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Male : New Disclosures Options • Clarus Therapeutics, Besins Healthcare, Lipocine, Prolor (Research support) Christina Wang, MD • Lipocine, TesoRX (Temporary advisor ) Professor of Medicine David Geffen School of Medicine at UCLA Associate Director UCLA Clinical and Translational Science Institute Harbor-UCLA Medical Center and Los Angeles Biomedical Research Institute

Hormonal Methods of Male Hormonal Contraception Male Contraception:

• Currently available methods include condom (high user failure rate) and Androgens + vasectomy (considered irreversible) Progest ins Androgens +GnRH • A variety of methods Antagonist FSH inhibition- should be available to men to meet the inhibin, FSH needs of different cultural and ethnic immuniz at backgrounds • Focus on hormonal male contraception though a number of new leads (testicular and post-testicular) are being investigated

Older Steroidal Efficacy of Male Hormonal Contraception Molecules/Esters/Formulations for Male (adapted from Wang, Festin, Swerdloff 2016) Contraception Study Sperm # Enrolled/ # Reaching Pregnancy/ Conc. # completing Threshold Failure Rate • esters enanthate and Threshold suppression (Pearl Index) undecanoate million/ml WHO 1990 0 271/225 157 (70%) 0.8 (0.0-4.5) • Testosterone pellets WHO 1996 < 3 399/357 349 (98%) 1.4 (0.4-3.7) Progestin Turner 2003 <1 55/55 53 (94%) 0 (0-8) • Depo-Medroxyprogesterone injections Gu 2003 <1 308/308 299 (97%) 2.3 (0.5-4.2) Gu 2009 <1 1045/898 855 (95%) 1.1 (0.4-1.8) • Levonorgestrel Oral and Implants WHO/Conrad <1 320/283 274(96%) 2.2(0.8-5.8)

• Oral, Implants WHO - T enanthate 200 mg/week IM Gu - T undecanoate 1000mg loading , 500 mg/month IM Turner - T implants 800 mg/4-6 month + DMAP 300mg/3 month IM WHO/CONRAD - T undecanoate 1000mg +Net-EN 200mg/8 w eek s IM

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Efficacy of Male Hormonal Contraception Suppression and Recovery of (adapted from Wang, Festin, Swerdloff 2016) Spermatogenesis in Male Contraceptive • Male hormonal contraceptive efficacy Clinical Trials studies indicate that the method is as effective as many female hormonal • De-identified individual subject data provided by investigators of 30 studies published/submitted contraceptives with comparable failure for publication between 1990-2006 rates • 1756 healthy (by physical, blood and semen • Will hormonally suppressed exam) men aged 18-51 years of predominately spermatogenesis recover? Caucasian (two-thirds) or Asian (one-third) descent. This represents about 85% of all the published data.

Liu et al, 2006, 2008

Recovery to Different Sperm Thresholds New Steroidal (Kaplan-Meier Plots) Liu et al 2006 Molecules/Esters/Formulations for Male 100 Contraception Androgen 80 • MENT Acetate (7α-methyl-19-nortestosterone)

Proportion 60 • Dimethandrolone Undecanoate (7α, 11β-dimethyl- recovered 19-nortestosterone 17β undecanoate) (%) 40 • Oral nanomilled testosterone Median (95% CI) • New in SEDDS 3 M/mL 2.5 (2.4-2.7) 20 10 M/mL 3.0 (2.9-3.1) • 11 bet a-methyl-19-nortestoster one 20 M/mL 3.4 (3.2-3.5) Baseline 5.4 (5.1-5.8) 0 Progestin 2.5 5 10 15 20 Months to threshold • Nestorone n 3 M/mL 790 136 16 4 0 • Butanoate n 10 M/mL 1054 228 26 6 2 n 20 M/mL 1234 308 49 11 3 n Baseline 1400 600 104 17 3

7 α - Methyl - 19 - Nortestosterone (MENT) • MENT does not undergo 5 α reduction but is aromatized to 7 α - methyl • About 10 to 12 times more potent than T in suppression of gonadotropins and only 3-4 times more potent in stimulating prostate growth in castrated animals (rats, monkeys)

(Agarwal et al, 1988; Kumar et al, 1992; Sundaram, 1995)

Von Eckardst ein S et al JC EM 2003

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Nestorone and Testosterone Gels for Male Contraception NES+ T Gels Study Rationale NICHD, NIH: Contraceptive Clinical Trials Network Centers (Male area), Contraceptive Research Centers Program Director: Diana Blithe, PhD • Develop a provider independent, user friendly Medical Monitor: Al ici a Chri sty, MD male contraceptive Population Council : Investigators: Regine Sitruk-Ware, MD • Gels applied to skin deliver relatively stable Narender Kumar, PhD levels of both Testosterone (T) and Los Angeles Biomedical Research Institute at Harbor- Nestorone (NES) UCLA Investigators: Ronald S. Swerdloff, MD (Center Director) • NES has no estrogenic, androgenic or Christina Wang, MD (PI CCN 005, 005A, 007) glucocorticoid activity and very potent Peter Liu, MD, PhD • Pilot study with NES + T gels showed University of Washington Investigators: William J. Bremner, MD, PhD (Center significant and effective suppression of Director) gonadotropina John Amory, MD (PI CCN005/007) Stephanie Page, MD, PhD Mara Roth, MD (PI CCN005A)

Sperm Concentration (million/mL) In Efficacy NES + T Gels Study Design Eligible subjects (Median, 25 and 75 percentile) 3 groups: T gel 10 g/day + Nes 0 mg/day

T gel 10 g/day + Nes 8 mg/day Pre Treatment Recovery 256 T gel 10 g/day +Nes 12 mg/day 81 Nes/FSH/LH at 16 FSH/LH/Nes 24, 48, 72 h, 1 and 2 weeks + Nes 0mg 1 T+Nes 8mg T+Nes 12mg Treatment Concentration Sperm Lower Limit 0 12 12 6 2 1 Screen Recovery

24 wks (million/ml root transformed) 4th 0 8 16 24 32 40 48 56 4 wks 12 wks Semen analyses

FSH/LH/NES/T/ SHBG Ilani et al, JCEM 2012

Percent Men With Sperm Concentrations What are next steps? Suppressed to 0, ≤ 1, ≤ 3, > 3 million/ml T + Nes 0 mg Treatment Recovery • Nes gel very effective in suppressing 100

80 Azoospermic spermatogenesis together with T gel with <=1 million/ml 60 <=3 million/ml few adverse events >3 million/ml 40 % Subjects Subjects %

20 • Transdermal preparation may have less

0 0 4 8 12 16 20 24 28 32 36 40 adverse effects than other modalities of Week T + Nes 8 mg T + Nes 12 mg delivery of Treatment Recovery Treatment Recovery 100 100 • Combined T and NES gel showed 80 80

60 60 equivalent suppression of gonadotropins

40

40 Subjects % % Subjects Subjects % • Adherence issues with user friendly but 20 20

0 0 non-provider dependent methods 0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 Week Week Ilani et al, JCEM 2012

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Clinical Evaluation of Nestorone® (NES) NES+ T Gel Phase 2b study and Testosterone (T) Combination Gel for • Contraceptive Efficacy Study with combined Male Contraception (Phase 2b) testosterone and nestorone gel to start in 2017 Sc r eening • Nine centers in US, Europe (UK, Sweden, Italy), South America (Chile) and Africa Kenya) Suppr es s ion Effic ac y Recovery 4 16 wks 52 weeks 24 weeks • 4 months suppression phase and 12 months efficacy Parameters to be assessed at enrollment and then : • 350 couples to be enrolled, expecting a bout 210 Male: Weekly phone calls or text message couples completing this 18 months study Monthly visits for semen analyses, NES and other hormone levels • Primary end point pregnancy in partner Safety labs every 3 months PHQ9, Psychosexual questionnaire and IPSS every 3 months • Need accurate assessment of adherence to Male acceptability questionnaire every 6 months treatment Contraceptive use, sexual activity every month Female: Every 3 months, option to attend more frequently • Safety and tolerability (mood changes) Monthly calls in between visits • Acceptability in male and female partners Bleeding and coital diary Female acceptability questionnaire every 3 months Pregnancy test at screening, entering suppression and efficacy,

Dimethandrolone Dimethandrolone Undecanoate 11 • 7 alpha, 11beta-dimethyl-19- Preclinical Studies (rats11 and nortestosterone (Dimethandrolone, DMA) rabbits), DMAU • Suppresses serum LH 11 • Has androgenic and 7 7 alpha methyl progestational activity DMA 11 11 beta methyl • Suppresses sperm counts and induced infertility at 7 2.5 mg/Kg in rabbits 19-nor-tes tos ter one • DMA has enhanced (Attardi et al, 2006, 2010) binding (Cook et al, 2005) Preclinical toxicology studies in rats and • Not aromatized and 5 alpha reduction not monkeys showed androgenic effects and no necessary for its activity (Attardi et al, 2008) toxicity

Phase 1 Clinical Study of DMAU in Tolerability and Safety of DMAU Men Primary Endpoint • No serious adverse events (AE) • Safety and tolerability of DMAU • Acne in 2 participants possibly related to Secondary Endpoint DMAU, other AEs not related to study • Pharmacokinetics of DMA and DMAU medications • Effect of food on the highest tolerable • No clinically significant changes in blood does of DMAU (single dose study) counts, clinical chemistry and EKGs • Suppression of serum LH, FSH and including QCT interval testosterone (28 day repeat dose study) Sur ampudi et al Andr ology 2014

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Serum DMAU and DMA after oral Serum LH, FSH and T Levels after dosing of DMAU ) Single Oral DMAU dosing 200mg 400mg 800mg 1000

6 200mg 400mg 800mg Placebo 100 5

4 10 3

LH(IU/l) 2 1 Fasting 1 Fasting DMAU(ng/ml) With Food With Food 0.1 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time(h) Time(h) 100 5 200mg 400mg 800mg 200mg 400mg 800mg Placebo 4

10 3

2 FSH(IU/l) Fasting 1 1 With Food

0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 DMA(ng/ml) Fasting With Food Time(h) 0.1 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time(h) Sur ampudi et al Andr ology 2014

Serum T and Calculated Free T after Oral DMAU Dosing) Next Steps for DMAU 25 200mg 400mg 800mg Placebo 20 • 28 days repeat dose study for safety and 15

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T(nmol/l) tolerability, pharmacokinetics and

5 Fasting suppression of gonadotropins ongoing With Food 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time(h) • Single IM of DMAU dose escalating study in castor oil with benzyl

0.6 200mg 400mg 800mg Placebo benzoate will begin in June 2016 0.5 0.4 • Complete longer term primate toxicology 0.3 and efficacy studies ongoing 0.2

0.1 Fasting With Food • Determine dose for 6 months oral oo 0.0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Calculated FreeT(nmol/l) Calculated Time(h) longer IM study

Hormonal Male Contraception

• Support from US National Institutes of Health, NICHD for male contraceptive development from pre-clinical to phase 3 clinical trials • Collaboration with academia, industry, professional societies and advocacy groups • Product available within 10 years

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