UprimaUprima®®

(apomorphine HCl tablets) sublingual(apomorphine HCl tablets) sublingualPresentation to the Presentation to the

Urology Subcommittee of the Advisory Urology Subcommittee of the Advisory

Committee for Reproductive Health DrugsCommittee for Reproductive Health Drugs

April 10, 2000April 10, 2000

TAP HOLDINGS INC.TAP HOLDINGS INC.

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SpeakersSpeakers

James Freston, M.D., Ph.D.James Freston, M.D., Ph.D.Professor of Medicine and Clinical PharmacologyProfessor of Medicine and Clinical PharmacologyUniversity of Connecticut Health CenterUniversity of Connecticut Health Center

Barbara Bopp, Ph.D.Barbara Bopp, Ph.D.Manager, Drug Metabolism and PharmacologyManager, Drug Metabolism and PharmacologyTAP Holdings Inc.TAP Holdings Inc.

Jeremy Heaton, M.D.Jeremy Heaton, M.D.Professor, Dept. of Urology, Dept. of Pharmacology & ToxicologyProfessor, Dept. of Urology, Dept. of Pharmacology & ToxicologyQueens UniversityQueens UniversityKingston, Ontario, CanadaKingston, Ontario, Canada

Timothy Fagan, M.D.Timothy Fagan, M.D.Professor of Medicine and Associate Professor of PharmacologyProfessor of Medicine and Associate Professor of PharmacologyUniversity of Arizona College of MedicineUniversity of Arizona College of Medicine

Introduction

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TAP ParticipantsTAP Participants

John Seely, Ph.D.John Seely, Ph.D.Vice President, Research and DevelopmentVice President, Research and Development

Dean SundbergDean SundbergDirector, Regulatory AffairsDirector, Regulatory Affairs

Karl Agre, M.D., Ph.D.Karl Agre, M.D., Ph.D.Senior Director, Medical AffairsSenior Director, Medical Affairs

Susan Buttler, M.S.Susan Buttler, M.S.Associate Director, Clinical DevelopmentAssociate Director, Clinical Development

Dennis Jennings, Ph.D.Dennis Jennings, Ph.D.Director of Scientific Data AnalysisDirector of Scientific Data Analysis

James Lancaster, Ph.D.James Lancaster, Ph.D.Manager, Clinical StatisticsManager, Clinical Statistics

Introduction

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TAP Participants TAP Participants (cont.)(cont.)

Anthony Edmonds, M.S.Anthony Edmonds, M.S.Senior StatisticianSenior Statistician

Dustin Ruff, Ph.D.Dustin Ruff, Ph.D.StatisticianStatistician

Renee Perdok, M.S.Renee Perdok, M.S.StatisticianStatistician

Farrel Fort, Ph.D., D.A.B.T.Farrel Fort, Ph.D., D.A.B.T.Manager, Drug SafetyManager, Drug Safety

Introduction

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TAP ConsultantsTAP Consultants

Cully Carson, M.D.Cully Carson, M.D.Chief - Division of UrologyChief - Division of UrologyUniversity of North CarolinaUniversity of North CarolinaChapel Hill, NCChapel Hill, NC

Eugene Dula, M.D.Eugene Dula, M.D.Medical DirectorMedical DirectorWestern Urologic AssociatesWestern Urologic AssociatesVan Nuys, CAVan Nuys, CA

Ronald Lewis, M.D.Ronald Lewis, M.D.Professor of UrologyProfessor of UrologyMedical College of Georgia Medical College of Georgia Augusta, GAAugusta, GA

Arnold Melman, M.D.Arnold Melman, M.D.Department of UrologyDepartment of UrologyMontefiore HospitalMontefiore HospitalBronx, NYBronx, NY

Introduction

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TAP ConsultantsTAP Consultants

Ray Rosen, Ph.D.Ray Rosen, Ph.D.Department of PsychiatryDepartment of PsychiatryRobert Wood Johnson Medical SchoolRobert Wood Johnson Medical SchoolPiscataway, NJPiscataway, NJ

Addison Taylor, M.D.Addison Taylor, M.D.Professor of Medicine and Clinical PharmacologyProfessor of Medicine and Clinical PharmacologyBaylor College of MedicineBaylor College of MedicineHouston, TXHouston, TX

Joel Morganroth, M.D.Joel Morganroth, M.D.Chief Executive OfficerChief Executive OfficerPremier ResearchPremier ResearchPhiladelphia, PAPhiladelphia, PA

Gary G. Koch, Ph.D.Gary G. Koch, Ph.D.Statistical ConsultantStatistical ConsultantChapel Hill, NCChapel Hill, NC

Introduction

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TAP PresentationsTAP Presentations

General IntroductionGeneral Introduction….…….……..…………………….….…….……..……………………. Dr. FrestonDr. Freston

Apomorphine Pharmacokinetics and MetabolismApomorphine Pharmacokinetics and Metabolism………… Dr. BoppDr. Bopp

ED Treatments……………………………………………ED Treatments…………………………………………… Dr. HeatonDr. Heaton

Summary of EfficacySummary of Efficacy….……....…………………………….……....………………………… Dr. HeatonDr. Heaton

Summary of SafetySummary of Safety .….……...…………………………...….……...………………………….. Dr. Freston, Dr. Freston, Dr. FaganDr. Fagan

Benefit-Risk Assessment/SummaryBenefit-Risk Assessment/Summary…………..……….…………..………. Dr. FrestonDr. Freston

Introduction

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Topics Identified in FDA Briefing DocumentTopics Identified in FDA Briefing Document

Comparison to other marketed ED drugsComparison to other marketed ED drugs

Representative ED patient populationRepresentative ED patient population

Pharmacokinetic variabiltyPharmacokinetic variabilty

Clinical relevance of 2 mgClinical relevance of 2 mg

Efficacy in diabeticsEfficacy in diabetics

Discontinuations in long-term studiesDiscontinuations in long-term studies

HemodynamicsHemodynamics

Nitrate interactionNitrate interaction

Alcohol interactionAlcohol interaction

Introduction

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Erectile dysfunction is the“inability to attain and/or maintain penile erection sufficient for satisfactory

sexual performance”

NIH Consensus Development Panel on ImpotenceNIH Consensus Development Panel on ImpotenceJAMAJAMA 270: 83-90, 1993 270: 83-90, 1993

Definition

Erectile Dysfunction (ED)Erectile Dysfunction (ED)Introduction-ED

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Laumann EO, Paik P, Rosen RC. Laumann EO, Paik P, Rosen RC. JAMAJAMA 1999;281(6): 537-544 1999;281(6): 537-544

Erectile DysfunctionErectile Dysfunction

US National Health and Social Life Survey (NHSLS)-1992US National Health and Social Life Survey (NHSLS)-1992– Probability sample study of sexual behavior in men and womenProbability sample study of sexual behavior in men and women

– Demographically representative cohort of 1,410 men, ages 18-59Demographically representative cohort of 1,410 men, ages 18-59

– Correlated ED to other diagnosesCorrelated ED to other diagnoses– ED in 10% of men, ages 18-59ED in 10% of men, ages 18-59

Epidemiology and Demographics

Introduction-ED

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Feldman et al. Feldman et al. J. UrologyJ. Urology 151: 54-61, 1994. 151: 54-61, 1994.

Epidemiology and Demographics

Erectile DysfunctionErectile Dysfunction

Massachusetts Male Aging Study (MMAS) – 1987-1989Massachusetts Male Aging Study (MMAS) – 1987-1989– Cross-sectional, community-based, random sample survey of Cross-sectional, community-based, random sample survey of

1,300 men, ages 40-701,300 men, ages 40-70– Overall ED rate 52%Overall ED rate 52%

- Complete 10%Complete 10%- Moderate 25%Moderate 25%- Minimal 17%Minimal 17%

– Extrapolation to US: 30 million men with EDExtrapolation to US: 30 million men with ED

– ED correlated with age, health status, emotional function ED correlated with age, health status, emotional function

Introduction-ED

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Age Related Changes in Erectile StatusAge Related Changes in Erectile Status

0

5

10

15

20

25

30

35

40 45 50 55 60 65 70

MinimalModerateComplete

AgeAge

%%

Extracted from Feldman et al. Extracted from Feldman et al. J. UrologyJ. Urology 151: 54-61, 1994. 151: 54-61, 1994.

Massachusetts Male Aging Study (MMAS)Introduction-ED

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Feldman et al. Feldman et al. J. UrologyJ. Urology 151: 54-61, 1994. 151: 54-61, 1994. Johannes et al. Johannes et al. J. UrologyJ. Urology 163: 460-463, 2000. 163: 460-463, 2000.

ED is Associated with:

Massachusetts Male Aging StudyMassachusetts Male Aging Study

AgeAge

DiabetesDiabetes

HypertensionHypertension

Heart diseaseHeart disease

MedicationsMedications

DepressionDepression

Psychological factorsPsychological factors

Introduction-ED

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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%

ED PopulationED Population

11 Johannes et al. Johannes et al. J. UrologyJ. Urology 163: 460-463, 2000. 163: 460-463, 2000.

Introduction-Uprima

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Introduction to ApomorphineIntroduction to Apomorphine USP drugUSP drug

Used as a pharmacologic agent since 1869Used as a pharmacologic agent since 1869– Over 1,100 literature citationsOver 1,100 literature citations– Therapeutic doses ranged from 0.2 to 1500 mg Therapeutic doses ranged from 0.2 to 1500 mg

– Approximately 8,000 patients/subjects treated in clinical trialsApproximately 8,000 patients/subjects treated in clinical trials

Approved in 12 countries for multiple indications, including Approved in 12 countries for multiple indications, including Parkinson’s DiseaseParkinson’s Disease– Daily administrationDaily administration

– Usual dose 3 to 30 mg, subcutaneouslyUsual dose 3 to 30 mg, subcutaneously

Dopaminergic properties recognized in 1967Dopaminergic properties recognized in 1967

Central erectogenic effect recognized in the late 1970’s Central erectogenic effect recognized in the late 1970’s

Activates DA receptors in hypothalamic and limbic neural pathwaysActivates DA receptors in hypothalamic and limbic neural pathways

Introduction-Uprima

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Introduction to UprimaIntroduction to Uprima®®

Formulated to treat erectile dysfunction Formulated to treat erectile dysfunction

Delivered sublingually (SL)Delivered sublingually (SL)

Unique central mechanism of actionUnique central mechanism of action

Rapid onset of actionRapid onset of action

Effective for erectile dysfunction (ED) in a wide spectrum Effective for erectile dysfunction (ED) in a wide spectrum of organic and non-organic etiologies and severitiesof organic and non-organic etiologies and severities

Introduction-Uprima

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Introduction to UprimaIntroduction to Uprima®®

SafetySafety– No deathsNo deaths

– No myocardial infarctions (MI) related to study drugNo myocardial infarctions (MI) related to study drug

– No cerebrovascular accidents (CVAs) related to study drugNo cerebrovascular accidents (CVAs) related to study drug

– No priapismNo priapism

Nausea was the most frequent adverse event, syncope the Nausea was the most frequent adverse event, syncope the most significantmost significant

Introduction-Uprima

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Uprima® is indicated for the

treatment of erectile dysfunction

Proposed IndicationProposed Indication

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DosesDoses

Proposed doses: 2, 3 and 4 mg

Uprima® will be available as a sublingual tablet

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Rationale for UprimaRationale for Uprima®® Treatment of ED Treatment of ED

ED is associated with a number of diseases and conditionsED is associated with a number of diseases and conditions

Drugs with different modes of action are desirable as with other Drugs with different modes of action are desirable as with other disorders with complex pathophysiology, e.g., hypertension, disorders with complex pathophysiology, e.g., hypertension, depressiondepression

Current therapies are limited:Current therapies are limited:– No drug is effective in all patientsNo drug is effective in all patients– Each drug has its own unique adverse event profileEach drug has its own unique adverse event profile

– The currently approved agents work by peripheral mechanismsThe currently approved agents work by peripheral mechanisms

Treatment is strongly influenced by couple and physician choiceTreatment is strongly influenced by couple and physician choice

New drugs with different mechanisms offer significant New drugs with different mechanisms offer significant potential benefitspotential benefits

Introduction-Uprima

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Rationale for UprimaRationale for Uprima®® Treatment of ED Treatment of ED

UprimaUprima®® has a: has a:– Unique central mechanism of actionUnique central mechanism of action

– Novel delivery systemNovel delivery system

– Rapid onsetRapid onset

UprimaUprima®® has been studied in 27 clinical trials and has been shown to 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 be a safe and effective treatment for ED in patients with and without known organic diseasesknown organic diseases

Introduction-Uprima

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(N = 3,035)

Phase III– Three controlled crossover

– Dose-optimization

- One controlled parallel

- Five long-term, open-label

- One first dose administered at home

UprimaUprima®® Clinical Trials Clinical Trials

Phase IPhase I– PharmacokineticsPharmacokinetics

– Metabolic fateMetabolic fate

– Elderly (Elderly (≥≥65 years)65 years)

– Renal/Hepatic ImpairedRenal/Hepatic Impaired

– Drug interactions Drug interactions (Zofran(Zofran®®, Compazine, Compazine®®))

Special Phase I/II/IIISpecial Phase I/II/III– Antihypertensives and nitratesAntihypertensives and nitrates

– DiabeticsDiabetics

– AlcoholAlcohol

– ProstatectomyProstatectomy

– Spinal cord injurySpinal cord injury

Introduction/Uprima