Arthritis Advisory Committee Meeting

4/20/01


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Table of Contents

Arthritis Advisory Committee Meeting

Presentation Outline

Consultants

GL701 (prasterone)

Proposed Indications

Background

Systemic Lupus Erythematosus (SLE)

Damage within SLE SLICC/ACR Damage Index1

DHEA and SLE: Preclinical Rationale

DHEA and SLE: Clinical Rationale

Study GL95-02 Baseline Endogenous DHEA-S and Testosterone Levels with and without Corticosteroid Treatment

Rationale for Androgen Therapy of SLE

Efficacy

Stanford University Phase I/II Studies DHEA use in Women with SLE

Overview of Clinical Trial Design Process

Burden of Disease

Clinical Domains of SLE

Development of Efficacy Endpoints for GL701 Clinical Trials

GL701 Principal SLE Clinical Trials

Study GL94-01 Objective

GL94-01: Corticosteroid Reduction Study Design

GL94-01: Corticosteroid Reduction Entry Criteria

GL94-01: Corticosteroid Reduction Primary Efficacy Endpoint (Responder)

GL94-01: Corticosteroid Reduction Baseline Demographics

GL94-01: Corticosteroid Reduction Baseline Characteristics

GL94-01: Corticosteroid Reduction Impact of Baseline SLEDAI

GL94-01: Corticosteroid Reduction Blinded Analysis of Patients by Baseline SLEDAI

Study GL94-01: Corticosteroid Reduction Analysis of the 54 Patients with Baseline SLEDAI Scores of 0-2

GL94-01: Corticosteroid Reduction Impact of Baseline SLEDAI Score (cont)

GL94-01: Corticosteroid Reduction Patient Disposition

GL94-01: Corticosteroid Reduction Responders

Study GL94-01 Responders

Responder Rate by Treatment and by Prednisone Dose

GL94-01: Corticosteroid Reduction Mean Prednisone Reduction at Last Visit

GL94-01: Corticosteroid Reduction Individual Patient Example of Prednisone Dose Changes from Baseline to Last Visit

GL94-01: Corticosteroid Reduction Number of Days Prednisone ? 7.5 mg/day

GL94-01: Corticosteroid Reduction Efficacy Summary

Study GL95-02 Objective

GL95-02: Improvement in SLE Study Design

GL95-02: Improvement in SLE Entry Criteria

GL95-02: Improvement in SLE Primary Endpoint: Responder

GL95-02: Improvement in SLE Primary Endpoint: Responder (cont)

GL95-02: Improvement in SLE Development of the Analysis Plan

GL95-02: Improvement in SLE Defining Stabilization for Each Instrument: Concept of a “Window”

GL95-02: Improvement in SLE Evidence-based Confirmation of Pre-Defined “Window”

Example of a Patient Classified as a Responder when Using the “Window”

GL95-02: Improvement in SLE Secondary Endpoints

GL95-02: Improvement in SLE Baseline Demographics: All Randomized (ITT)

GL95-02: Improvement in SLE Baseline Characteristics: All Randomized (ITT)

GL95-02: Improvement in SLE Patient Disposition: All Randomized (ITT)

GL95-02: Improvement in SLE Percent Responders: ITT

GL95-02: Improvement in SLE Populations for Analysis

GL95-02: Improvement in SLE Reasons for Withdrawal for Patients Excluded from Per-Protocol Population

GL95-02: Improvement in SLE Baseline Characteristics of Excluded Patients from Per-Protocol Analysis

GL95-02: Improvement in SLE Percent Responders: Per-Protocol (With Window)

Study GL95-02 Responders by Baseline SLEDAI Score (Per-protocol)*

GL95-02: Improvement in SLE Patients with Baseline SLEDAI Scores 0-2 Are a Different Population (Inactive Disease)

GL95-02: Improvement in SLE Mean Changes in Scoring Instruments* (Per-protocol)

GL95-02: Improvement in SLE Flare Definition*

GL95-02: Improvement in SLE Percent of Patients with Flares

Study GL95-02 Selected Baseline Characteristics of Patients Assessed for BMD

GL95-02: Improvement in SLE Percent Change in BMD at 1-year (N = 37)

GL95-02: Improvement in SLE Percent of Patients with ɯ% Gain or Loss in BMD at 1 Year

GL95-02: Improvement in SLE Efficacy Summary

GBL96-01: Improvement in SLE – Taiwan Study Design

GBL96-01: Taiwan Study Demographic & Baseline Characteristics

GBL96-01: Taiwan Efficacy Results: ITT

GBL96-01: Taiwan Time to First Flare

Overall Efficacy Summary

Statistical Discussion

Statistical Issues

Strategy in Uncharted Territory

Target Population: Predefined Subgroup Analysis Based on SLEDAIɮ

Measurement Tolerance for Definition of Stabilization of Disease

Sensitivity Analysis - Per Patient Window (% Change from Baseline) Response Rate by Window Size Target Population Baseline SLEDAI > 2, GL95-02

Measurement Tolerance for Definition of Stabilization of Disease

GL94-01: Corticosteroid Reduction Differential Outcomes for Two Primary Endpoints

GL94-01: Corticosteroid Reduction Differential Outcomes for Two Primary Endpoints

GL95-02: Improvement in SLE Sensitivity Analysis ITT Subset (Baseline SLEDAI > 2) with Window

GL95-02: Improvement in SLE All Randomized ITT vs. Modified ITT vs. Per-Protocol Population

GL95-02: Improvement in SLE All Randomized ITT vs. Modified ITT vs. Per-Protocol Population (Continued)

Conclusion

Safety

Presentation of Safety Data

Duration of Exposure to GL701

All Reported Deaths: GL701 Group (N = 495)

All Reported Deaths: Placebo Patients who Never Received GL701 (N = 77)

Reported Serious Adverse Events from Studies GL94-01 and GL95-02

Studies GL94-01 & GL95-02 Withdrawals Due to Medically Serious Adverse Events

Premature Withdrawals: Total and Due to Androgenic Complaints from Studies GL95-02 and GL94-01

Adverse Events with a Frequency of ? 10%

Selected Adverse Events with a Frequency of ᝺%**

Mean Testosterone Pre and Post Treatment Pooled Data GL94-01 and GL95-02

Mean Estradiol Pre and Post Treatment Pooled Data GL94-01 and GL95-02 Pre-menopausal Patients

Mean / Median Estradiol Pre and Post Treatment Pooled Data GL94-01 and GL95-02 Post-menopausal Women* Not on Hormone Replacement Therapy

Mean / Median Estradiol Pre and Post Treatment Pooled Data GL94-01 and GL95-02 Post-menopausal Women on Hormone Replacement Therapy

Breast Cancer

Breast Cancer Incidence* Normalized for Period of Observation for all Patients and for those ? 45 years of age

Implications: Effects on Hormones

Routine Clinical Laboratories

Mean Changes in Serum Lipids

HDL-Cholesterol Change

Possible Mechanisms of Decrease in HDL and Triglycerides

Serum Complement

Study GL96-02 Percent Change in Serum C3 Complement in Normal Premenopausal Women (N=14)

Studies GL96-02 and GL94-01: Mean C3 Complement Percent Change from Baseline in Normal Women and SLE Patients During GL701 Treatment

Shift Table: Change in C3 from Baseline to Last Visit

Patients with C3 Normal to Low

Possible Mechanism of Action: Effects on C3 Complement

Implications: Effects on C3

Patients with Hematuria as an Adverse Event

Patients with Creatinine Increase of ? 0.3 mg/dl from Baseline to Last Visit

Patients with Clinically Meaningful Increases in 24 Hour Urine Protein at Last Visit

24 Hour Urine Protein at Last Visit: Patients with Doubling of Protein for at least 2 Visits

Study GL94-01 Renal Analysis per Patients Identified by FDA Reviewer Any Two Abnormalities*

Study GL95-02 Renal Analysis per Patients Identified by FDA Reviewer Any Two Abnormalities*

Signs of Renal Flare

Signs of Renal Flare

DHEA Administration in Severe SLE1 Responders at 6 Months

Implications: Renal Safety

Overall Safety Summary

Clinical Perspective

Review of GL701 Clinical Designs and Outcomes

GL94-01: Corticosteroid Reduction

GL94-01: Corticosteroid Reduction

GL95-02: Improvement in SLE

GL95-02: Improvement in SLE (cont)

GL95-02: Improvement in SLE

Potential Role of GL701 in the Management of SLE Patients

Author: Kenneth Schwartz