John R. Gibson, MD Senior Vice President Pharmaceutical Development Allergan, Inc.

8/18/99


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Table of Contents

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John R. Gibson, MD Senior Vice President Pharmaceutical Development Allergan, Inc.

Restasis™ (Cyclosporine Ophthalmic Emulsion 0.05%) Is Safe and Effective for the Treatment of Keratoconjunctivitis Sicca

Cyclosporine Regulatory History

Restasis™ for the Treatment of Keratoconjunctivitis Sicca (KCS; Dry Eye)

Restasis™ for the Treatment of Keratoconjunctivitis Sicca (KCS; Dry Eye)

Agenda

Agenda

Expert Respondents

Stephen C. Pflugfelder, MD Professor of Ophthalmology Bascom Palmer Eye Institute University of Miami

Objectives

Dry Eye — A Major Health Problem

Dry Eye — A Major Health Problem

Dry Eye — A Major Health Problem

Dry Eye — More than an Annoyance

Dry Eye — More Than an Annoyance

Dry Eye Causes Serious Corneal Disease

KCS May Be Sight Threatening

Dry Eye is a Major Risk Factor for Corneal Transplant Failure

NEI / Industry Definition of Dry Eye

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Clinical Diagnosis of Dry Eye

Schirmer Test

Dye Staining

Correlation of Rose Bengal and Schirmer

Variable Clinical Presentation and Poor Correlation Between Diagnostic Tests and Irritation Symptoms Make Dry Eye a Difficult Disease to Study

Evolution of Knowledge of KCS

Evolution of Knowledge of KCS

Evolution of Knowledge of KCS

Evolution of Dry Eye Therapy

Artificial Tears

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Anti-inflammatory Therapy for KCS

SS KCS

Steroid Toxicity

Unmet Need

CsA Therapy of Dry Eye

Cyclosporine Therapy of Dry Eye

Cyclosporine Therapy of Dry Eye

Michael E. Stern, Ph.D.

Presentation Agenda

Lacrimal Gland Functional Unit

Patient Population: Component Spectrum

Spontaneously Dry Eye Dog

Dry Eye Dog: Experimental Design

Dry Eye Dog Study

Dry Eye Dog

Dry Eye Dog Conjunctiva

Apoptosis (Programmed Cell Death)

TUNEL Assay: Apoptosis - Conjunctiva

TUNEL Assay: Apoptosis - Lacrimal Gland

Conclusion: Spontaneously Dry Eye Dog

NEI & Allergan Human Biopsy Study (Pilot)

NEI & Allergan Human Biopsy Study (Pilot)

NEI & Allergan Human Biopsy Study (Pilot)

NEI/Allergan Pilot Study: Marker Means

NEI/Allergan Pilot Study: Marker Means

Conclusions

Conclusions (con’t)

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Clinical Program Overview

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Phase 2 Study Design

Phase 2 Key Ocular Inclusion Criteria

Phase 2 Key Ocular Exclusion Criteria

Phase 2 Efficacy Assessments

Phase 2 Safety Assessments

Phase 2 Study Patient Disposition

Phase 2 Demographics

Phase 2 Efficacy Analysis

Phase 2 Efficacy Results Conjunctival Staining - Nasal

Phase 2 Efficacy Results OSDIŠ

Phase 2 Efficacy Results

Phase 2 Study Results

Phase 2 Safety Results

Phase 2 Conclusions

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Phase 3 Study Design

Phase 3 Key Ocular Inclusion Criteria

Phase 3 Key Ocular Exclusion Criteria

Phase 3 Efficacy Assessments

Phase 3 Efficacy Assessments

Phase 3 Safety Assessments

Phase 3 Enrollment

Phase 3 Patient Disposition

Phase 3 Demographics

Statistical Methods

Phase 3 Efficacy Results

Phase 3 Efficacy Results

Phase 3 Efficacy Results Corneal Staining

Phase 3 Efficacy Results Corneal Staining

Phase 3 Efficacy Results Sum of Staining

Phase 3 Efficacy Results Categorized Schirmer With Anesthesia

Phase 3 Efficacy Results OSDIŠ

Phase 3 Efficacy Results Faces

Phase 3 Efficacy Results Composite Symptoms

Phase 3 Efficacy Results Sensitivity to Light

Phase 3 Efficacy Results Itching

Phase 3 Efficacy Results

Clinical Significance

Signs and Symptoms Do Not Correlate

Multifactorial Nature of Dry Eye

Phase 3 Efficacy Results

Phase 3 Efficacy Results

Phase 3 Efficacy Results Change in Overall Disease Severity

Phase 3 Efficacy Results Change in Overall Disease Severity

Phase 3 Efficacy Results Change in Overall Disease Severity

Overall Disease Severity Analysis

Overall Disease Severity Responder Analysis

Phase 3 Specialized Laboratory Tests

Phase 3 Efficacy Results - CD3

CD3, CD4 and CD8

CD11a and HLA-DR

Phase 3 Efficacy Results

Efficacy Summary

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Presentation Outline

Ophthalmic Dose of Cyclosporine Is Small

Monitoring CsA Systemic Exposure

Comparative Systemic Exposure

Comparative Systemic Exposure

Comparative Systemic Exposure

Systemic Safety

Cyclosporine: Intraocular

Cyclosporine Is Lipophilic

Disposition of CsA Upon Reaching Ocular Surface

CsA: Minimal Intraocular Distribution

CsA: Steady Exposure at Ocular Surface

Comparative Tissue Concentrations of CsA

Ocular CsA Concentrations Corresponding to Systemic Drug Exposure from One-Year Toxicity Study of Oral CsA in Dogs

Ocular CsA Concentrations Corresponding to Systemic Drug Exposure in a Two-Year Oral Carcinogenicity Study in Rats

CsA: Long-Term Ocular Safety Demonstrated in Animals

CsA: Ocular Safety Demonstrated in Animals

PK and Safety Profile Supports Human Use

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Safety Presentation

Systemic and Serious Adverse Events

Phase 2 & 3 Pooled Safety Results

Phase 3 Safety Results

Phase 3 Safety Results

Phase 3 Safety Results

Phase 3 Safety Results

Phase 2/3 Safety Results

Safety Summary

Benefit : Risk Assessment

Study 002 - 0.05% CsA (n = 129)

Benefit : Risk

Benefit : Risk

Benefit: Risk Summary

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Current Therapies / Risk

Rose Bengal Staining

Current Therapies / Risk

Current Therapies / Risk

Cyclosporine

Cyclosporine / Benefit to Patient

Clinical Conclusion

John R. Gibson, MD Senior Vice President Pharmaceutical Development Allergan, Inc.

Conclusions Keratoconjunctivitis Sicca

Conclusions Restasis™

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Author: John Sigler: Proforma