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E001451 Primary 1 6/9/2014

Uprima ® (apomorphine HCl tablets) sublingual Presentation to the Urology Subcommittee of the Advisory Committee for Reproductive Health Drugs April 10, 2000 TAP HOLDINGS INC. E001451 Primary 1 6/9/2014. Speakers. Introduction.

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E001451 Primary 1 6/9/2014

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  1. Uprima®(apomorphine HCl tablets) sublingualPresentation to the Urology Subcommittee of the Advisory Committee for Reproductive Health DrugsApril 10, 2000TAP HOLDINGS INC. E001451 Primary 1 6/9/2014

  2. Speakers Introduction • James Freston, M.D., Ph.D.Professor of Medicine and Clinical Pharmacology University of Connecticut Health Center • Barbara Bopp, Ph.D.Manager, Drug Metabolism and Pharmacology TAP Holdings Inc. • Jeremy Heaton, M.D.Professor, Dept. of Urology, Dept. of Pharmacology & Toxicology Queens University Kingston, Ontario, Canada • Timothy Fagan, M.D.Professor of Medicine and Associate Professor of Pharmacology University of Arizona College of Medicine

  3. TAP Participants Introduction • John Seely, Ph.D.Vice President, Research and Development • Dean SundbergDirector, Regulatory Affairs • Karl Agre, M.D., Ph.D.Senior Director, Medical Affairs • Susan Buttler, M.S.Associate Director, Clinical Development • Dennis Jennings, Ph.D.Director of Scientific Data Analysis • James Lancaster, Ph.D.Manager, Clinical Statistics

  4. TAP Participants (cont.) Introduction • Anthony Edmonds, M.S.Senior Statistician • Dustin Ruff, Ph.D.Statistician • Renee Perdok, M.S.Statistician • Farrel Fort, Ph.D., D.A.B.T.Manager, Drug Safety

  5. Cully Carson, M.D.Chief - Division of Urology University of North Carolina Chapel Hill, NC Eugene Dula, M.D.Medical Director Western Urologic Associates Van Nuys, CA Ronald Lewis, M.D.Professor of Urology Medical College of Georgia Augusta, GA Arnold Melman, M.D.Department of Urology Montefiore Hospital Bronx, NY TAP Consultants Introduction

  6. TAP Consultants Introduction • Ray Rosen, Ph.D.Department of PsychiatryRobert Wood Johnson Medical School Piscataway, NJ • Addison Taylor, M.D.Professor of Medicine and Clinical PharmacologyBaylor College of Medicine Houston, TX • Joel Morganroth, M.D. Chief Executive Officer Premier Research Philadelphia, PA • Gary G. Koch, Ph.D.Statistical Consultant Chapel Hill, NC

  7. TAP Presentations Introduction • General Introduction ….…….……..……………………. Dr. Freston • Apomorphine Pharmacokinetics and Metabolism …… Dr. Bopp • ED Treatments…………………………………………… Dr. Heaton • Summary of Efficacy ….……....………………………… Dr. Heaton • Summary of Safety .….……...………………………….. Dr. Freston, Dr. Fagan • Benefit-Risk Assessment/Summary …………..………. Dr. Freston

  8. Topics Identified in FDA Briefing Document Introduction • Comparison to other marketed ED drugs • Representative ED patient population • Pharmacokinetic variabilty • Clinical relevance of 2 mg • Efficacy in diabetics • Discontinuations in long-term studies • Hemodynamics • Nitrate interaction • Alcohol interaction

  9. Erectile dysfunction is the “inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance” Erectile Dysfunction (ED) Introduction-ED Definition NIH Consensus Development Panel on ImpotenceJAMA 270: 83-90, 1993

  10. Erectile Dysfunction Introduction-ED Epidemiology and Demographics • US National Health and Social Life Survey (NHSLS)-1992 • Probability sample study of sexual behavior in men and women • Demographically representative cohort of 1,410 men, ages 18-59 • Correlated ED to other diagnoses • ED in 10% of men, ages 18-59 Laumann EO, Paik P, Rosen RC. JAMA 1999;281(6): 537-544

  11. Erectile Dysfunction Introduction-ED Epidemiology and Demographics • Massachusetts Male Aging Study (MMAS) – 1987-1989 • Cross-sectional, community-based, random sample survey of 1,300 men, ages 40-70 • Overall ED rate 52% • Complete 10% • Moderate 25% • Minimal 17% • Extrapolation to US: 30 million men with ED • ED correlated with age, health status, emotional function Feldman et al. J. Urology 151: 54-61, 1994.

  12. Age Related Changes in Erectile Status Introduction-ED Massachusetts Male Aging Study (MMAS) % Age Extracted from Feldman et al. J. Urology 151: 54-61, 1994.

  13. Massachusetts Male Aging Study Introduction-ED ED is Associated with: • Age • Diabetes • Hypertension • Heart disease • Medications • Depression • Psychological factors Feldman et al. J. Urology 151: 54-61, 1994. Johannes et al. J. Urology 163: 460-463, 2000.

  14. ED Population Introduction-Uprima Uprima® Studies MMAS1 Duration of ED (mean) 4.8 years Medical Condition (%) Hypertension 31% 33% Coronary Artery Disease (CAD) 16% 16% Hyperlipidemia 16% — Diabetes 16% 9% 1 Johannes et al. J. Urology 163: 460-463, 2000.

  15. Introduction to Apomorphine Introduction-Uprima • USP drug • Used as a pharmacologic agent since 1869 • Over 1,100 literature citations • Therapeutic doses ranged from 0.2 to 1500 mg • Approximately 8,000 patients/subjects treated in clinical trials • Approved in 12 countries for multiple indications, including Parkinson’s Disease • Daily administration • Usual dose 3 to 30 mg, subcutaneously • Dopaminergic properties recognized in 1967 • Central erectogenic effect recognized in the late 1970’s • Activates DA receptors in hypothalamic and limbic neural pathways

  16. Introduction to Uprima® Introduction-Uprima • Formulated to treat erectile dysfunction • Delivered sublingually (SL) • Unique central mechanism of action • Rapid onset of action • Effective for erectile dysfunction (ED) in a wide spectrum of organic and non-organic etiologies and severities

  17. Introduction to Uprima® Introduction-Uprima • Safety • No deaths • No myocardial infarctions (MI) related to study drug • No cerebrovascular accidents (CVAs) related to study drug • No priapism • Nausea was the most frequent adverse event, syncope the most significant

  18. Proposed Indication Uprima® is indicated for thetreatment of erectile dysfunction

  19. Doses Proposed doses: 2, 3 and 4 mgUprima® will be available as a sublingual tablet

  20. Rationale for Uprima® Treatment of ED Introduction-Uprima • ED is associated with a number of diseases and conditions • Drugs with different modes of action are desirable as with other disorders with complex pathophysiology, e.g., hypertension, depression • Current therapies are limited: • No drug is effective in all patients • Each drug has its own unique adverse event profile • The currently approved agents work by peripheral mechanisms • Treatment is strongly influenced by couple and physician choice • New drugs with different mechanisms offer significant potential benefits

  21. Rationale for Uprima® Treatment of ED Introduction-Uprima • Uprima® has a: • Unique central mechanism of action • Novel delivery system • Rapid onset • Uprima® has been studied in 27 clinical trials and has been shown to be a safe and effective treatment for ED in patients with and without known organic diseases

  22. Uprima® Clinical Trials Introduction/Uprima (N = 3,035) • Phase I • Pharmacokinetics • Metabolic fate • Elderly (³65 years) • Renal/Hepatic Impaired • Drug interactions (Zofran®, Compazine®) • Special Phase I/II/III • Antihypertensives and nitrates • Diabetics • Alcohol • Prostatectomy • Spinal cord injury • Phase III • Three controlled crossover • Dose-optimization • One controlled parallel • Five long-term, open-label • One first dose administered at home

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