Overview of the Endocrine Society Guidelines for the Treatment of Hypogonadism. Edward D. Kim, M.D. Professor of Surgery/Urology

Transcription

1 Overview of the Endocrine Society Guidelines for the Treatment of Hypogonadism Edward D. Kim, M.D. Professor of Surgery/Urology

2 Objectives Primary focus on treatment options Overview of criteria for treatment of hypogonadal men Detrimental effect of testosterone therapies on sperm production

3 Testosterone: Adult Physiological Effects

4 How Is Hypogonadism Defined by Endocrine Society? A clinical syndrome that results from failure of the testis to produce physiological levels of testosterone (androgen deficiency) and the normal number of spermatozoa caused by the disruption of one or more levels of the hypothalamic-pituitary testicular (HPT) axis. Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab. 2010;96(6):

5 DIAGNOSIS Clinical hypogonadism is defined as symptoms + low testosterone (<300 ng/dl) Main symptoms and signs: low sexual desire, ED, ejaculatory dysfunction, low energy, low mood, decreased mental concentration, high fat mass/low muscle mass, decreased muscle strength, osteoporosis, anemia, and others Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab. 2010;96(6):

6 TESTOSTERONE SALES ARE INCREASING

7 We recommend testosterone therapy for men with symptomatic androgen deficiency to induce and maintain secondary sex characteristics and to improve their sexual function, sense of well-being muscle mass and strength, and bone mineral density.

8 Endocrine Society Recommendations-1 We suggest initiating testosterone therapy with any of the following regimens, chosen on the basis of the patient s preference, consideration of pharmacokinetics, treatment burden, and cost mg of testosterone enanthate or cypionate administered IM weekly, or mg administered every 2 weeks. One or two 5-mg nongenital, testosterone patches applied nightly over the skin of the back, thigh, or upper arm, away from pressure areas.

9 Endocrine Society Recommendations-2 30 mg of a bioadhesive buccal testosterone table applied to buccal mucosa every 12 hours. Testosterone pellets implanted SQ at intervals of 3 to 6 months; the dose and regimen vary with the formulation used. Oral testosterone undecanoate, injectable testosterone undecanoate, testosterone-inadhesive matrix patch, and testosterone pellets where available.

10 Intramuscular Injections Pros History (available for 50 years) Self administration Pain Cons Frequency of injections (every 1 2 weeks) Inexpensive Flexibility of dosing Dandona P, Rosenberg M. Int J Clin Pract. 2010;64(6): Symptomatic peaks and troughs resulting in variations in breast tenderness, libido, emotional stability, energy Erythrocytosis

11 Transdermal Patches Pros Nonscrotal patches Cons Skin irritation Nighttime application results in good approximation of normal circadian plasma testosterone levels Flexibility of dosing Need for daily, continuous application Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6):

12 Transdermal Gels Pros Application sites (upper arms, shoulder, axilla) Cons Transfer to others (risk is minimized with high-dose, lowvolume preparations) Low skin irritation Invisibility of application Flexibility of dosing Cost Daily application Skin residue Various concentrations Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6):

13 PHARMACOKINETIC PROFILES Injectable administration results in considerable fluctuation in testosterone levels.

14 Buccal Tablets: Striant Pros Application site Relative invisibility Bypass first-pass hepatic metabolism Cons Application site Inadvertent loss of tablet Gum and buccal irritation, alteration in taste Slow release Twice daily dosing No dose titration Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6),

15 Subcutaneous Pellets Pros History (started in 1940s) Relative invisibility Long acting Slow release Cons Painful application Surgical procedure unlikely to be used by the PCP Long acting Inconvenient removal Procedure can result in infection, fibrosis or pellet extrusion Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6), Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab. 2010, 96(6):

16 Oral Testosterone Not approved in U.S. Methytestosterone Methitest, Android, and Testred Poor absorption High risk of hepatic toxicity, hepatoma and cholestatic jaundice Risk of anaphylaxis Edelstein D, et al. Expert Opin Emerg Drugs. 2006;11:

17 TESTOSTERONE PRESCRIBING INFORMATION Potential for adverse effects on spermatogenesis Exogenous administration of androgens may lead to azoospermia These warnings are not based on clinical trials Topical gel prescribing information

18 Why Testosterone Therapy Is Detrimental To Sperm Production Leydig cells produce testosterone Exogenous T decreases intratesticular testosterone (ITT) concentrations Profound decreases in spermatogenesis, including azoospermia, may result

19 Higher Centers Hypothalamus GnRH Germinal Epithelium Inhibin - Anterior Pituitary - Testosterone FSH LH Sertoli Cells Leydig Cell

20 WHO CONTRACEPTIVE EFFICACY 271 men 12 months efficacy phase IM-TE 200 mg/wk Time to azoospermia: Estimated time to recovery: To >20 million sperm/ml To baseline 120 days 3.7 months 6.7 months Lancet. 1990;336(8721):955-9.

21 DISCONTINUATION OF IM- TESTOSTERONE CAN RESTORE SPERM PRODUCTION 93% developed azoospermia Median time of 108 days Method failure rate of 6.1% Median time to recovery was 3.5 months >99% of men had spermatogenesis return to normal fertile range by 15 months after T discontinuation

22 Exogenous T supplementation decreases sperm production. Studies of hormonal contraception indicate that most men have a return of normal sperm production within 1 year after discontinuation. SERMs are a safe and effective therapy for men who desire to maintain future fertility. Fertil Steril 2013; 99:

23 Androxal Improves T without Affecting Sperm Count p< No statistical difference

24 Androxal Exhibits No Negative Effects on Important Sperm Parameters No statistical difference

25 ZA-203: Effect of Treatment on Median Sperm Concentration versus Testim 100 p= Sperm count in millions/ml p= p= Baseline EOS

26 Symptoms and Signs Suggestive of Hypogonadism-Summary No symptoms are unique to hypogonadism Screening with testosterone level is appropriate when presented with symptoms Diagnosis of hypogonadism is made when one or more symptoms are combined with low testosterone concentration Dandona P, Rosenberg M.. Int J Clin Pract. 2010;64(6):

27 Treatment Options-Summary Current choices: Injections, topicals, buccal and pellets No effective oral therapies in U.S. Testosterone replacement has negative effects on sperm production Androxal does not have adverse effects on sperm

28 PROGRESSION OF TESTOSTERONE THERAPIES

29 What does Enclomiphene mean to me? Andrew R. McCullough, MD Professor of Surgery/Division of Urology Director of Men s Health Albany Medical College, Albany, New York

30

31 Overweight and Obesity among U.S. Adults Obesity Overweight Prevalence (%) Overweight/Obese= Million Age overweight =23.6 obese= NHANES Data Collection Period Flegal KM et al. JAMA 2002;288: Hedley AA et al. JAMA 2004;291: Ogden CL et al. JAMA 2006;295:

32

33 Are we Over Diagnosing low T? Are we Over Diagnosing Obesity? Are we Over Diagnosing Diabetes? Are we Over Diagnosing Aging?

34 Hypogonadism: Treatment Topical: patch or gel. Daily Injected: I.M. testosterone q 1-2 weeks Implant: testosterone pellets q 4-6 months

35 Current Treatments Gels and Patches Compliance: Daily application required!!! 1 year refill rate is less than 20% Expense: Variable Co-pays and shifting playing field for re-imbursement Hassle of controlled substance script (in NY): Monthly hard copy prescription needed Transference: Partners and young children Skin Reaction: Suppresses endogenous production: Causes testicular atrophy Infertility

36 Current Treatments Injections Bimonthly IM Injections Erratic Levels Increased Hematocrit Hassle of controlled substance script in NY Suppresses endogenous production Results in Infertility Generic (less expensive) No transference

37 Current Treatments Pellets Surgical Procedure Risk of Infection, Extrusion, Pain Prior Auth Hassle Suppresses endogenous production Results in Infertility Burden of expense is on Physician Better Compliance Sustained levels

38 Change in Paradigm is Needed Do we treat all diabetics with Insulin? Why are we ignoring the testes? Currently we can use clomiphene off label with great efficacy in normalizing T The PCP WILL NOT prescribe off label treatments WE NEED an FDA approved SERM!!!!!!!!!!!!! Free T (pg/ml) RespPart Non- Resp Resp Base 4moRx

39 Summary We are not over diagnosing low T! T will not correct Obesity, Type 2 Diabetes or Aging. Stimulating endogenous production makes sense The time for a paradigm shift in the treatment of low T is now.

40 SHARED CARE: THE INTERFACE BETWEEN THE PATIENT, PRIMARY CARE PHYSICIAN AND SPECIALIST DR JOHN DEAN

41 PRIMARY CARE PRIMARY HEALTH CARE PROVIDES THE FIRST POINT OF CONTACT IN THE HEALTHCARE SYSTEM; THE EXEMPLAR PRIMARY CARE PROVIDER IS THE FAMILY PHYSICIAN THE AIM OF PRIMARY CARE IS TO PROVIDE AN EASILY ACCESSIBLE ROUTE TO CARE, WHATEVER THE PATIENT S PROBLEM. PRIMARY HEALTH CARE IS BASED ON CARING FOR PEOPLE RATHER THAN SPECIFIC DISEASES FAMILY PHYSICIANS ARE GENERALISTS, DEALING WITH A BROAD RANGE OF PHYSICAL, PSYCHOLOGICAL AND SOCIAL PROBLEMS, NOT A SINGLE DISEASE AREA

42 MANAGING THE INTERFACE THE FAMILY PHYSICIAN ACTS AS THE PATIENT S ADVOCATE WITHIN THE HEALTHCARE SYSTEM AND WITH SPECIALISTS FAMILY PHYSICIANS MANAGE THE INTERFACE BETWEEN PRIMARY AND SPECIALIST CARE THEY CO-ORDINATE THE CARE OF THE MANY PEOPLE WHO HAVE MULTIPLE HEALTH PROBLEMS THEY OFTEN CARE FOR PEOPLE OVER EXTENDED PERIODS OF TIME, THE RELATIONSHIP BETWEEN PATIENT AND DOCTOR IS PARTICULARLY IMPORTANT THEY MANAGE MANY COMPLEX, MULTI-SYSTEM, LONG-TERM HEALTH PROBLEMS, AND ALSO PREVENT FUTURE PROBLEMS THROUGH ADVICE, IMMUNISATION AND SCREENING PROGRAMMES

43 AN ALWAYS-MOVING INTERFACE OVER RECENT DECADES, MANY HEALTH PROBLEMS PREVIOUSLY CONSIDERED AS SPECIALIST PROBLEMS ARE SAFELY AND SUCCESSFULLY MANAGED IN PRIMARY CARE, WITH BENEFIT TO PATIENTS, THROUGH ACCESSIBILITY, AND TO THE HEALTHCARE SYSTEM, THROUGH COST SAVING SOME EXAMPLES INCLUDE: PEPTIC ULCER DISEASE ASTHMA DIABETES ERECTILE DYSFUNCTION HYPOGONADISM IS CURRENTLY CROSSING THE GENERALIST/SPECIALIST INTERFACE

44 WHAT ARE THE CHARACTERISTICS OF A HEALTH PROBLEM SUITABLE FOR PRIMARY CARE MANAGEMENT? A WELL-DEFINED AND RELATIVELY PREDICTABLE NATURAL HISTORY DOES NOT USUALLY REQUIRE EXPENSIVE, DIFFICULT-TO-ACCESS, HIGH-RISK OR HIGHLY-INVASIVE DIAGNOSTIC TESTING HAS A CLEARLY-DEFINED MANAGEMENT PROTOCOL DOES NOT REQUIRE HIGHLY-SPECIALISED SKILLS (E.G. SURGICAL SKILLS) FOR MANAGEMENT HAS READILY-AVAILABLE, APPROVED, LOW-RISK, AFFORDABLE TREATMENT OPTIONS CHRONIC CONDITIONS ARE PARTICULARLY WELL-SUITED TO PRIMARY CARE MANAGEMENT

45 HYPOGONADISM: A MULTI- SYSTEM DISORDER, AFFECTING MIND AND BODY Target Organ Clinical Features Bone Musculature Adipose tissue Blood Vascular system Brain Sexual organs Bone mineral density Muscle mass/strength Abdominal fat Haemoglobin Dyslipidaemia Mood changes, impaired cognition Libido, erectile dysfunction, subfertility Patient/Social Consequences Clinical Consequences 45 Quality of life Disability Productivity Dependency on carers Impact on relationships Osteopenia, osteoporosis, fracture risk Muscle atrophy, accidents, physical activity Metabolic abnormalities, endothelial dysfunction, increased cardiovascular risk Sexual activity, erectile and ejaculatory dysfunction Orgasm quality Spermatogenesis, semen volume, Depression, visual-spatial ability, memory

46 Vermeulen, JCEM, 1999 WELL-ESTABLISHED NORMAL VALUES TOTAL TESTOSTERONE: <230 NG/DL (< 8 NAMOL/L) = OVERT HYPOGONADISM NG/DL (8-12 NMOL/L) = EQUIVOCAL, «GREY» ZONE > 346 NG/DL (> 12 NMOL/L) = EUGONADISM TOTAL TESTOSTERONE 8 nmol/l 230 ng/dl 12 nmol/l 350 ng/dl

47 AGE-RELATED CHANGES IN TESTOSTERONE IN MEN FT (ng/dl) x T (ng/dl) SHBG (nmol/dl) Age (years) Comhaire FH Eur Urol 2000, 38:

48 HIDDEN HYPOGONADISM IN PRIMARY CARE TYPE 2 DIABETES HISTORY OF PITUITARY PATHOLOGY/SELLAR IRRADIATION OR SURGERY OBESITY/METABOLIC SYNDROME COPD CHRONIC RENAL DISEASE HIV DISEASE DEPRESSION UNEXPLAINED FATIGUE THE HEART-SINK PATIENT ( OH, NO! NOT HIM AGAIN ) 48

49 HYPOGONADISM TREATMENT AIMS THERAPY SHOULD AIM TO RAISE SERUM TESTOSTERONE LEVELS INTO THE MID-NORMAL RANGE WE RECOMMEND TESTOSTERONE THERAPY FOR SYMPTOMATIC MEN AIMED AT INDUCING AND MAINTAINING THEIR SECONDARY SEX CHARACTERISTICS IMPROVING SEXUAL FUNCTION IMPROVING THEIR SENSE OF WELLBEING IMPROVING THEIR BONE MINERAL DENSITY Bhasin S (2006). J Clin Endocrinology & Metabolism, Vol. 91, issue 6, pages

50 IMPACT ON THE MAN How did I end up like this? Insidious onset, typically from middle age Increased risk of lifechanging health problems Impairment of work and home life Financial consequences What can I do about it Concern over self-efficacy - resistant to modification by lifestyle change Concern over self-image Life in years, not just years on life Confusion over convenience and safety of treatment

51 Androxal: Effects on Fertility A Clinical Perspective Larry I. Lipshultz, M.D. Professor of Urology Chief, Division of Male Reproductive Medicine and Surgery Baylor College of Medicine Houston, Texas

52 Case Study A 42 year old man with a 30 year old wife is referred by his PCP after symptomatic failure on anti-depressants He is complaining of mild depression, increased fatigue, impaired libido, and progressive erectile dysfunction His laboratory evaluation reveals: Testosterone: 175 ng/dl (normal ) FSH: 4 miu/ml (normal 4-10) LH: 6 miu/ml (normal 4-12) 2*

53 Can we safely and effectively treat This man demonstrates adult-onset idiopathic this man s secondary low testosterone? hypogonadism How will treatment impact his When told of his hormone deficiency, he requests ability to testosterone establish therapy! a pregnancy? 2*

54 Testosterone Replacement Therapy Treatment Options Oral Tablets Intramuscular Injections Transdermal Patches Transdermal Gels Pellet Implants 5*

55 Transdermal Gels are the Most Commonly Prescribed Form of TRT Gels Injectables 17% Patches 10% Other 70% 3% IMS NPA; *

56 T Gel Therapy 2013 WARNING: SECONDARY EXPOSURE TO TESTOSTERONE (TRANSFERRENCE) Virilization has been reported in children who were secondarily exposed to testosterone gel. Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel. Healthcare providers should advise patients to strictly adhere to recommended instructions for use. Fortesta, Testim, Androgel, Axiron Package Insert, *

57 Testosterone Levels after Replacement Therapy with Patch, Gel or Injection T Testosterone ng/dl Patch or Gel Normal range 1400 Injection Day Adapted from Bhasin and Bremner. J Clin Endocrinol Metab. 1997;82:3-8 Testosterone gel (AndroGel 1%) Unimed Pharmaceuticals and Solvay Pharmaceuticals, *

58 Higher Centers Hypothalamus GnRH Germinal Epithelium Inhibin - Anterior Pituitary - Testosterone FSH LH Sertoli Cells Leydig Cell 4*

59 Higher Centers Hypothalamus GnRH Germinal Epithelium Inhibin - Anterior Pituitary - Testosterone FSH LH Sertoli Cells Leydig Cell 4*

60 The Ideal Testosterone Therapy Effective in correcting signs and symptoms of androgen deficiency Convenient and acceptable route of administration A pill would be best Predictable pharmacokinetics Safe Would not interfere with sperm production 3*

61 SERMs Selective Estrogen Receptor Modulators (SERMs) are a class of compounds that act on the estrogen receptor A characteristic that distinguishes SERMS from pure receptor agonists and antagonists is that their action is different in various tissues In the brain they act as antagonists 2*

62 Higher Centers SERMs: Clomiphene Hypothalamus GnRH Estrogen Germinal Epithelium Inhibin - Anterior Pituitary - Testosterone FSH LH Sertoli Cells Leydig Cell 2*

63 Androxal (enclomid) Background Clomiphene Citrate (Clomid TM ) is considered a selective estrogen receptor modulator (SERM) First used clinically in early 60 s to enhance ovulation Used off label for secondary hypogonadism and male infertility Mixture of 2 geometric isomers Trans-isomer (Enclomiphene) Androxal Zu-isomer (Zuclomiphene): longer acting Both isomers modulate estrogen receptor increased production of LH and FSH increased testosterone 2*

64 Effects of Clomid and its Isomers on T Pre-clinical Studies in Baboons 1 Testosterone (ng/dl) Last Day of Dosing Enclomid (Androxal) Clomid Zuclomid Days 1. Int. Congress Endocr. Abstract # 1212, Lisbon, 2004

65 Clomid Pharmacokinetics 24 hour Comparison of Isomers ng/dl Zu-clomid En-clomid hours Zu isomer still detected after 300 hours ~2.75 ng/ml after single dose Mikkelson et al. Fertility and Sterility Vol. 46, No. 3, September 1986

66 ZA-201 Protocol Summary Proof of Concept Study Androxal vs Topical T in previous topical T users A randomized, open-label, fixed dose, active-control, phase IIB study to evaluate fertility in men previously treated with topical testosterone (Testim ) for at least 6 months All men had secondary hypogonadism After stopping treatment with topical gels, Androxal was compared to Testim at 3 and 6 months Visit 2 was start of comparison Last visit was 1 month after treatment discontinued 5*

67 Only Androxal Restores both T and Sperm Counts Testosterone (ng/dl) Total Testosterone Testim Androxal V1 V2 V4 V5 V6 Sperm (million/ml) Sperm Concentration Testim Androxal 0 V2 V4 V5 V6 1*

68 Only Androxal Raises LH and FSH Luteinizing Hormone 10 LH (miu/ml) Testim Androxal V1 V2 V4 V5 V6 FSH (miu/ml) Follicle Stimulating Hormone Testim Androxal 0 V1 V2 V4 V5 V6 1*

69 Androxal Clinical Trial ZA-203 Multicenter, double-blind, placebo-controlled, multi-dose study of hypogonadal males on Androxal (N=120) Primary endpoint Changes in baseline T level in men on Androxal 12.5 mg and 25 mg on Day 90 compared to placebo and Testim Secondary endpoints Changes in FSH and LH levels in men on Androxal 12.5 mg and 25 mg on Day 90 compared to placebo and Testim Ophthalmic safety as assessed by visual acuity changes and slit lamp examinations Reproductive safety as assessed by changes in semen quality at month 3 comparing Androxal 12.5 and 25 mg to placebo and Testim 2*

70 ZA-203 Patient Disposition 920 Screened 124 Entered Study 74 (60%) Completed Study Double-blind Randomized Placebo-controlled Open-label for TRT 50 (40%) patients discontinued: 3 due to AEs 7 early termination 17 non-compliance 2 exclusion criteria 10 withdrew 11 lost to follow up

71 ZA-203 Clinical Findings TT (ng/dl) Effect of Treatment on Median Serum TT Comparison to Placebo P < mg 25 mg PL Testim Treatment Before After P = *

72 ZA-203 Clinical Findings Effect of Treatment on Median LH Comparison to Testim P < Before After LH P = mg 25 mg PL Testim Treatment 2*

73 FSH ZA-203 Clinical Findings Effect of Treatment on Median FSH Comparison to Testim P < mg 25 mg PL Testim Treatment P = Before After 2*

74 ZA-203 Clinical Findings Sperm (Millions/ml) Effect of Treatment on Median Sperm Concentration Comparison to Testim P = P = P = mg 25 mg PL Testim Treatment Baseline EOS 2*

75 ZA-203 Clinical Findings Effects on Semen Parameters Average of all assessments after dosing has stopped (2 or more analyses) Sperm Concentration (Millions/ml) Mean Median Placebo 12.5 mg 25 mg Testim

76 ZA-203 Effects on Semen Parameters Average of all assessments after dosing has stopped (2 or more analyses) Motility % Motile Sperm Placebo 12.5 mg 25 mg Testim 10 0 Mean Median

77 ZA-301 Protocol Summary Three parallel arms Placebo, 12.5 mg, 25 mg Androxal Three and Six month dosing duration Assessing morning T, semen quality, LH and FSH between groups at end of dosing Up to two additional semen assessments after dosing is completed Randomized 152 men; Treated 149 men 1*

78 Androxal Improves T without Affecting Sperm 83 % in Normal Range 79% in Normal Range ITT Placebo Androxal Total T (ng/dl) Baseline End of Study Sperm Concentration X Androxal Up titration NSD 0 Androxal Placebo P < Baseline End of Study 3*

79 Androxal Exhibits No Negative Effects on Important Sperm Parameters % Motile Placebo Androxal Androxal Up titration % Normal Morphology Sperm 50 Motility NSD Placebo Androxal Androxal Up titration Sperm Morphology NSD 0 Baseline End of Study 0 Baseline End of Study 1*

80 Overall Observations ZA-201 restores T and sperm counts in former topical T users ZA-203 maintains T and sperm counts in naïve men ZA-301 meets the FDA requirements for T and sperm counts In all: Marked increase in T Marked increase in LH and FSH Maintains normal sperm count, motility, morphology Few adverse effects 3*

81 Thank You Texas Medical Center, Houston

82 ZA-203 Conclusions: Androxal Represents a potential oral option for treatment of hypogonadism Significantly raised total testosterone equivalent to FDA approved topical gel Its ability to maintain semen quality and raise T will be attractive to many patients Androxal will be a potential FDA approved option to the widespread off-label use of Clomid 3*

83 Androxal (enclomid) Background The trans-isomer (Enclomiphene) has been purified and patented as Androxal Only therapy in development that restores testicular function Therapy addresses majority of men with low T Avoids the longer half-life and unwanted estrogenic activity of Zuclomiphene 1*

84 ANDROXAL Safety Review 6 June 2013

85 Potential Safety Issues Clomiphene Cataracts Increased estrogen (opposes testosterone increase) Hypogonadism - osteopenia Testosterone Deep Vein Thrombosis (DVTs) Prostate Specific Antigen (PSA) Elevation T level above normal Decreased sperm count (infertility) Gynecomastia

86 ANDROXAL Safety Review 6 June 2013 Treatment Emergent Adverse Events (TEAEs) Discontinuation due to Adverse Events (DCAEs) Serious Adverse Events(SAEs) Testosterone Prostate Specific Antigen (PSA) Other Safety Issues Related to Testosterone Therapy

87 ANDROXAL Safety Review TOPICS Treatment Emergent Adverse Events (TEAEs) Discontinuation due to Adverse Events (DCAEs) Serious Adverse Events(SAEs) STUDIES 003: Phase 3 301: Phase 3 300: long-term safety 303: bone density Testosterone Prostate Specific Antigen 300: long-term safety

88 Data for 300 and 303 is interim and not fully monitored and validated TREATMENT EMERGENT ADVERSE EVENTS Studies 301, 300, and 303 Preferred Term 12.5 mg (%) Study 301 Study 300 Study mg (%) PBO (%) 12.5 mg (%) 25 mg (%) 12.5 mg (%) 25 mg (%) PBO (%) N Any Event Upper respiratory infection Headache Muscle twitch Diarrhea < Dyspepsia Influenza Lethargy < Pollakiuria Sinus congestion < Any event occurri ng in 2 or more subjects in pivotal Study 301.

89 Data for 300 and 303 are interim and not fully monitored and validated DC/AEs: Studies 301, 300, 303 (green font indicates single subject) 12.5 mg Study 301 Study 300 Study 303 Study mg PBO 12.5 mg 25 mg 12.5 mg 25 mg PBO 12.5 mg 25 mg Androgel PBO N = Any DCAE (n = ) PREFERRE D TERM Ocular Nause Abdomina Hot flush discomfo a l pain rt Erectile dysfuncti on Blood luteinising hormone increased Hemoglob in Increase Hot flash Hematocrit Increased Edema due to cardiac disease Upper respirator y tract infection Breast enlargeme nt Prostatic specific antigen increased Hypertensi on Hemoglobin Increased Hypertensi on Fatigue Abnormal weight gain Change in sustained attention Erectile dysfunctio n Testicular atrophy Muscle spasms Renal function Cellulitis tests elevated Hemoglobin Increase Hemoglobin Increase Diplopia Vision blurred Allergic Dermatitis

90 Serious Adverse Events Reported in Studies 301, 300, and 303 (green font indicates single subject) 12.5 mg Study 301 Study 300 Study mg PBO 12.5 mg 25 mg 12.5 mg 25 mg PBO n Any SAE (number of subjects) Preferred Terms Atrial Bradycardia flutter Knee arthroplasty Cholelithia sis Hypotension Diverticuliti s (2) deep vein Kidney thrombosis * infection Skin injury Nephrolithi asis * DVT - Tightness in leg after 5 hour flight, treated with anticoagulants Data for 300 and 303 is interim and not fully monitored and validated

91 TESTOSTERONE Study 300 at 6-month point No excursions beyond normal range at 6-months Plasma Testosterone concentration TESTOSTERONE LEVELS ON LAST DAY OF DOSING (Study 300) 86% in NORMAL RANGE ( ) 0

92 PSA: baseline, end of treatment, follow-up Study 300 (only subjects with data after Vis 5) PSA (ng/ml) BASELINE VIS 3, 4, 5, ET VIS 6,7,ET

93 PSA PSA elevation is NOT an Adverse Drug Reaction PSA elevation is an expected result of testosterone increase PSA is not a cancer marker but a normal enzyme Elevated PSA included in package insert for Axiron Incidence and magnitude noted in Androxal studies is not alarming and has been reviewed by a panel of experts

94 OTHER SAFETY ISSUES RELATED TO TESTOSTERONE THERAPY Cataracts Osteoporosis Deep Vein Thrombosis

95 Safety Profile - Cataracts 1) 2) After 4 months, nuclear cataract in left eye disappeared, cortical cataract in right eye progressed Described as age-related progression of senile cataract Described as having cataract after 5 months of therapy, but all entries are 0, same as baseline.

96 Safety Profile - DVT Deep Vein Thrombosis One subject taking 12.5 mg Androxal developed a DVT after a 5 hour flight Treated with anticoagulants to resolution No other adverse events suggest incidence of DVT or other thrombotic events

97 Safety Profile Bone Health Hypogonadism is associated with osteopenia Study ZA-303 captures bone mineral density assessments via DEXA for subjects over one year of Androxal exposure Some subjects have completed DEXA analyses after 6 months of treatment Early data suggests that Androxal subjects are no worse than placebo subjects in study at 6 months Subjects bone loss associated with low testosterone may be reversed Relevant events reported in Phase 3 3 foot fractures, 12.5 mg Androxal 1/443 (0.2%), 25 mg Androxal 2/331 (0.6%) 1 spinal column injury, 12.5 mg Androxal 1 compression fracture, 12.5 mg Androxal

98 CONCLUSIONS Androxal is well tolerated Findings are consistent with known pharmacology No new safety issues

99 Clinical and Regulatory Team J.F. Wernicke, Ph.D., M.D., Chief Medical Officer 30 years in clinical research Ph.D. Biochemistry and MD Neurologist Eli Lilly and Company, Clinical Research and Patient Safety Jaye Thompson, Ph.D., Senior VP Clinical and Regulatory Ph.D. Biostatistics 25 years in clinical trials Founder and President of full-service Contract Research Organization Jennifer Wike, Director of Regulatory Affairs and Clinical Quality Assurance 30 years in research and clinical development 15 years with a full-service Contract Research Organization

100 Clinical and Regulatory Team Jennifer Nydell, Androxal Clinical Program Director 17 years clinical research and development 13 years Boehringer Ingelheim Michele Rosner, Clinical Program Director MS Biological Chemistry and Management 16 years clinical development 13 years with Pfizer

101 Androxal Study Status

102 NDA Preparations Building team Contracting consultants and acquiring some additional staff Evaluating and purchasing software and hardware for electronic NDA filing Conducting audits of key clinical sites and vendors No findings to date jeopardize data Completed audit of central laboratory with excellent results Preparing sites for NDA site audits Weekly team meetings Begun publishing files for the NDA

103 NDA Timeline

104 Potential benefits of testosterone supplementation Dr John Dean

105 The Massachusetts Male Aging Study 3,518 men were followed for 17 years Total Testosterone levels were measured and divided into five categories at 200 ng/dl increments Multivariate Analysis depicting the association with overall mortality, CVD, and Prostate Cancer specific mortalities was conducted Araujo AB, et al: Total Testosterone as a Predictor of Mortality in Men. The Endocrine Society 2005 Annual Meeting, San Diego, CA, June 4-7.

106 Low T associated with increased probability of all-cause mortality, cancer and CVD death Findings from follow up of 17 years: Age-adjusted Hazard Ratio for men with total T< 200 ng/dl vs. total T ng/dl 1.93 or two fold for all-cause mortality 3.30 or three fold for cancer death 1.93 or two fold for CVD death * Hazard Ratio Araujo AB, et al: Total Testosterone as a Predictor of Mortality in Men. The Endocrine Society 2005 Annual Meeting, San Diego, CA, June 4-7.

107 Type 2 diabetic men with hypogonadism % Hypogonadal Age Range Dhindsa S, et al. J Clin Endocrinol Metab. 2004;89:5465

108 Hypogonadism and Metabolic Syndrome The HIM Study 2165 men >45 in 95 US practices attending for routine appointments with primary care physicians (87% acceptance rate) Bloods taken between 8am and Noon for TT (by RIA), FT (Equilibrium Dialysis), BAT and SHBG Co-morbid conditions, weight, BMI, BP recorded Hypogonadism defined as <10.4nmol/l Prevalence 38.7% by TT, 40% by FT and 45% by BAT Mulligan et al IJCP 2006

109 HIM study: odds ratios for association of hypogonadism with co-morbid conditions Prevalence % Range Odds Ratio Obesity 52.4 ( ) 2.38 Diabetes 50 ( ) 2.09 Hypertension 42.4 ( ) 1.84 Hyperlipidaemia 40.4 ( ) 1.47 Osteoporosis 44.4 ( ) 1.41 BPH 41.3 ( ) 1.29 Mulligan et al IJCP 2006

110 The Metabolic Syndrome People with metabolic syndrome have: waist circumference of 40 inches or more (men) and 35 inches or more (women) dyslipidaemia high blood pressure (>140/90mmHg) insulin resistance and/or diabetes increased risk of developing blood clots tendency to develop tissue inflammation

111 6 5 Risk of Metabolic Syndrome rises with low T tt nmol/l tt nmol/l tt nmol/l tt < 11 nmol/l 4 p<0.001* p<0.001* 3 2 p=0.002* 1 0 Odds Ratio (95% c/i) Model 1 Model 2 Model 3 adjusted for age category adjusted for age, smoking, alcohol, adjusted for age, smoking, alcohol, CVD, socioeconomic status CVD, socioeconomic status, and BMI * for linear trend N=1,865 Non-diabetic Men Laaksonen DE et al. Eur J Endocrinol 2003, 149:

112 Hypogonadism and 35 Depression 2-y depression incidence (%) ng/dl 5.21 nmol/l 278 Elderly Men (mean age 62.4 years) 200 ng/dl 6.94 nmol/l Declining testosterone level 250 ng/dl 8.68 nmol/l 300 ng/dl nmol/l 350 ng/dl nmol/l Shores MM et al. Arch Gen Psychiatry 2004, 61:

113 The BLAST STUDY Conducted in the UK cities and towns of Birmingham, Lichfield, Atherstone, Sutton Coldfield and Tamworth) The first double blind placebo controlled intervention study in a primary care type 2 diabetic population Routine screening of diabetic populations of 8 high-performing family medicine practices to determine men with symptomatic hypogonadism

114 The BLAST study A 30 week double blind placebo controlled study of long acting testosterone undecanoate versus placebo in men with type 2 diabetes 211 patients screened (mean age 62) 12 screen failues 1 AF, 10 raised PSA of which 9 were BPH and 1 new CaP 1 withdrew consent) 199 Randomised 97 randomised to TESTOSTERONE UNDECANOATE 1000mg for 30 weeks 102 randomised to matching placebo for 30 weeks 190 Completed 4 SAEs 3 treatment unrelated deaths and 1 new CaP in PLACEBO arm 5 withdrawn consent 106 entered 52 week open label extension

115 Baseline, 18 and 30 week data for HbA1c and Waist Circumference HbA1c (%) (cm) N T N Placebo Estimated Mean 95% Confidence Interval P-Value Baseline ± ± Weeks ± ± (-0.34,-0.05) p= Weeks Waist 4 91 n 7.68±1.26 T 95 n 7.54±1.2 Placebo Estimated (-0.34,0.13) 95% p=0.36 P-Value 4 Mean Confidence Interval Baseline ± Weeks ± Weeks ± ± ± ± (-1.8,0.9) p= (-3.0,-.2) p=0.023

116 RESULTS HbA1c Testosterone Undecanoate 1000mg (TU) significantly lowered HbA1c at 18 weeks versus placebo and in the poorly controlled group this reduction was 0.42% at 30 weeks and 0.72% after further 52 weeks open label medication Baseline HbA1c (%) Nebido 18 weeks 30 weeks Placebo P=0.007 P=0.36

117 HbA1c in poorly vs. wellcontrolled men Poorly-controlled Well-controlled

118 T therapy reduces abdominal visceral fat (determined by MRI) in 36 Elderly Men (age: 60, BMI ~ 25.5, WC ~ 94.5 cm, T ~ 14 nmol/l) p=0.480 p=0.001 % change in abdominal subcutaneous fat % change in abdominal visceral fat Allan CA et al. J Clin Endocrinol Metab 93: (20

119 Men aged 65 years (N=108). * P= P< Change in lean mass (kg) * T therapy improves body composition in 108 elderly men Testosterone patch Placebo Time (months) Change in fat mass (kg) Time (months) Snyder PJ, et al. J Clin Endocrinol Metab. 1999;84: Figure 1.

120 T improves depression scores in ageing males (T Rx in Refractory Depression; n=22; T<350) 22 Hamilton Depression Rating Scale Mean Score Testosterone Placebo Weeks Pope HG et al. Am J Psychiatry. 2003;160(1):

121 T= testosterone F= finasteride T therapy increases bone mineral density (BMD) BMD (% Change) Changes in Lumbar Spine BMD Time (months) T T+F P <0.001 Placebo Mean ± SEM n=70 Amory JK, et al. J Clin Endocrinol Metab. 2004;89:

122 T improved sexual parameters in 40 hypogonadal men (mean age 41, range: 18-74) Sexual thought/fantasy Satisfaction with sex life * * * * * * * * * * * * * * * * * * * Sexual interest/desire S Weeks # * * * * * * * * * * S Weeks * * * * * * * * * * * * * * * * * * * S Weeks * * T-Enanthate T-Undecanoate * p < 0.05 * * * * * * * Huebler D et al. Int J Impot Res 14 (Suppl. 4), Abstract P52

123 T increases spontaneous morning erection rate in 40 hypogonadal men (mean age 41, range: 18-74) 4,5 SME per 3,5 4 week 2,5 3 * 1,5 2 0, Weeks Schulmann C et al. J Sex Med 3 (Suppl. 1): 57

124 Summary Restoring testosterone to the eugonadal range has the potential not only to improve well-being, but also aids in the management of some chronic health problems It may also reduce the risk of developing chronic health problems Not only might this benefit the individual, it may reduce the overall cost of chronic illness to society

125 A Clinical Perspective of Androxal s Effects on Carbohydrate and Bone Metabolism Glenn Cunningham, MD Baylor College of Medicine

126 2011 by Endocrine Society Distribution of Total and Free T Levels in the FHS, EMAS and Mr. OS Samples Bhasin S et al. JCEM 2011;96:

127 European Male Aging Study Distribution and Selected Characteristics of Men Ages (Tajar et al)

128 Low Testosterone Signs and Symptoms Low Frequency Morning Erections Erectile Dysfunction Low Frequency Sexual Thoughts FHS EMAS MrOS TTFT Low Walking Speed Difficulty Climbing Stairs Frailty Diabetes Composite FT, free testosterone; TT, total testosterone. Bhasin S, et al. J Clin Endocrinol Metab. 2011;96(8): Odds Ratio

129 Age specific Prevalence (95% Confidence Interval) of Symptomatic Androgen Deficiency (AD) Araujo, A B, et al. J Clin Endocrinol Metab 2007;92: Patients With AD Age, y Copyright 2007 The Endocrine Society.

130 Age & BMI of Subjects in Repros Androxal Studies Study IND # of Subjects Mean Age Mean BMI ZN , ZA , ZA , ZA , ZA ,

131 ZA 203 Impact of Androxal on glycemic control in men with 2 hypogonadism and type 2 diabetes currently receiving oral hypoglycemic agents 3 month treatment, double blind study comparing placebo, 12.5 and 25mg Androxal Endpoints Testosterone HbA1c HOMA 19 clinical sites randomizing up to 120 subjects 252 screened, 92 randomized, 39 completed dosing

132 BMI Distribution in ZA 003

133 ZA 203 Total T After 12 Weeks Dosing N=39

134 ZA 203 Changes in Metabolic Parameters after 12 Weeks (Men<65) 25 mg Dose p versus Placebo A1c = 0.09 HOMA = 0.05

135 Mean (95% CI) percentage change from baseline in HOMA- IR and change from baseline in HbA1c among patients with type 2 diabetes Jones T H et al. Dia Care 2011;34: Copyright 2011 American Diabetes Association, Inc.

136 48 subjects ZA 204 Protocol Data reflects the difference between Androgel and an anti estrogen (enclomiphene citrate, Androxal) At weeks 2 and 4, the AndroGel group morning T was assessed at 4 hours post application, and the Androxal groups were assessed between 8 and 10 am. Few values out of normal range for Androxal Many more for AndroGel Good correlation exists between morning T, T avg, and T max for the Androxal arms Legacy Effects

137 Summary of ZA 204 Dose Baseline T ng/dl (stdev) Week 6 T Follow up T ITT LOCF 24 hr Average T Subjects With 24 hr Avg. 6 Subjects with any T >1100 Week mg 247 (75.6) 392 (154.2) 341 (150.7) n= (159.3) N= (152.8) 4 out of 12 0 out of mg 312 (110.5) 495 (170.4) 437 (188.2) n= (163.9) n=9 461 (129.2) 2 out of 10 0 out of mg 248 (114.8) 577 (133.4) 612 (125.4) n= (159.0) n= (142.1) 0 out of 13 0 out of 13 Androgel 293 (117.5) 452 (243.0) (89.3) n= (243.1) n= (230.1) 2 out of 13 3 out of 13

138 ZA 204 Total Testosterone Week mg 12.5 mg 25 mg Androgel

139 ZA 204 Total Testosterone Levels

140 ZA 202 Increased Estradiol Levels 1 Month after Stopping Treatment Group before TxT 6 weeks 3 months after TxT E2 SD E2 SD E2 SD E2 SD 12.5 mg Androxal * * * mg Androxal * * * 27.4 Testim * * Placebo * different vs. before TxT ^ different vs. Testim different vs. Placebo

141 Change in Total Hip BMD by Quintile of Baseline B Estradiol, B T and SHBG Cauley JA, et al. J Clin Endocrinol Metab 95: , 2010 Bioavailable E2 Bioavailable T SHBG Results have been adjusted for age, race, baseline weight, and weight change.

142 Effects of Androxal on Bone Markers of Bone Turnover P1NP 1 (type 1 procollagen peptide) is made by osteoblasts and measures bone formation. Lower levels indicate lower bone formation. CTX (type 1 C terminal collagen peptide) is a product of osteoclastic activity. It reflects bone resorption. observations suggest an antiresorptive effect of Androxal, as is seen in women with another SERM, Raloxifene

143 ZA 202 Effect of Treatment on Serum CTx Levels (Bone Resorption)

144 ZA 202 Effect of Treatment on Serum P1NP 1 Levels (Bone Formation)

145 Androxal appears to enhance Bone Mineral Density top line results from ZA 303

146 Is the Active Form of Enclomiphene Like Raloxifene? Does this explain the DEXA Effects?

147 Summary Studies ZA 202, ZA 203, ZA 204 indicate that Androxal has effects on carbohydrate and bone metabolism Larger, longer and more rigorous studies are needed Androxal effects on LH, T and E2 persist for some time after stopping treatment implications for dosing

148 Baseline 0 time: 7:31 AM Week 6 0 time: 6:19 AM 24 Hour T & LH Androgel Subject Study ZA 204 Subject Age: 58, BMI: 24.1

149 Day to Day Morning T Variability Sampling of Placebo Subjects ZA 003

150 Key Study Discussion Points for Upcoming Type B Meeting 2012 ZA 204 Results Predictable Cmax and Cavg for Androxal compared to testosterone Continuing benefit for Androxal after stopping treatment ZA 203 Results No negative impact on sperm parameters compared to testosterone Equivalent impact on testosterone levels

151 Baseline 0 time: 8:09 AM Week 6 0 time: 7:25 AM 24 Hour T & LH 25 mg Androxal Subject Study ZA 204 Subject Age: 55, BMI: 32

152 Legacy Effect Prolongation of Testosterone in Serum after 1 Week Cessation

153 Effects of Aging on Hormone Levels Feldman HA et al. J Clin Endocrinol Metab. 2002;87: Massachusetts Male Aging Study (MMAS) T FT Albumin-bound T SHBG Trend Cross-sectional, baseline, N=1,709 Cross-sectional, follow-up, N=1,156 Longitudinal Age Trend (%/year) FT=free testosterone. SHBG=sex hormone-binding globulin. T=testosterone.

154 Benign, monoclonal, hormone sensitive, smooth muscle tumors of the uterus Most common tumor of the female reproductive tract Heavy bleeding / anemia Abdominal pressure / pain / urinary frequency Affect 20-77% of women age ,000 hysterectomies annually Infertility particularly with delayed childbearing Courtesy of Jay Goldberg, MD, MSCP Director, Jefferson Fibroid Center Director, Division of General OB/GYN Jefferson Medical College, Philadelphia, PA

155 Patient Relieve symptoms Bleeding Bulk symptoms Shrink tumors Physician Patient Acceptance Normal menses Simple, effective (medication compliance) FDA: Reduce heavy menstrual bleeding related to fibroids

156 This was a Phase II, randomized, single-blinded study of four doses of Proellex (Telapristone) vaginally administered 12 weeks. 12 subjects in each arm (36) were years old with symptomatic uterine fibroids ultrasound confirmed. At the three-month treatment visit, subjects were entered into an open-label extension treatment protocol, if deemed eligible. 24 hr PK, MRI where performed at beginning and UFSQOL at each visit.

157 Proellex induced amenorrhea Mimics early follicular phase Without progesterone

158 Average: PK Oral (1, 3, 6, 9 and 12 mg vs Vaginal 12 mg) 600 Conc. (ng/ml) Time (Hr) 1 mg oral 3 mg oral 6 mg oral 9 mg oral 12 mg oraql 12 mg vaginal

159 Validated method for the determination of blood loss during menses All patients provided with same sanitary product Menstrual Pad Scoring Score (ml of blood) Number per Category per period Score Wyatt et al. Fertil Steril 2001; 76: x x x x x Total Score

160 Validated method for the determination of blood loss during menses All patients provided with same sanitary product Clot scoring added to pad scoring to yield PBAC total score Clot Size Dime (1 ml) Penny (3 ml) Quarter (5ml) Total score Number Wyatt et al. Fertil Steril 2001; 76:

161 PBAC Score >80 = menorrhagia (Normal menses 60 cc)

162 1. Heavy bleeding during your menstrual period 2. Passing blood clots during your menstrual period 3. Fluctuation in the duration of your menstrual period compared to your previous cycle 4. Fluctuation in the length of your monthly cycle compared to your previous cycles 5. Feeling tightness or pressure in your pelvic area 6. Frequent urination during the daytime hours 7. Frequent nighttime urination 8. Feeling fatigued

163 Each question can be scored as follows: Not at all A little bit Somewhat A great deal A very great deal Sum Item Values: Questions 1-8 Lowest and Highest Possible Scores; 8, 40 Possible Raw Score Range: 32 Formula for Transformation of Symptom Severity Raw Scores Transformed Score = (Actual raw score lowest possible raw score)x 100 Possible raw score range

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165

166 Paired Comparison for Subjects Dosed at 12 Throughout Study Baseline to Cycle 1 p=0.005 Cycle 1 to Cycle 2 p= 0.003

167 Observations Significant reduction in menstrual bleeding (amenorrhea in most cases) Significant improvement in bulk symptoms and quality of life with most subjects becoming symptom free while on drug Significant reduction in tumor burden over time If approved 12 mg daily vaginal dosing of Proellex may offer women suffering from the symptoms of uterine fibroids medical treatment and an alternative to surgery

168 Projected Cash Requirements Through H (in millions) 2014 H Total Androxal $7.5 $0 $7.5 Proellex $8.0 $6.0 $14.0 General Corporate $8.0 $4.5 $12.5 Total Cash Required Through Androxal Approval $34.0 Assumptions: Androxal - NDA filed in mid-2014, expected approval mid-2015; includes FDA filing fee Proellex - Phase 3 requirements: subjects treated for 6 months; 200 subjects treated for 1 year; NDA projected to be filed in 2016 General Corporate Includes all personnel related costs, facilities, legal, accounting, patent and patent application costs and all costs related to being a public company

169 Financial Summary Cash and equivalents (as of 4/1/13-unaudited) $17.2 M Cash runway: Q Current shares outstanding: 18.7 M shares Warrants Outstanding Series A 877,137 (purchased in unit $2.45); Series B $2.49 exercise price.