data supports the use of PD5 inhibitors with women who suffer from SSRI induced orgasmic complaints of increased latency or decreased intensity or anorgasmia 10

Flibanserin/ Addyi Novel, non hormonal therapy that works on key sexual pathways in the brain Over 11,000 women studied in trials to date Once daily pill taken at bedtime Demonstrated efficacy on

Ingelheim Re submission to FDA with 14 new trials and a validation June 2015 FDA meeting 18 6 Approval Data is August 18! Change from Baseline of (SSE) Study 511.147 ** ** ** ** ** * *p= 0.

11 Flibanserin/ Addyi Novel, non hormonal therapy that works on key sexual pathways in the brain Over 11,000 women studied in trials to date Once daily pill taken at bedtime Demonstrated efficacy on measurements of desire, distress and satisfying sexual events (SSEs) Most common side effects dizziness, nausea, fatigue and somnolence Flibanserin acquired by Sprout Pharmaceuticals from Boehringer Ingelheim Re submission to FDA with 14 new trials and a validation June 2015 FDA meeting 18 6 Approval Data is August 18! Change from Baseline of (SSE) Study ** ** ** ** ** * *p= 0.033; ** p < for difference between placebo and flibanserin M. Katz, L. DeRogatis, R. Ackerman, P. et. al. Efficacy of flibanserin in women with Hypoactive Sexual Desire Disorder: results from the BEGONIA trial. J Sex Med (in press). 11

Change from Baseline of FSFI DESIRE DOMAIN (FSFI d) Study 511.147 * ** ** ** *p = 0.0002; ** p < 0.0001 difference between placebo and flibanserin M. Katz, L. DeRogatis, R. Ackerman, P. et. al.

12 Change from Baseline of FSFI DESIRE DOMAIN (FSFI d) Study * ** ** ** *p = ; ** p < difference between placebo and flibanserin M. Katz, L. DeRogatis, R. Ackerman, P. et. al. Efficacy of flibanserin in women with Hypoactive Sexual Desire Disorder: results from the BEGONIA trial. J Sex Med (in press). Consistent Efficacy: 4 Different US Phase III Clinical Trials* Rate of First Onset of Most Common Side Effects in all trials % of subjects *Somnolence, fatigue, or sedation in phase III placebo controlled trials (%) Data on file Sprout Pharmaceuticals

13 Side Effect Profile Phase 3 clinical trial program, *60% of women studied mild to moderate drinkers. *This is in line with the general population *Alcohol consumption was not excluded from trials in women. *This study required participants to drink the alcoholic equivalent of a half to full bottle of wine within 10 minutes on a nearly empty stomach before taking the drug. *More men than women enrolled for the challenge trial with body weights and consumption capability that likely made them less likely to vomit than women 37 Flibanserin Interaction with Alcohol Cross-over study: 100 mg flibanserin + alcohol dosed in the morning 25 healthy subjects: Somnolence experienced: 67% ADDYI alone 74% ADDYI g/kg alcohol 92% ADDYI + 0.8g/kg alcohol Hypotension experienced: 17% ADDYI g/kg alcohol 25% ADDYI + 0.8g/kg alcohol 0.4g/kg alcohol 2 drinks 0.8g/kg alcohol 4 drinks * Very rough estimation, need to consider individual metabolism* Degree of additive CNS inihibition likely proportional to the amount of alcohol ingested. Caution that consumption of >3.5 drinks may increase risk of severe hypotension and syncope Unclear why the combination of flibanserin and alcohol would cause hypotension. Alcohol program underway to bring clarity to these associations: frequency/quantity/timing Cialis is an example of a drug where a similar study was conducted - the outcomes are much like flibanserin s. Their prescription labeling warns not to take Cialis if you have had 5 or more drinks 39 13

14 Flibanserin & Hypotension/Syncope (low blood pressure and fainting) FDA identified 6 cases of hypotension and/or syncope in the Flibanserin Phase 3 trials a combined incidence of 0.5%. The placebo incidence was 0.3%. Hypotension specifically was 0.2% Syncope specifically was 0.3% Bupropion, a drug commonly used off-label to treat HSDD today in the absence of an FDA approved treatment option, has a much higher incidence of both. Buproprion hypotension is 2.5%, or 12x the Flibanserin rate syncope is 1.2%, or 4x the Flibanserin rate 40 New Alcohol Study This post marketing study, required by the FDA, further assessed the risks associated with consuming varying concentrations of alcohol with flibanserin in premenopausal women Single-center, randomized, double-blind, single-dose, 7-treatment, 12-sequence, crossover study Eligible participants were healthy, non lactating, premenopausal women aged 18 to 45 years with a body mass index of 18 to 35 kg/m2 Random assignment to 1 of 12 sequence groups to receive each of 7 treatments: Flibanserin 100 mg with ethanol 0.6 g/kg, 0.4 g/kg, or 0.2 g/kg; placebo with each dose of ethanol; and Flibanserin 100 mg without alcohol 0.2 g/kg of 95% ethanol is equivalent in a 70-kg (~154-lb) person to one 12-oz can of beer containing 5% alcohol by volume, one 5-oz glass of wine containing 12% alcohol by volume, or one 1.5-oz shot of 80-proof spirit 41 After an overnight fast and a light snack, participants were given up to 10 minutes to ingest study medication and a liquid solution of orange juice with or without ethanol Adverse events of special interest included dizziness, orthostatic blood pressure, vertigo, hypotension, and syncope Syncope was defined as a temporary loss of consciousness caused by a decrease in blood pressure; the Medical Dictionary for Regulatory Activities (MedDRA) terminology used for syncope was faint, fainting, and fainted Orthostatic blood pressure was de ned as a decrease of 20 mm Hg in systolic blood pressure or a decrease of 10 mm Hg in diastolic blood pressure when a participant stood up from a lying-down position Subjective impression of drowsiness was measured using a 100-mm visual analog scale (VAS) with verbal anchors of alert and drowsy Breath ethanol test was performed on admission to the clinical unit and approximately 1 hour after the start of each treatment administration. 96 participants were enrolled and received at least 1 study treatment; 84 participants (87.5%) completed the study 42 14

15 Conclusions 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 The prescribing information for Flibanserin includes a boxed warning due to increased risk of severe hypotension and syncope with alcohol use based on a previous alcohol challenge study1; however, there was 1 instance of hypotension in this study (after administration of placebo g/kg ethanol) and no instance of syncope The 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 43 Driving and Cognition Study Objective Evaluate potential next-day residual effects of flibanserin the morning after bedtime dosing in healthy premenopausal women Design Randomized, double-blind, placebo-controlled, 4-way crossover study Primary endpoint: standard deviation of lateral position Driving/Cogni tive Assessments Driving/Cogni tive Assessments Day 1 Day 2 Day 7 Day 8 Day 15 Placebo Zop 7.5 mg Placebo qhs FLI 100 mg qhs FLI 100 mg qhs Zop 7.5 mg qhs FLI 200 mg qhs 15- day washo ut Zop=zopiclone. Standard Deviation of Lateral Position (SDLP) Driving and Cognition Study Furthest Left Lane Center Furthest Right Day 2 Day 8 Change in SDLP LS Mean (95% CI), cm Flibanserin 100 mg qhs Zopiclone 7.5 mg qhs Flibanserin 200 mg qhs Flibanserin 100 mg qhs Zopiclone 7.5 mg qhs Better Worse LS=least squares. 15

16 Summary of Results from the Dedicated Driving Study No evidence of worsening of driving performance with either acute or steady state administration of flibanserin 100 mg or acute administration of 200 mg No evidence of impaired cognitive performance REMS Program Certification and more information 47 Single Drugs Investigational Medications in the Pipeline Combination Drugs Bremelanotide Femprox Intranasal Testosterone Lybrido Lybridos Lorexys 16

Bupropion Treatment for HSDD Bupropion versus placebo Increased desire Frequency of sexual activity correlated with total testosterone, baseline and during treatment Depressed minority switched from

17 Bupropion Treatment for HSDD Bupropion versus placebo Increased desire Frequency of sexual activity correlated with total testosterone, baseline and during treatment Depressed minority switched from SSRI to Buproprion SR mg; CSFQ improved desire, arousal, orgasm Seagraves et al. J Clin Psychopharmacology 2004;24: Dobkin et al. J Clin Psychopharmacol 2006;26:21-6. Bremelanotide for Hypoactive Sexual Desire Disorder 50 Bremelanotide Profile Has been evaluated in 33 clinical studies (n = >3000) showing efficacy in both female sexual dysfunction and erectile dysfunction Phase 2B trial in premenopausal women with HSDD showed a statistically significant and clinically meaningful beneficial treatment effect Bremelanotide was well tolerated. Most frequent adverse events were nausea, flushing and headache Long term carcinogenicity and reproductive toxicity studies are completed and were negative No evidence of significant hepatic CYP interactions No food or alcohol interaction Currently completing additional safety studies to well define metabolic profile 17

Function Index Female Sexual Dysfunction Scale Currently completing the long term treatment safety extension studies NDA Submission completed Summary of Bremelanotide Phase 3 Data Pivotal phase 3

18 Bremelanotide Profile and Current Status Potential to be the first on demand subcutaneous treatment taken as needed for the treatment of HSDD Rapid onset of activity ~30 minutes Treatment effect for 8 10 hours Phase 3 Reconnect Studies completed in over 1,200 premenopausal women with HSDD, demonstrating highly significant, clinically meaningful benefit for both coprimary endpoints Female Sexual Function Index Female Sexual Dysfunction Scale Currently completing the long term treatment safety extension studies NDA Submission completed Summary of Bremelanotide Phase 3 Data Pivotal phase 3 Reconnect Studies consisted of 2 North American trials following FDA draft design guidance Top-line Phase 3 results released 4Q Co-primary efficacy endpoints met. Efficacy data supports bremelanotide increasing desire and decreasing distress, the two diagnostic pillars of HSDD Co-primary endpoints were validated patient reported outcome measures: Sexual Desire as measured by the Female Sexual Function Index: Desire Domain (FSFI-D) Study 301: Mean change of 0.54 vs. 0.24, median change of 0.60 vs. 0.00, p=0.0002; and, Study 302: Mean change of 0.63 vs. 0.21, median change of 0.60 vs. 0.00, p< Distress associated with low sexual desire as measured by the Female Sexual Distress Scale - (FSDS- DAO) Item 13 Study 301: Mean change of vs , median change of -1.0 vs. 0.0, p<0.0001; and, Study 302: Mean change of vs , median change of -1.0 vs. 0.0, p= Preliminary review of the overall safety population (1,247 patients) Safety profile of bremelanotide was consistent with prior clinical experience Bremelanotide appeared to be generally well tolerated Most frequent adverse events were nausea, flushing, headache the majority were mild in nature Intimate Wipes Oral Sex strips Semen Pills Butt Bleach Revirginizing Cream Bizarre Sex Products 18

Dangerous G Shot Enhancement Amplification Hyaluronic Acid Pulmonary Embolism: a consequence of an illegal cosmetic vaginal procedure Park et al.

Well-being Sexual Functioning Cognitions/ Beliefs Family Beliefs Society/ Culture Early Sexual Experiences Partner Relationship Subjective sexual experience 56 Treatment Paradigm

19 Dangerous G Shot Enhancement Amplification Hyaluronic Acid Pulmonary Embolism: a consequence of an illegal cosmetic vaginal procedure Park et al. 55 Factors Affecting Sexual Functioning Medical History Illness/ Medications of patient and partner Hormones Your sexual -Self-image -Behavior External Stressors Psychological Well-being Sexual Functioning Cognitions/ Beliefs Family Beliefs Society/ Culture Early Sexual Experiences Partner Relationship Subjective sexual experience 56 Treatment Paradigm Behavior Modification Alternative Medicine Structured Sexual Tasks Sexual Device Treat Systemic Illnesses Sexual Pharmacology Treatment Evaluate medications Consultations Psycho therapy Pain management Patient And Partner Education 57 19

20 Is Sex Medically Necessary? Enhances intimacy Longevity, chronic illness Decreases pain/increases oxytocin and endorphines pair bonding/cuddle hormone May increase overall happiness by decreasing stress Sex improves cardiovascular health and stamina Sexually active men had lowered rates of stroke Sex burns calories ( 85 calories per act) 42 sessions of 30 minutes each is 3570 calories or a pound Sex improves immunity Increased IgA antibodies Sex improves sexual self esteem Sex Reduces cancer risk Prostate cancer reduced with more than 21 ejaculations per month Sex strengthens pelvic floor Sex improves sleep Oxytocin release Follow me on Michael L Krychman MD mkrychman@icloud.com Reference HSDD (Hypoactive Sexual Desire Disorder). CogniMed Inc, 2016, Accessed

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