# Presentation: 347575

## 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

## Speakers

**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

- Introduction

## TAP Participants

**John Seely, Ph.D.**	*Vice President, Research and Development*
**Dean Sundberg**	*Director, 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*

- Introduction

## TAP Participants (cont.)

**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*

- Introduction

## TAP Consultants

**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

- Introduction

## TAP Consultants

**Ray Rosen, Ph.D.****	***Department of Psychiatry***	**Robert Wood Johnson Medical School	Piscataway, NJ
**Addison Taylor, M.D.****	***Professor of Medicine and Clinical Pharmacology***	**Baylor 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

- Introduction

## TAP Presentations

- 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

- Introduction

## Topics Identified in FDA Briefing Document

- 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

- Introduction

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

*“**inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance”*

- NIH Consensus Development Panel on Impotence*JAMA* 270: 83-90, 1993

*Definition*

- Erectile Dysfunction (ED)

- Introduction-ED

## Erectile Dysfunction

- 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

*Epidemiology and Demographics*

- Introduction-ED

## Erectile Dysfunction

*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

- Introduction-ED

## Age Related Changes in Erectile Status

- Age

- %

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

- Massachusetts Male Aging Study (MMAS)

- Introduction-ED

## Massachusetts Male Aging Study

*ED is Associated with:*

- Age
- Diabetes
- Hypertension
- Heart disease
- Medications
- Depression
- Psychological factors

- Introduction-ED

## ED Population

**MMAS****1**

**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.

- Introduction-Uprima

## Introduction to Apomorphine

- 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

- Introduction-Uprima

## Introduction to 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

- Introduction-Uprima

## Introduction to 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

- Introduction-Uprima

## Proposed Indication

**Uprima****®**** is indicated for the****treatment of erectile dysfunction**

## Doses

**Proposed doses: 2, 3 and 4 mg****Uprima****®**** will be available as a ****sublingual tablet**

## Rationale for Uprima® Treatment of ED

- Rationale for Uprima® Treatment of ED

- 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

- Introduction-Uprima

## Rationale for Uprima® Treatment of ED

- 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

- Introduction-Uprima

## Uprima® Clinical Trials

- Phase III
- Three controlled crossover
- Dose-optimization
- One controlled parallel
- Five long-term, open-label
- One first dose administered at home

- Uprima® Clinical Trials

- Phase I
- Pharmacokinetics
- Metabolic fate
- Elderly (65 years)
- Renal/Hepatic Impaired
- Drug interactions (Zofran®, Compazine®)
- Special Phase I/II/III
- Antihypertensives and nitrates
- Diabetics
- Alcohol
- Prostatectomy
- Spinal cord injury

- Introduction/Uprima