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
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