Overview of the Endocrine Society Guidelines for the Treatment of Hypogonadism Edward D. Kim, M.D. Professor of Surgery/Urology Objectives w Primary focus on treatment options w Overview of criteria for treatment of hypogonadal men w Detrimental effect of testosterone therapies on sperm production Testosterone: Adult Physiological Effects 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):2536-2559. DIAGNOSIS w Clinical hypogonadism is defined as symptoms + low testosterone (<300 ng/dL) w 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):2536-2559. TESTOSTERONE SALES ARE INCREASING “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.” http://www.endo-society.org/guidelines 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.” • 75–100 mg of testosterone enanthate or cypionate administered IM weekly, or 150–200 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. 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. Intramuscular Injections Pros Cons History (available for 50 years) Pain Self administration Frequency of injections (every 1 – 2 weeks) Inexpensive Symptomatic peaks and troughs resulting in variations in breast tenderness, libido, emotional stability, energy Flexibility of dosing Erythrocytosis Dandona P, Rosenberg M. Int J Clin Pract. 2010;64(6):682-696. Transdermal Patches Pros Cons Nonscrotal patches Skin irritation Nighttime application results in good approximation of normal circadian plasma testosterone levels Need for daily, continuous application Flexibility of dosing Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6):682-696. Transdermal Gels Pros Cons Application sites (upper arms, shoulder, axilla) Transfer to others (risk is minimized with high-dose, lowvolume preparations) Low skin irritation Cost Invisibility of application Daily application Flexibility of dosing Skin residue Various concentrations Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6):682-696. PHARMACOKINETIC PROFILES Injectable administration results in considerable fluctuation in testosterone levels. Buccal Tablets: Striant™ Pros Cons Application site Application site Relative invisibility Inadvertent loss of tablet Bypass first-pass hepatic metabolism 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), 682-696. Subcutaneous Pellets Pros Cons History (started in 1940s) Painful application Relative invisibility Surgical procedure unlikely to be used by the PCP Long acting Long acting Slow release Inconvenient removal Procedure can result in infection, fibrosis or pellet extrusion Dandona P, Rosenberg M. Int J Clin Pract. 2010; 64(6), 682-696. Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab. 2010, 96(6): 2536-2559. Oral Testosterone w Not approved in U.S. w Methytestosterone ¾ Methitest, Android, and Testred Poor absorption w High risk of hepatic toxicity, hepatoma and cholestatic jaundice w Risk of anaphylaxis w Edelstein D, et al. Expert Opin Emerg Drugs. 2006;11:685-707. 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 Why Testosterone Therapy Is Detrimental To Sperm Production • Exogenous T Leydig cells produce testosterone decreases intratesticular testosterone (ITT) concentrations • Profound decreases in spermatogenesis, including azoospermia, may result Higher Centers Hypothalamus Germinal Epithelium Inhibin Anterior Pituitary + Sertoli Cells GnRH FSH Testosterone - + LH Leydig Cell WHO CONTRACEPTIVE EFFICACY • 271 men • 12 months efficacy phase • IM-TE 200 mg/wk Time to azoospermia: 120 days Estimated time to recovery: To >20 million sperm/ml 3.7 months To baseline 6.7 months Lancet. 1990;336(8721):955-9. DISCONTINUATION OF IMTESTOSTERONE 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 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; 99:718-24. . Androxal Improves T without Affecting Sperm Count p<0.00001 No statistical difference Androxal Exhibits No Negative Effects on Important Sperm Parameters No statistical difference ZA-203: Effect of Treatment on Median Sperm Concentration versus Testim 100 p=0.012 90 Sperm count in millions/ml 80 p=0.0021 70 p=0.0049 60 50 Baseline EOS 40 30 20 10 0 12.5 mg 25 mg PL Testim Symptoms and Signs Suggestive of Hypogonadism-Summary w No symptoms are unique to hypogonadism w Screening with testosterone level is appropriate when presented with symptoms w 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):682-696. Treatment Options-Summary w Current choices: Injections, topicals, buccal and pellets w No effective oral therapies in U.S. w Testosterone replacement has negative effects on sperm production w Androxal does not have adverse effects on sperm PROGRESSION OF TESTOSTERONE THERAPIES 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 Overweight and Obesity among U.S. Adults Obesity Prevalence (%) Overweight 2012- Overweight/Obese= 149.3 Million Age 2-19- overweight =23.6 obese= 12.6 1960– 1962 1971– 1974 1976–1980 1988–1994 1999–2002 2003–2004 NHANES Data Collection Period Flegal KM et al. JAMA 2002;288:1723-1727. | Hedley AA et al. JAMA 2004;291:2847-2850. | Ogden CL et al. JAMA 2006;295:1549-1555. Are we Over Diagnosing low T? }Are we Over Diagnosing Obesity? }Are we Over Diagnosing Diabetes? }Are we Over Diagnosing Aging? Hypogonadism: Treatment } Topical: patch or gel. Daily } Injected: I.M. testosterone q 1-2 weeks } Implant: testosterone pellets q 4-6 months 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 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 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 Change in Paradigm is Needed } Do we treat all diabetics with Insulin? } The PCP WILL NOT prescribe off label treatments } WE NEED an FDA approved SERM!!!!!!!!!!!!! T (pg/ml) } Currently we can use clomiphene off label with great efficacy in normalizing T 21.2 Free } Why are we ignoring the testes? 25 20 15 10 5 Part Non0RespResp Resp 18 9.3 9.2 17.6 9.8 Base 4moRx 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. SHARED CARE: THE INTERFACE BETWEEN THE PATIENT, PRIMARY CARE PHYSICIAN AND SPECIALIST DR JOHN DEAN 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 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 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 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 HYPOGONADISM: A MULTISYSTEM DISORDER, AFFECTING MIND AND BODY Target Organ • Bone • Musculature • Adipose tissue • Blood •Vascular system • Brain • Sexual organs Patient/Social Consequences • ↓ Quality of life • Disability • ↓ Productivity • ↑ Dependency on carers • Impact on relationships 45 Clinical Features • ↓ Bone mineral density • ↓ Muscle mass/strength • ↑ Abdominal fat • ↓ Haemoglobin • Dyslipidaemia • Mood changes, impaired cognition • ↓ Libido, erectile dysfunction, subfertility Clinical Consequences • 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 WELL-ESTABLISHED NORMAL VALUES • TOTAL TESTOSTERONE: • <230 NG/DL (< 8 NAMOL/L) = OVERT HYPOGONADISM • 230-346 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 Vermeulen, JCEM, 1999 AGE-RELATED CHANGES IN TESTOSTERONE IN MEN FT (ng/dL) x 100 1250 1000 750 500 SHBG (nmol/dL) T (ng/dL) 250 0 47 25 - 34 35 - 44 45 - 54 55 - 64 65 - 74 75 - 84 85 - 100 Age (years) Comhaire FH Eur Urol 2000, 38: 655-662. 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 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 1995‐2010 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 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 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 250-1000) • FSH: 4 mIU/ml (normal 4-10) • LH: 6 mIU/ml (normal 4-12) 2* • Can we safely and effectively treat • This man demonstrates adult-onset this man’s low testosterone? idiopathic secondary hypogonadism How told willof treatment impact his he • •When his hormone deficiency, ability to establishtherapy! a pregnancy? requests testosterone 2* Testosterone Replacement Therapy Treatment Options Intramuscular Injections Oral Tablets Transdermal Patches Transdermal Gels Pellet Implants 5* Transdermal Gels are the Most Commonly Prescribed Form of TRT Gels Injectables Patches 17% Other 10% 70% IMS NPA; 2006. 3% 1* 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, 2011 1* T Testosterone ng/dL Testosterone Levels after Replacement Therapy with Patch, Gel or Injection Patch or Gel Normal range Injection 1400 1200 1000 800 600 400 200 0 0 3 5 7 12 Day 17 21 30 34 Adapted from Bhasin and Bremner. J Clin Endocrinol Metab. 1997;82:3-8 Testosterone gel (AndroGel ®1%) Unimed Pharmaceuticals and Solvay Pharmaceuticals, 2002 2* Higher Centers Hypothalamus Germinal Epithelium Inhibin - Anterior Pituitary + Sertoli Cells GnRH FSH Testosterone - + LH Leydig Cell 4* Higher Centers Hypothalamus Germinal Epithelium Inhibin - Anterior Pituitary + Sertoli Cells GnRH FSH Testosterone - + LH Leydig Cell 4* 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* 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* Higher Centers Hypothalamus SERMs: Estrogen GnRH Clomiphene Germinal Epithelium Inhibin - Anterior Pituitary + Sertoli Cells FSH Testosterone - + LH Leydig Cell 2* Androxal (enclomid) Background • Clomiphene Citrate (ClomidTM) 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* Effects of Clomid and its Isomers on T Pre-clinical Studies in Baboons1 Testosterone (ng/dl) 1400 Last Day of Dosing 1200 Enclomid (Androxal) Clomid 1000 800 600 Zuclomid 400 200 0 0 6 Days 1. Int. Congress Endocr. Abstract # 1212, Lisbon, 2004 12 18 Clomid Pharmacokinetics ng/dl 24 hour Comparison of Isomers 8 7 6 5 4 3 2 1 0 Zu-clomid En-clomid 0 10 hours 20 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 30 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* Total Testosterone 1000 900 800 700 600 500 400 300 200 100 0 Testim Androxal 300 V1 V2 V4 V5 V6 Sperm (million/ml) Testosterone (ng/dl) Only Androxal Restores both T and Sperm Counts Sperm Concentration 250 200 Testim 150 Androxal 100 50 0 V2 V4 V5 V6 1* Only Androxal Raises LH and FSH 8 Testim 6 Androxal 4 2 10 0 V1 V2 V4 V5 V6 FSH (mIU/ml) LH (mIU/ml) Luteinizing Hormone 10 Follicle Stimulating Hormone 8 Testim 6 Androxal 4 2 0 V1 V2 V4 V5 V6 1* 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* ZA-203 Patient Disposition 920 Screened • • • • Double-blind Randomized Placebo-controlled Open-label for TRT 124 Entered Study 50 (40%) patients discontinued: • 3 due to AEs • 7 early termination • 17 non-compliance • 2 exclusion criteria 74 (60%) Completed Study • 10 withdrew • 11 lost to follow up TT (ng/dl) ZA-203 Clinical Findings 500 450 400 350 300 250 200 150 100 50 0 Effect of Treatment on Median Serum TT Comparison to Placebo P < 0.00001 Before P = 0.0002 After 12.5 mg 25 mg PL Testim Treatment 2* ZA-203 Clinical Findings Effect of Treatment on Median LH Comparison to Testim 12 10 Before After P < 0.00001 LH 8 6 P = 0.0004 4 2 0 12.5 mg 25 mg PL Testim Treatment 2* ZA-203 Clinical Findings Effect of Treatment on Median FSH Comparison to Testim 14 12 P < 0.00001 Before After FSH 10 8 P = 0.0004 6 4 2 0 12.5 mg 25 mg PL Testim Treatment 2* ZA-203 Clinical Findings Sperm (Millions/ml) Effect of Treatment on Median Sperm Concentration Comparison to Testim 100 90 80 70 60 50 40 30 20 10 0 P = 0.012 12.5 mg Baseline P = 0.0021 P = 0.0049 25 mg PL EOS Testim Treatment 2* ZA-203 Clinical Findings Effects on Semen Parameters Sperm Concentration (Millions/ml) Average of all assessments after dosing has stopped (2 or more analyses) 120 Placebo 12.5 mg 25 mg Testim 100 80 60 40 20 0 Mean Median ZA-203 Effects on Semen Parameters Average of all assessments after dosing has stopped (2 or more analyses) 60 Motility % Motile Sperm 50 Placebo 40 12.5 mg 30 25 mg Testim 20 10 0 Mean Median 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* Androxal Improves T without Affecting Sperm 450 Baseline 400 End of Study 350 300 250 200 150 100 50 60 Sperm Concentration X 106 Total T (ng/dL) 83 % in Normal Range 79% in Normal Range ITT Placebo Androxal Androxal Up‐titration 50 40 NSD 30 20 10 0 0 Androxal P <Placebo 0.00001 Baseline End of Study 3* Androxal Exhibits No Negative Effects on Important Sperm Parameters 60 80 70 Androxal Androxal Up‐titration 50 % Motile Placebo Placebo % Normal Morphology 70 Androxal Androxal Up‐titration 60 Sperm 50 Motility 40 30 20 40 20 10 0 0 End of Study Sperm Morphology 30 10 Baseline NSD NSD Baseline End of Study 1* 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* Thank You Texas Medical Center, Houston 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* 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* ANDROXAL Safety Review 6 June 2013 Potential Safety Issues • Clomiphene • Testosterone – Cataracts – Increased estrogen (opposes testosterone increase) • Hypogonadism - osteopenia – Deep Vein Thrombosis (DVTs) – Prostate Specific Antigen (PSA) Elevation – T level above normal – Decreased sperm count (infertility) – Gynecomastia 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 ANDROXAL Safety Review TOPICS STUDIES • Treatment Emergent Adverse Events (TEAEs) • Discontinuation due to Adverse Events (DCAEs) • Serious Adverse Events(SAEs) • Testosterone • Prostate Specific Antigen 003: Phase 3 301: Phase 3 300: long-term safety 303: bone density 300: long-term safety TREATMENT EMERGENT ADVERSE EVENTS Studies 301, 300, and 303 Data for 300 and 303 is interim and not fully monitored and validated Study 301 Preferred Term N Any Event Upper respiratory infection Headache Study 300 12.5 25 mg PBO mg (%) (%) (%) 90 22 37 28 23 24 Study 303 12.5 12.5 25 mg 25 mg PBO mg mg (%) (%) (%) (%) (%) 259 240 94 69 104 38 44 19 39 30 6 5 0 6 5 4 6 5 3 9 5 5 3 1 1 2 Muscle twitch 2 0 0 0 0 0 0 0 Diarrhea 2 0 3 <1 1 2 1 0 Dyspepsia 2 0 0 1 1 0 0 0 Influenza 2 0 3 3 1 1 1 0 Lethargy 2 0 0 <1 0 0 0 0 Pollakiuria Sinus congestion 2 0 0 1 1 0 0 0 2 0 0 <1 1 0 0 0 Any event occurri ng in 2 or more subjects in pivotal Study 301. Data for 300 and 303 are interim and not fully monitored and validated DC/AEs: Studies 301, 300, 303 (green font indicates single subject) N= Any DCAE (n = ) PREFERRE D TERM Study 301 12.5 25 mg PBO mg 90 22 37 0 1 1 Study 300 12.5 mg 25 mg Study 303 12.5 mg 25 mg PBO 12.5 mg Study 003 25 mg Androgel PBO 259 240 94 69 104 47 50 48 49 5 1 1 2 0 1 1 5 1 Ocular Nause Abdomina Hot flush discomfo a l pain rt Erectile Blood dysfuncti luteinising on hormone increased Breast Upper respirator enlargeme nt y tract infection Prostatic specific antigen increased Fatigue Muscle spasms Erectile dysfunctio n Abnormal Testicular weight atrophy gain Change in sustained attention Diplopia Vision blurred Hemoglob Hot flash in Increase Hematocrit Increased Hypertensi Hemoglobin on Increased Edema due to cardiac disease Hypertensi on Renal function Cellulitis tests elevated Hemoglobin Increase Hemoglobin Increase Allergic Dermatitis Serious Adverse Events Reported in Studies 301, 300, and 303 (green font indicates single subject) Study 301 Study 300 12.5 25 mg PBO mg Study 303 12.5 mg 25 mg 12.5 mg 25 mg PBO 104 n 90 22 37 259 240 94 69 Any SAE (number of subjects) 0 0 0 2 5 0 2 Preferred Terms Atrial Skin injury flutter Nephrolithi Knee arthroplasty Cholelithia sis asis Diverticuliti Hypotension s (2) deep vein Kidney thrombosis * infection * DVT - Tightness in leg after 5 hour flight, treated with anticoagulants Bradycardia Data for 300 and 303 is interim and not fully monitored and validated TESTOSTERONE Study 300 at 6-month point TESTOSTERONE LEVELS ON LAST DAY OF DOSING (Study 300) 1000 800 600 400 200 0 86% in NORMAL RANGE (300-1040) 1200 Plasma Testosterone concentration No excursions beyond normal range at 6-months PSA: baseline, end of treatment, follow-up Study 300 (only subjects with data after Vis 5) 7 6 PSA (ng/mL) 5 4 3 2 1 0 BASELINE VIS 3, 4, 5, ET VIS 6,7,ET 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 OTHER SAFETY ISSUES RELATED TO TESTOSTERONE THERAPY • Cataracts • Osteoporosis • Deep Vein Thrombosis Safety Profile - Cataracts • 1) – After 4 months, nuclear cataract in left eye disappeared, cortical cataract in right eye progressed – Described as age-related progression of senile cataract • 2) – Described as having cataract after 5 months of therapy, but all entries are “0”, same as baseline. 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 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 CONCLUSIONS • Androxal is well tolerated • Findings are consistent with known pharmacology • No new safety issues 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 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 Androxal Study Status 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 NDA Timeline Potential benefits of testosterone supplementation Dr John Dean 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. 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 410-509 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. % Hypogonadal Type 2 diabetic men with hypogonadism Age Range Dhindsa S, et al. J Clin Endocrinol Metab. 2004;89:5465 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 HIM study: odds ratios for association of hypogonadism with co-morbid conditions Obesity Prevalence Range % 52.4 (47.9-56.9) Odds Ratio 2.38 Diabetes 50 (45.5-54.5) 2.09 Hypertension 42.4 (39.6-45.2) 1.84 Hyperlipidaemia 40.4 (37.6-43.3) 1.47 Osteoporosis 44.4 (25.5-64.7) 1.41 BPH 41.3 (36.4-46.2) 1.29 Mulligan et al IJCP 2006 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 6 Risk of Metabolic Syndrome rises with low T tT 23.4-51.7 nmol/L tT 17.0-23.3 nmol/L tT 1.1-16.9 nmol/L tT < 11 nmol/L 5 4 p<0.001* p<0.001* 3 p=0.002* 2 1 0 Odds Ratio (95% c/i) Model 1 Model 2 Model 3 adjusted for age, smoking, alcohol, adjusted for age category adjusted for age, smoking, alcohol, CVD, socioeconomic status, and BMI CVD, socioeconomic status * for linear trend N=1,865 Non-diabetic Men Laaksonen DE et al. Eur J Endocrinol 2003, 149: 601-608. 2-y depression incidence (%) 35 Hypogonadism and Depression 278 Elderly Men (mean age 62.4 years) 30 25 Declining testosterone level 20 15 10 5 0 150 ng/dL 5.21 nmol/L 200 ng/dL 6.94 nmol/L 250 ng/dL 300 ng/dL 350 ng/dL 8.68 nmol/L 10.41 nmol/L 12.14 nmol/L Shores MM et al. Arch Gen Psychiatry 2004, 61: 162-167. 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 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) 1 AF, 10 raised PSA of which 9 were BPH and 1 new CaP – 1 withdrew consent) 12 screen failues 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 Baseline, 18 and 30 week data for HbA1c and Waist Circumference HbA1c N T (%) N Placebo Estimated Mean Baseline 97 7.74±1.31 18 Weeks 95 7.49±1.26 Waist 91n T 7.68±1.26 Baseline 96 18 Weeks 96 30 Weeks 91 115.1±13. 102 112.6±13. 1 3 114.7±13. 100 113.5±13. -0.5 5 2 112.8±14. 95 112.0±12. -1.6 0 4 30 Weeks (cm) 102 7.47±1.2 4 100 7.44±1.1 -0.20 4 n Placebo -0.11 Estimated 95 7.54±1.2 Mean 4 95% Confidence Interval (-0.34,-0.05) P-Value p=0.007 95% P-Value (-0.34,0.13) p=0.36 Confidence Interval (-1.8,0.9) p=0.49 (-3.0,-.2) p=0.023 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 HbA1c (%) 7.8 7.75 7.7 7.65 7.6 7.55 7.5 7.45 7.4 7.35 7.3 7.25 P=0.007 P=0.36 Baseline 18 weeks 30 weeks Nebido Placebo HbA1c in poorly vs. wellcontrolled men Poorly-controlled Well-controlled 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: 139-146 (20 Testosterone patch Placebo 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 0 12 24 36 Time (months) Change in fat mass (kg)† Change in lean mass (kg)* T therapy improves body composition in 108 elderly men 1.0 0.0 -1.0 -2.0 -3.0 -4.0 0 12 24 36 Time (months) Men aged ≥65 years (N=108). *P=0.001. †P<0.001. Snyder PJ, et al. J Clin Endocrinol Metab. 1999;84:2647-2653. Figure 1. T improves depression scores in ageing males (T Rx in Refractory Depression; n=22; T<350) Mean Score 22 Hamilton Depression Rating Scale 20 18 Testosterone Placebo 16 14 12 0 1 2 4 6 8 Weeks Pope HG et al. Am J Psychiatry. 2003;160(1):105-111. BMD (% Change) T therapy increases bone mineral density (BMD) 1 Changes in Lumbar Spine BMD 1 42 T T+F 0 8 6 P <0.001 4 2 Placebo 0 -2 2-4 0 Mean ± SEM 0 T= testosterone F= finasteride 10 20 30 Time (months) 40 n=70 Amory JK, et al. J Clin Endocrinol Metab. 2004;89:503-510. 70 60 50 40 * * * * * * * * * * * * * * * * * * * * 30 20 Satisfaction with sex life 10 0 70 60 50 40 * * * * * * * * * * * * * * * * ** * * 30 20 10 0 S 0 3 6 9 12151821242730 Weeks 70 60 50 40 30 20 10 0 Sexual interest/desire Sexual thought/fantasy T improved sexual parameters in 40 hypogonadal men (mean age 41, range: 18 - 74) S 0 3 6 9 12151821242730 Weeks T-Enanthate T-Undecanoate * * * * * * * * * * * * * * * * * * * * * p < 0.05 # S 0 3 6 9 12151821242730 Weeks Huebler D et al. Int J Impot Res 14 (Suppl. 4), Abstract P52 (2002) T increases spontaneous morning erection rate in 40 hypogonadal men (mean age 41, range: 18 - 74) 4,5 SME per 4 week 3,5 3 * 2,5 2 1,5 1 0,5 0 -6-30 3 6 9 1215182124273030 95Weeks Schulmann C et al. J Sex Med 3 (Suppl. 1): 57 (2006) 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 A Clinical Perspective of Androxal’s Effects on Carbohydrate and Bone Metabolism Glenn Cunningham, MD Baylor College of Medicine Distribution of Total and Free T Levels in the FHS, EMAS and Mr. OS Samples Bhasin S et al. JCEM 2011;96:2430-2439 ©2011 by Endocrine Society European Male Aging Study Distribution and Selected Characteristics of Men Ages 40‐70 (Tajar et al) Low Testosterone Signs and Symptoms TTFT Low Frequency Morning Erections Erectile Dysfunction Low Frequency Sexual Thoughts FHS EMAS MrOS Low Walking Speed Difficulty Climbing Stairs Frailty Diabetes Composite 0.5 1.0 2.0 Odds Ratio FT, free testosterone; TT, total testosterone. Bhasin S, et al. J Clin Endocrinol Metab. 2011;96(8):2430-2439. 3.0 Age‐specific Prevalence (95% Confidence Interval) of Symptomatic Androgen Deficiency (AD) Araujo, A B, et al. J Clin Endocrinol Metab 2007;92:4241‐4247 Patients With AD 40 30 20 10 0 30-39 Copyright 2007 The Endocrine Society. 40-49 50-59 60-69 Age, y 70-79 Age & BMI of Subjects in Repros Androxal Studies Study IND # of Subjects Mean Age Mean BMI ZN‐018 65,396 52 51.2 31.95 ZA‐003 65,396 194 52.6 32.4 ZA‐202 104,921 116 57.3 33.5 ZA‐203 65,396 108 50.7 32.0 ZA‐204 65,396 60 53.1 31.8 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 BMI Distribution in ZA‐003 ZA‐203 Total T After 12 Weeks Dosing N=39 ZA‐203 Changes in Metabolic Parameters after 12 Weeks (Men<65) 25 mg Dose p versus Placebo A1c = 0.09 HOMA = 0.05 Mean (95% CI) percentage change from baseline in HOMAIR and change from baseline in HbA1c among patients with type 2 diabetes Jones T H et al. Dia Care 2011;34:828-837 Copyright © 2011 American Diabetes Association, Inc. ZA‐204 Protocol • 48 subjects • 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, Tavg, and Tmax for the Androxal arms • “Legacy Effects” 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. T<300ng/dl @Week 6 Subjects with any T >1100 ng/dl @ Week 6 6.25 mg 247 (75.6) 392 (154.2) 341 (150.7) n=15 402 (159.3) N=12 392 (152.8) 4 out of 12 0 out of 12 12.5 mg 312 (110.5) 495 (170.4) 437 (188.2) n=14 493 (163.9) n=9 461 (129.2) 2 out of 10 0 out of 10 25 mg 248 (114.8) 577 (133.4) 612 (125.4) n=16 541 (159.0) n=13 587 (142.1) 0 out of 13 0 out of 13 Androgel 293 (117.5) 452 (243.0) 242.3 (89.3) n=14 452 (243.1) n=13 544 (230.1) 2 out of 13 3 out of 13 ZA‐204 Total Testosterone max @ Week 6 6.25 mg 12.5 mg 25 mg Androgel ZA‐204 Total Testosterone Levels ZA‐202 Increased Estradiol Levels 1 Month after Stopping Treatment Group before TxT E2‡ SD 12.5 mg Androxal 20.8 12.4 25 mg Androxal 24.7 26.3 22.3 Testim Placebo * different vs. before TxT ^ different vs. Testim ¶ different vs. Placebo 6 weeks E2 SD 3 months after TxT E2 SD E2 SD 52.1*¶ 35.3 56.7*¶ 31.5 39.1* 24.2 15.9 48.3*¶ 28.3 46.3*¶ 30.7 40.2* 27.4 21.8 15 44.2*¶ 27.1 26.5 20.3 37.9*¶ 23.9 21.7 17.9 29 33.3 16.6 26.1 Change in Total Hip BMD by Quintile of Baseline B‐Estradiol, B‐T and SHBG Cauley JA, et al. J Clin Endocrinol Metab 95: 4314–4323, 2010 Bioavailable T Bioavailable E2 SHBG Results have been adjusted for age, race, baseline weight, and weight change. 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 ZA‐202 Effect of Treatment on Serum CTx Levels (Bone Resorption) ZA‐202 Effect of Treatment on Serum P1NP‐1 Levels (Bone Formation) Androxal appears to enhance Bone Mineral Density top line results from ZA‐303 Is the Active Form of Enclomiphene Like Raloxifene? Does this explain the DEXA Effects? 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 24 Hour T & LH Androgel Subject Study ZA‐204 Subject 2‐049 Age: 58 , BMI: 24.1 Baseline 0 time: 7:31 AM Week 6 0 time: 6:19 AM Day to Day Morning T Variability Sampling of Placebo Subjects ZA‐003 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 24 Hour T & LH 25 mg Androxal Subject Study ZA‐204 Subject 2‐003 Age: 55, BMI: 32 Baseline 0 time: 8:09 AM Week 6 0 time: 7:25 AM “Legacy Effect” Prolongation of Testosterone in Serum after 1 Week Cessation Effects of Aging on Hormone Levels Feldman HA et al. J Clin Endocrinol Metab. 2002;87:589‐598 Massachusetts Male Aging Study (MMAS) -6 -4 -2 0 2 4 6 -4 -2 0 2 4 6 T FT Albumin-bound T SHBG Trend -6 Cross-sectional, baseline, N=1,709 Cross-sectional, follow-up, N=1,156 Longitudinal FT=free testosterone. SHBG=sex hormone-binding globulin. T=testosterone. Age Trend (%/year) ` ` 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 35 – 55 600,000 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 ` Patient ◦ Relieve symptoms x Bleeding x Bulk symptoms ◦ Shrink tumors ` Physician ◦ Patient Acceptance ◦ Normal menses ◦ Simple, effective (medication compliance) ` FDA: Reduce heavy menstrual bleeding related to fibroids ` ` ` ` 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 18 – 47 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. Proellex induced amenorrhea Mimics early follicular phase Without progesterone Average: PK Oral (1, 3, 6, 9 and 12 mg vs Vaginal 12 mg) Conc. (ng/ml) 600 500 400 300 200 100 0 0 4 8 12 16 20 Time (Hr) 1 mg oral 3 mg oral 6 mg oral 9 mg oral 12 mg oraql 12 mg vaginal 24 Validated method for the determination of blood loss during menses •All patients provided with same sanitary product Menstrual Pad Scoring Score (ml of blood) 1 2 3 4 5 Wyatt et al. Fertil Steril 2001; 76:125-131 Number per Category per period x x x x x Score Total Score 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) Number Wyatt et al. Fertil Steril 2001; 76:125-131 Quarter (5ml) Total score PBAC Score >80 = menorrhagia (Normal menses 60 cc) 1. 2. 3. 4. 5. 6. 7. 8. Heavy bleeding during your menstrual period Passing blood clots during your menstrual period Fluctuation in the duration of your menstrual period compared to your previous cycle Fluctuation in the length of your monthly cycle compared to your previous cycles Feeling tightness or pressure in your pelvic area Frequent urination during the daytime hours Frequent nighttime urination Feeling fatigued Each question can be scored as follows: Not at all A little bit Somewhat A great deal 1 2 3 4 Sum Item Values: Lowest and Highest Possible Scores; Possible Raw Score Range: A very great deal Questions 1-8 8, 40 32 Formula for Transformation of Symptom Severity Raw Scores Transformed Score = (Actual raw score – lowest possible raw score)X 100 Possible raw score range 5 Paired Comparison for Subjects Dosed at 12 Throughout Study •Baseline to Cycle 1 p=0.005 •Cycle 1 to Cycle 2 p= 0.003 ` 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 Projected Cash Requirements Through H1 2015 (in millions) 2014 H1 2015 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: 300 – 600 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 Financial Summary • Cash and equivalents (as of 4/1/13-unaudited) $17.2 M • Cash runway: Q1 2014 • Current shares outstanding: 18.7 M shares – Warrants Outstanding – Series A – 877,137 (purchased in unit deal @ $2.45); Series B – 810,496 @ $2.49 exercise price.
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