Arthritis

Advisory Committee Meeting

April 19th, 2001

NDA 21-239: GL701 for

Systemic Lupus Erythematosus

Genelabs Technologies, Incorporated

5465.01 1
Presentation Outline
Intoduction Marc Gurwith, MD, JD
Vice President of Drug Development
and Chief Medical Officer
Genelabs Technologies, Inc.

Background Robert Lahita, MD, PhD

Professor of Medicine
New York Medical College

Efficacy Michelle Petri, MD, MPH

Associate Professor of Medicine
Johns Hopkins University School of Medicine

Statistical Frank Hurley, PhD

Senior Scientist
Quintiles

Safety Michelle Petri, MPH, MD

Clinical Perspective Murray Urowitz, MD, FRCPC
Professor of Medicine
University of Toronto
5466.02
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Consultants

Allan Tall, MD Vibeke Strand, MD

Professor of Medicine Clinical Professor of Medicine (VCF)
Columbia University Stanford University

William Kramer, PhD Samuel S.C. Yen, MD, DSc

President Professor of Reproductive Medicine
Kramer Consulting LLC University of California at San Diego

Michael Madaio, MD Ronald F. van Vollenhoven, MD, PhD

Professor of Medicine Associate Chief, Rheumatology
University of Pennsylvania Karolinska Hospital

5467.03
3
GL701 (prasterone)
• Prasterone is the USAN designation for DHEA
• Prasterone is the synthetic equivalent of DHEA
• GL701 is the Genelabs formulation of
Prasterone
CH3 O

CH3

5468.01 HO 4
Proposed Indications
• Improvement in SLE disease activity and/or
symptoms in women with mild to moderate SLE
• Reduction in corticosteroid requirements in
women with mild to moderate SLE

5469.01
5
 Background
Robert Lahita, MD PhD

5470.01 6
Systemic Lupus Erythematosus (SLE)
• Inflammatory autoimmune disease of unknown
etiology
• Morbidity
– Disease associated
– Corticosteroid associated
• Corticosteroid use as high as 89% 1-2

• Mortality 5-10% at 10 years

– Early - active disease and infections
– Late - atherosclerosis
1. Zonana-Nacach et al., 2000 2. Urowitz et al., ACR meeting 2000 (Abstract)

5471.01
7
Damage within SLE
SLICC/ACR Damage Index1
Damage Index Domain N %

Musculoskeletal 121 22%

Neuropsychiatric 110 20%
Renal 79 15%
Ocular 68 13%
Cardiovascular 47 9%
Pulmonary 39 7%
Skin 45 8%
Peripheral vascular 34 6%
Diabetes mellitus 30 6%
Gastrointestinal 19 4%
Malignancy 14 3%
Premature gonadal failure 12 2%
1. Zonana-Nacach et al., 2000
5472.01
8
DHEA and SLE:
Preclinical Rationale

• Female NZB/W murine model

– 100% mortality at 10 months
– Mortality reduced with DHEA administration 1-3
1. Lucas et al., 1985; 2. Matsunaga et al., 1989; 3. van Vollenhoven and McDevitt, 1992

• Murine in vitro studies

– Altered cytokine profile with DHEA
•  IL-6,  IL-2 4-5
4. Padgett and Loria, 1998; 5. Daynes et al., 1990

5474.02
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DHEA and SLE:
Clinical Rationale
• Sex distribution in SLE, 90% F : 10% M
• Low levels of DHEA and other androgens in women
with SLE 1-2
1. Lahita et al., 1987; 2. Verthelyi et al., 2001

• DHEA and testosterone further suppressed by

corticosteroid use 3
3. Hedman et al., 1989

• IL-2 levels suppressed in SLE 4-5

– In vitro (T lymphocytes) DHEA increased IL-2 production 6

• DHEA inhibits IL-6 secretion (mononuclear cells) 7

4. Alcocer-Varela and Alarcon-Segovia, 1982; 5. Linker-Israeli et al., 1983; 6. Suzuki et al., 1991;
7. Straub et al., 1998
5475.02
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Study GL95-02
Baseline Endogenous DHEA-S and Testosterone
Levels with and without Corticosteroid Treatment

Baseline DHEA-S Baseline Testosterone

200 30
180
25
160

Testosterone (ng/dl)
140
DHEA-S (ug/dl)

20
120
100 15
80
10
60
40
5
20
0 0
No Prednisone Prednisone No Prednisone Prednisone
N=145 N=183 N=172 N=202

5478.02
11
Rationale for Androgen Therapy of SLE

• Endocrinologic:
– Low androgen levels in women with lupus.
– Higher oxidation of testosterone at C17 in women with
lupus

• Immunologic:
– Decrease of IL4, IL5, IL6 (TH2) cytokines and increase
of IL2 (TH2)

5710.01
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 Efficacy
Michelle Petri, MD

5479.01 13
Stanford University Phase I/II Studies
DHEA use in Women with SLE
• Double-Blind, Placebo Controlled Study(1)
– 28 women with mild to moderate SLE treated for 3
months
• SLE Disease Activity Index (SLEDAI), Physician Visual Analog
Scale (VAS) stabilized or improved
• Patient VAS improved significantly (P = 0.022)
• Number of disease flares decreased (P = 0.053)
• Decreased prednisone requirements

• Open-Label Study(2)
– 50 women with SLE
– Improvements similar to those noted in the placebo
controlled study
1. van Vollenhoven et al., 1995 ; 2. van Vollenhoven et al., 1998
5480.03
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Overview of Clinical Trial Design Process

• Collaborative process between Genelabs, FDA

and Consultants
• 1995 Arthritis Advisory Committee
– Two efficacy per-patient endpoints
• steroid reduction
• improved disease activity

• 1999 Arthritis Advisory Committee

– Clinical trial endpoints discussed

5481.02
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Burden of Disease

• Most patients have either recurrent flares or

continuously active disease 1
• Flares remain common in established disease 2
• Morbidity also associated with corticosteroid
use 3

1. Barr et al., 1999 ; 2. Petri et al., 1991; 3. Zonana-Nacach, et al., 2000

5482.01
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Clinical Domains of SLE
• Disease Activity
SLEDAI
SLAM
• Organ Damage
Clinical Deterioration
SLICC Damage Index
• Health Related Quality of Life
KFSS
Patient VAS
SF-36
5483.02
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Development of Efficacy Endpoints for
GL701 Clinical Trials

1) Reduction in Corticosteroid Requirements

• If SLEDAI was stable or improved, an algorithm
dictated steroid taper
2) Improvement or Stabilization of SLE
• Based upon improvement or stabilization in
each of SLEDAI, SLAM, KFSS and Patient VAS,
without clinical deterioration

5488.02
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GL701 Principal SLE Clinical Trials
Total Patients
Two Prospective RCT for 1º Efficacy:
GL94-01 Corticosteroid Reduction 191
GL95-02 Improvement in SLE - US 381
Prospective RCT non-US IND by Taiwan licensee:
GBL96-01 Improvement in SLE - Taiwan 119
Long Term Safety (GL701):
GL95-01 Long-term Open Label Safety 371
Study
Male Lupus Study:
GL97-01 Male lupus study (ongoing, still 28
blinded)
5489.02
19
 Study GL94-01
Objective
Reduction in Corticosteroid
Requirements

5490.01 20
GL94-01: Corticosteroid Reduction

Study Design

• Double-blind, randomized, parallel design

• GL701 100 or 200 mg/day vs. placebo
• 7-9 months dosing, assessments monthly
• Prednisone dose reduced at each visit if SLEDAI
stable or improved, based on a pre-determined
algorithm

5491.01
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GL94-01: Corticosteroid Reduction

Entry Criteria

Women with Mild to Moderate Steroid Dependent

SLE Defined as:

–Stable prednisone dose at entry 10-30 mg/day

and
–Unsuccessful prednisone taper, or
no taper, stable dose in last 12 weeks

5492.03
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GL94-01: Corticosteroid Reduction

Primary Efficacy Endpoint (Responder)

Sustained prednisone reduction:

–Prednisone decreased to  7.5 mg/day
• For  2 consecutive months
• Including last visit

5493.01
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GL94-01: Corticosteroid Reduction

Baseline Demographics
Placebo GL701 100 mg GL701 200 mg
N=64 N=63 N=64

Age Mean 40.6 40.0 40.2

Median 39.0 39.0 41.0
Race
Caucasian 44 (69%) 36 (57%) 35 (55%)
African-American 17 (27%) 16 (25%) 17 (27%)
Hispanic 0 (0%) 8 (13%) 9 (14%)
Asian 2 (3%) 2 (3%) 1 (2%)
Menopausal Status
Post-Menopausal 21 (33%) 21 (33%) 12 (19%)
Pre-Menopausal 43 (67%) 42 (67%) 52 (81%)

5494.02
24
GL94-01: Corticosteroid Reduction

Baseline Characteristics
Placebo GL701 GL701 P-Values
100 mg 200 mg
N = 64 N = 63 N = 64
Prednisone mg/d Mean 15 14 14 ns
Median 15 13 10

Antimalarial Use 33 (52%) 27 (43%) 33 (52%) ns

SLEDAI Mean 6.4 5.5 5.9 ns

Median 4.0 4.0 6.0

DHEA-S (g/dl) Mean 29.0 28.9 86.5 ns

Median 22.0 17.0 18.0

5495.02
25
GL94-01: Corticosteroid Reduction

Impact of Baseline SLEDAI

• At the pre-study investigator meeting there was

concern whether patients with 0 or low SLEDAI
scores should be enrolled
– Indicative of either smoldering disease that would
flare when prednisone was tapered?
or
Indicative of inactive disease that was not steroid-
dependent?
• To address this, a blinded analysis of
responders, without treatment group attribution,
was reviewed prior to study unblinding
5496.03
26
GL94-01: Corticosteroid Reduction
Blinded Analysis of Patients by Baseline
SLEDAI

70 64% 65%
60
% Responders

50 43% 43%
40 31%
30
20 N=28 N=26 N=42 N=53 N=42

10
0
0 1-2 >2 - 4 >4 - 8 >8
Baseline SLEDAI Score
5497.01
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Study GL94-01: Corticosteroid Reduction
Analysis of the 54 Patients with Baseline
SLEDAI Scores of 0-2
• 28 (51%) with score of 0
• 20 (38%) with scores of 2 due to serologies
• 6 (11%) with scores of 1-2 due to other:
• Mucosal ulcers (N = 2)
• Leukopenia (N = 1)
• Alopecia (N = 1)
• New rash or pleurisy (N = 2)
Therefore, the SLEDAI 0-2 subgroup differed in
clinical characteristics, not just in response

5575.03
28
GL94-01: Corticosteroid Reduction

Impact of Baseline SLEDAI Score (cont)

• These data suggested that baseline SLEDAI >2

(yes/no) might represent different populations
• Therefore, patients with baseline SLEDAI > 2
were defined as a subgroup prior to unblinding

5498.01
29
GL94-01: Corticosteroid Reduction

Patient Disposition

Placebo GL701 GL701

100 mg 200 mg
Total Number Randomized 64 63 64
Total Number Completed 49 (77%) 46 (73%) 47 (73%)

Primary Reason for Withdrawal:

Due to Lack of Efficacy 7 (11%) 6 (10%) 5 (8%)
Due to Adverse Events 3 (5%) 4 (6%) 6 (9%)
Other Reasons 5 (8%) 7 (11%) 6 (9%)

5500.03
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GL94-01: Corticosteroid Reduction

Responders
60
^ Placebo
*
55% 100 mg
51%
50
44%
200 mg
Percent Responders

41%
40 38%

29%
30

20
26/64 28/63 35/64 13/45 18/47 23/45
10

0
All Patients SLEDAI >2
200 mg vs. placebo: ^P = 0.110 *P = 0.031
5501.01
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Study GL94-01

Responders
100 Placebo
GL701 100 mg
Percent Responders

80 GL701 200 mg
68%
63%
62%
60 56%
50% 50% 50%
44% 44%
40 33% 31%
22% 22% 25% 25%
12/19 3/6 3/6
20 10/16 8/18
5/9
7/16
12/24
2/9 1/4
13/19 5/15 2/9 2/8
4/13

0
0-2 3-4 5-8 8 - 12 >12
Baseline SLEDAI Score
5319.02
32
Responder Rate by Treatment and by
Prednisone Dose
• There was a statistically significant (P = 0.039)
difference in prednisone at baseline for the
SLEDAI > 2 group between GL701 200 mg and
placebo
Treatment Baseline Prednisone Dose
10 mg to 15 mg > 15 mg to 30 mg
No. of No. of No. of No. of
Pts Responders Pts Responders
Placebo 30 11 (36.7%) 15 2 (13.3%)
100 mg 39 17 (43.6%) 8 1 (12.5%)
200 mg 38 21 (55.3%) 7 2 (28.6%)

5648.02
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GL94-01: Corticosteroid Reduction

Mean Prednisone Reduction at Last Visit

Treatment Change % Change
Group (mg/d)
Mean/Median Mean/Median

Placebo -5.1/-5.5 -36/-50

GL701 100 mg -2.1/-5.0 -14/-41

GL701 200 mg -4.2/-6.0 -30/-53

• This endpoint does not fully reflect prednisone reduction

because:
– There was no algorithm for prednisone increases, and
– This analysis only reflected prednisone reduction on the last day
5502.02
34
GL94-01: Corticosteroid Reduction
Individual Patient Example of Prednisone
Dose Changes from Baseline to Last Visit

60 25
Prednisone
50
SLEDAI 20
Prednisone Dose (mg)

40

SLEDAI Score
15
30
10
20

5
10

0 0
0 1 2 3 4 5 6 7 8 9
Visit
5632.03
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GL94-01: Corticosteroid Reduction

Number of Days Prednisone  7.5 mg/day

All Patients Baseline SLEDAI > 2

Treatment Patients Mean(Median) Patients Mean(Median)
Placebo 64 71.7 (66.5) 45 59.7 (28.0)
100 mg 63 77.7 (81.0) 47 74.0 (55.0)
200 mg 64 92.1 (111.5^) 45 93.4* (110.0**)

* Parametric: GL701 200 mg vs. placebo, P = 0.015

** Nonparametric: GL701 200 mg vs. placebo, P = 0.013 by
Wilcoxon Rank-Sum test
^ Nonparametric GL701 200 mg vs. placebo, P = 0.069 by
Wilcoxon Rank-Sum test

5503.01
36
GL94-01: Corticosteroid Reduction

Efficacy Summary
• All patients:
– Sustained corticosteroid reduction (responder):
200 mg (55%) vs. placebo (41%), P = 0.110
– Greater number of days on prednisone  7.5 mg/day (P =
0.069)
• In patients with baseline SLEDAI > 2:
– Higher response rate: 200 mg (51%) vs. placebo (29%),
P = 0.031
– Dose response (test for trend, P = 0.033)
– Greater number of days on prednisone  7.5 mg/day (P =
0.015)
5505.02
37
 Study GL95-02
Objective
Improvement or stabilization
in SLE

5506.01 38
GL95-02: Improvement in SLE

Study Design
• Double-blind, randomized, parallel design
• 12 month study; assessments every 90 days
• GL701 200 mg/day vs. placebo
• Concomitant prednisone, immunosuppressives,
and antimalarials allowed at baseline and
continued unchanged
• DEXA for BMD performed at 8 investigator sites
for patients on chronic steroids prior to and
during study
5507.02
39
GL95-02: Improvement in SLE

Entry Criteria

• Women with active SLE

–SLAM  7 at screen and qualifying visits
–Prednisone  10 mg/day
–There was an evidence-based (GL94-01)
protocol amendment to require active SLE
(SLEDAI > 2) at baseline and enrollment
increased to capture more of these patients

5508.02
40
GL95-02: Improvement in SLE

Primary Endpoint: Responder

• Improvement or stabilization in all of the
following:
–Two disease activity measures:
SLEDAI and SLAM
–Two constitutional measures:
Patient VAS and KFSS
Based on mean of on-treatment visits, compared to
baseline mean
and
• No clinical deterioration

5514.03
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GL95-02: Improvement in SLE

Primary Endpoint: Responder (cont)

• Clinical Deterioration defined as:

– New or progressive organ disease
– Serious drug toxicity
– New or increased dose of prednisone or cytotoxic
agents

5515.01
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GL95-02: Improvement in SLE

Development of the Analysis Plan

• No previous experience
• Collaborative process with FDA and consultants
on study design
• Two additional key issues identified from
inception of study to completion of the final
analysis plan (Dec 95 - April 99)
– Defining stabilization as part of responder definition
(“window concept”)
– Identifying primary analysis data set

5509.02
43
GL95-02: Improvement in SLE
Defining Stabilization for Each Instrument:
Concept of a “Window”
• Two baseline pre-treatment evaluations of
disease activity typically used in rheumatology
clinical trials because of inherent variability in
instruments
• Test/re-test variability of the instruments used in
this trial is well known:
Liang et al, 1989; Bombardier et al, 1992; Petri et al, 1992;
DeLoach et al, 1998; Fitzgerald and Grossman, 1999

• Definition of “stabilization” was not finalized

prior to initiating the study
5581.03
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GL95-02: Improvement in SLE
Evidence-based Confirmation of Pre-Defined
“Window”
• Pre-defined window (Oct 1998): 0.5 SLEDAI and KFSS,
1.0 SLAM and 10 Patient VAS
• After study completion, a comparison of the differences
for each patient in the two baseline visits (screening and
qualifying visits < 10 days apart) showed the following
variability:
Instrument Mean  Median  Range  SD’s
SLEDAI 0.57 0.0 0 - 12 1.50
SLAM 0.71 0.0 0-8 1.12
Patient VAS 11.4 8.0 0 - 59 10.91
KFSS 0.54 0.37 0 - 5.8 0.61

This agrees well with the pre-defined window

5511.04
45
Example of a Patient Classified as a
Responder when Using the “Window”

SLEDAI Patient VAS SLAM KFSS

Baseline  Baseline  Baseline  Baseline 

4.00 -0.49 64.50 -27.50 13.00 -4.05 4.72 <0.01

5653.02
46
GL95-02: Improvement in SLE

Secondary Endpoints

• Mean changes in scoring instruments: SLEDAI,

SLAM, Patient VAS, KFSS
• Bone mineral density (BMD) by DEXA in patients
on chronic corticosteroids
• Proportion of patients with SLE flare

5516.02
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GL95-02: Improvement in SLE
Baseline Demographics: All Randomized
(ITT)
Placebo GL701 200 mg
N=192 N=189
Age
Mean 44 44
Median 43 44
Race
Caucasian 137 (71%) 146 (77%)
African-American 33 (17%) 22 (12%)
Asian 3 (2%) 2 (1%)
Hispanic 16 (8%) 15 (8%)
Menopausal Status
Post-menopausal 92 (48%) 83 (44%)
Pre-menopausal 100 (52%) 106 (56%)

5520.02
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GL95-02: Improvement in SLE
Baseline Characteristics: All Randomized
(ITT)
GL701 P-Values
Placebo 200 mg
N = 192 N = 189
SLAM Mean 12.0 12.2 ns
SLEDAI Mean 5.8 6.5 ns
KFSS Mean 5.7 5.9 ns
Patient VAS Mean 55.8 55.2 ns
Prednisone use 54% 55% ns
Prednisone mg/d Mean 6.9 6.4 ns
Median 7.3 5.0
Antimalarial use 25% 23% ns
Immunosuppressive use 15% 17% ns
Baseline DHEA-S (g/dl) 103 107 ns

5521.02
49
GL95-02: Improvement in SLE

Patient Disposition: All Randomized (ITT)

Placebo GL701
200 mg
Total number randomized 192 189
Total number completed 142 (74%) 124 (66%)

Primary Reason for Withdrawal:

Due to lack of efficacy 9 (5%) 11 (6%)
Due to adverse events 18 (9%) 31 (16%)
Other reasons 23 (12%) 23 (12%)

5519.03
50
GL95-02: Improvement in SLE

Percent Responders: ITT

70
Placebo 59%
60 GL701
Percent Responders

50 45%
40
31%
30 27%

20
52/192 58/189 65/146 86/147
10
0
All ITT SLEDAI > 2 with window

P = 0.438 * P = 0.017
5584.01
51
GL95-02: Improvement in SLE

Populations for Analysis

• Original protocol specified ITT
• Analysis plan specified per-protocol population (N = 346)
– Patients treated for  60 days and at least 1 assessment beyond
60 days
– Patients excluded from per protocol
• Excluded 32 patients with no post-baseline measurements
• Excluded 1 placebo patient who took no drug for first 90 days (non-
responder)
• Excluded 2 placebo patients with < 60 days treatment (1 responder, 1
non-responder)
– This population is virtually identical to a modified ITT (3 patient
difference)

5518.03
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GL95-02: Improvement in SLE
Reasons for Withdrawal for Patients
Excluded from Per-Protocol Population

Excluded
Patients
N = 35

Possibly Related Lack of Unrelated to Safety No Information

AE’s Efficacy or Efficacy

GL701 N = 4 GL701 N = 4 GL701 N = 8 GL701 N = 3

Placebo N = 3 Placebo N = 2 Placebo N = 7 Placebo N = 4

5574.02
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GL95-02: Improvement in SLE
Baseline Characteristics of Excluded
Patients from Per-Protocol Analysis
Excluded Patients Per-Protocol Patients
Placebo GL701 Placebo GL701
200mg 200mg
N = 16 N = 19 N = 176 N = 170
Mean
SLEDAI 5.6 5.8 5.8 6.5
SLAM 11.2 11.7 12.3 12.3
Patient VAS 58.8 54.9 55.1 55.2
KFSS 5.6 5.7 5.6 5.5
Age 43.9 47.2 43.8 44.1
Prednisone Dose(mg) 7.0 6.5 6.9 6.3
Frequency (%)
Race-Caucasian 12 (75%) 14 (74%) 125 (71%) 132 (78%)
Pre-Menopausal 10 (63%) 10 (53%) 90 (51%) 96 (56%)
SLEDAI>2 13 (81%) 15 (79%) 133(76%) 132 (78%)
Prednisone Use 5 (31%) 12 (63%) 98 (56%) 91 (54%)

5449.01
54
GL95-02: Improvement in SLE
Percent Responders: Per-Protocol
(With Window)
**
70 * 66%
58%
60
Percent Responders

49%
50 46%

40 Placebo
GL701
30
20
10 80/176 99/170 65/133 87/132
0
Per-Protocol SLEDAI > 2

* P = 0.018 ** P = 0.005
5522.01
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Study GL95-02
Responders by Baseline SLEDAI Score
(Per-protocol)*
100 Placebo
GL701 200 mg
Percent Responders

80 74%
66%
60% 57%
60 56%
47%
39%
40 35%32%

15/25 43/58
23% 8/12
12/38 27/32
20 15/43 20/36 35/62 5/22 5/13

0
0-2 3-4 5-8 8 - 12 >12
5320.02 *With Window
56
GL95-02: Improvement in SLE
Patients with Baseline SLEDAI Scores 0-2
Are a Different Population (Inactive Disease)

Baseline SLEDAI Score Study GL94-01 Study GL95-02

0 28 (51%) 38 (43%)

1-2 due to serologies 20 (38%) 25 (28%)

1-2 due to other 6 (11%) 25 (28%)

5610.01
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GL95-02: Improvement in SLE
Mean Changes in Scoring Instruments*
(Per-protocol)

Placebo GL701 P-Values

N = 133 N = 132
SLEDAI -2.57 -3.17 ns

Patient VAS -2.85 -7.22 0.057

KFSS -0.27 -0.32 ns

SLAM -2.63 -3.16 ns

*Baseline SLEDAI > 2
5525.02
58
GL95-02: Improvement in SLE

Flare Definition*
• Any one of the following:
Corticosteroids An increase of 2.5 mg for at
least 7 days for SLE related
reasons
Hospitalization Hospitalization for new SLE
manifestation
Immunosuppressives New use of or increase in dose
for at least 7 days for SLE
related reasons
Clinical Worsening New/worse CNS lupus,
vasculitis, myositis,
nephritis, thrombocytopenia
anemia
5517.01 *Definition of definite flare adapted from SELENA (NIH) study 59
GL95-02: Improvement in SLE

Percent of Patients with Flares

35
31%
30 27%
Percent with Flares

25 24%
22% Placebo
20 GL701
15
10
5 47/176 37/170 41/133 31/132
0
Per-Protocol SLEDAI > 2
P = ns P = ns
5526.01
60
Study GL95-02
Selected Baseline Characteristics of Patients
Assessed for BMD
Parameter Placebo GL701 200 mg
N = 19 N = 18
Age, Mean 44 46
Post-menopausal (%) 9 (47%) 10 (56%)
Prednisone mg/d, Mean 6.6 6.1
Estrogen use (%) 6 (31.6%) 3 (16.7%)
Immunosuppressive use (%) 5 (26.3%) 5 (27.8%)
Antimalarials (%) 4 (21%) 3 (16.7%)
Calcitonin (%) 0 (0.0%) 2 (11.1%)
Alendronate (%) 2 (10.5%) 0 (0.0%)
Calcium Supplements (%) 6 (31.5%) 9 (50%)
Hip T-score, Mean -0.8 -1.0
L-Spine T-score, Mean -0.8 -1.1

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GL95-02: Improvement in SLE

Percent Change in BMD at 1-year (N = 37)

3% * **

2%
Mean (SEM) % Change

1%

0%

-1%

-2% Placebo (n=19)

GL701 (n=18)

-3%
L-Spine Total Hip

5527.02 *P = 0.004 **P = 0.080

62
GL95-02: Improvement in SLE
Percent of Patients with >3% Gain or Loss in
BMD at 1%Year
of Patients with >3% Gain or Loss in BMD
at 1 Year in Study GL95-02
35
>3% Gain >3% Loss
30
Placebo (n=19)
Percent of Patients

25 GL701 (n=18)

20

15

10

5
0/19 4/18 1/19 5/18 6/19 2/18 1/19 1/18
0
L-Spine Hip L-Spine Hip
5444.01
63
GL95-02: Improvement in SLE

Efficacy Summary
• ITT:
– Baseline SLEDAI > 2 group: higher responder rate in GL701 (59%)
vs. placebo (45%), P=0.017 (with window)
• Per-protocol:
– Higher responder rate in GL701 (58%) vs. placebo (46%), P=0.018
– Baseline SLEDAI > 2 group: higher responder rate in GL701 (66%)
vs. placebo (49%), P=0.005
• Secondary:
– Improved BMD (L-Spine, P=0.004 vs. placebo) in patients on
chronic corticosteroids
– Patient global assessment improved
– Flares reduced

5528.02
64
GBL96-01: Improvement in SLE – Taiwan

Study Design
• Double-blind, randomized, parallel design
• Objective: disease improvement (similar to
GL95-02)
• Women with active SLE
– Baseline SLAM  7 and later amended to also require
SLEDAI > 2 required for entry

• GL701 200 mg vs. placebo

• 6 month study duration

5529.02
65
GBL96-01: Taiwan Study

Demographic & Baseline Characteristics

Placebo GL701 200 mg P-
N = 59 N = 60 values
Age Mean 32 33
ns
Median 32 32
Pre-menopausal 49 (83%) 51 (85%) ns
Prednisone Use 98% 97% ns
Prednisone mg/d Mean 6.7 7.0
ns
Median 5.0 7.5
Immunosuppressive Use 41% 40% ns
Antimalarial Use 70% 65% ns
SLEDAI Mean 6.6 8.2 ns
SLAM Mean 10.4 10.3 ns
DHEA-S g/dl Mean 55.9 70.6
ns
Median 43.3 43.1

5530.01
66
GBL96-01: Taiwan

Efficacy Results: ITT

Placebo GL701 200 mg
N = 59 N = 60 P-Values

SLAM % Change -17.5% -24.2% ns

Flare 20 (34%) 11 (18%) 0.044*

SLEDAI -1.4 -1.2 ns

Patient VAS 5.4 -5.5 0.005
Physician VAS -6.3 -9.2 ns

*Time to flare
5532.02
67
GBL96-01: Taiwan

Time to First Flare

GL701
Percent without Flares

P = 0.044

Placebo

5533.02 Days
68
Overall Efficacy Summary
• Disease Activity
– Improvement and stabilization in SLE activity
– Fewer patients with disease flares

• Damage
– Sustained reduction of corticosteroids
– Improvement in bone mineral density in prednisone-
treated patients

• Health Related Quality of Life

– Improvement in patient global assessment (VAS)

5535.01
69
 Statistical Discussion
Frank Hurley, PhD

5654.01 70
Statistical Issues
• Strategy of new drug development in uncharted
territory
• Target Population: Predefined Subgroup
analysis based on baseline SLEDAI>2
• Measurement tolerance for definition of
stabilization of disease
• Differential outcomes for two primary endpoints
for study GL94-01
• All randomized ITT vs. modified ITT vs. per-
protocol
5735.01
71
Strategy in Uncharted Territory
• Flexibility needed in design and analysis of clinical trials
in diseases such as SLE
• Flexible approach with careful planning, proper
execution and scientific rigor would not compromise
scientific validity
– Target population (SLEDAI >2, patients with active disease) based
on GL94-01 and implemented in an amendment in GL95-02
– Per protocol population
• Minimizing noise and maximizing ability to detect treatment
difference; a strategy needed without prior knowledge of treatment
effect using an instrument (responder) with unknown properties
– ITT population
• Preferred with prior knowledge of treatment effect in target
population and measurement instrument sensitivity - allows sample
size calculation with adequate statistical power
5736.01
72
Target Population:
Predefined Subgroup Analysis Based on
SLEDAI>2
• Baseline SLEDAI > 2 identified as clinically important
subgroup based on blinded review of aggregated data in
study GL94-01
• Prednisone target reduction achieved in 2/3 of subjects with
baseline SLEDAI  2 regardless of treatment group
• Analysis of GL94-01 shows significantly different responses
for the subgroups (placebo group: SLEDAI  2: 68%
responders; SLEDAI>2: 29% responders)
• SLEDAI >2 defined as protocol inclusion target population
criterion (by amendment) for study GL95-02
• The appropriateness of the target population definition was
confirmed in GL95-02 study

5737.01
73
Measurement Tolerance for
Definition of Stabilization of Disease

• All of the scales used to assess efficacy in GL95-02 have

inherent intra-patient, intra-rater variability (test-retest
variability)
• Definition of stabilization should include reasonable
tolerance to inherent measurement variability
– Example: ACR20 for improvement in rheumatoid arthritis trials
– Too stringent if no variability allowed in all four components

• Tolerance window concept discussed during early

stages of study; proposal finalized prior to breaking
blind
5738.01
74
Sensitivity Analysis - Per Patient Window (% Change from
Baseline) Response Rate by Window Size Target Population
Baseline SLEDAI > 2, GL95-02

Windows in this area

require improvement in
all 4 instruments
(SLAM, SLEDAI,
A too wide Patient VAS, KFSS)
window turns
the majority into
responders.
This is not
Clinically
Meaningful

5739.01
75
Measurement Tolerance for
Definition of Stabilization of Disease

• Robustness of pre-defined window assessed

using % of baseline score on per patient basis
– Conclusions unchanged for a range of windows from -
3% to -30%

• Placebo response of 30% to 45% is not

uncommon in mild to moderate diseases (esp.
rheumatologic diseases), particularly with
significant background therapy

5740.01
76
GL94-01: Corticosteroid Reduction
Differential Outcomes for Two Primary
Endpoints
• Protocol Specified two primary endpoints:
– Responder: decrease in prednisone dose to 7.5 mg/day for
three consecutive visits (i.e. 2 months) including last visit
(Subpart E)
– Percent decrease in prednisone dose at last visit compared to
baseline

• Responder endpoint based on down titration of dose to

pre-specified lower limit
• For the target population (SLEDAI>2), the GL701 200mg
group had a 51% responder rate compared to 29% for
the placebo group (p=0.031)

5741.01
77
GL94-01: Corticosteroid Reduction
Differential Outcomes for Two Primary
Endpoints
• Percent reduction in dose highly influenced by
large percentage dose increases in a small
number of patients
• The average percent reduction from baseline to
the last visit for the overall population was 30%
for the GL701 200mg compared to 35% for the
placebo group
• Seven patients increased 100-300% of baseline;
excluding these data results in mean percent
reduction of 48% for GL701 200 mg compared to
41% for placebo
5742.01
78
GL95-02: Improvement in SLE
Sensitivity Analysis ITT Subset
(Baseline SLEDAI > 2) with Window
• Patients had no post baseline assessments but:
– Reported deterioration, or
– Were discontinued early due to lack of efficacy
(These patients are reclassifed as non-responders)

• Results:
– GL701 200 mg Responders 58%
– Placebo Responders 43%
P = 0.012

5743.01
79
GL95-02: Improvement in SLE
All Randomized ITT vs. Modified ITT vs. Per-
Protocol Population
All Randomized ITT
– Patients without post-baseline measurements were considered
as non-responders:
• Patients without treatment
• Missing all post baseline measurements
• No evidence of clinical deterioration

Modified ITT
– Commonly used in clinical trials
– Patients excluded if no post baseline assessments and no known
clinical deterioration
Per Protocol Population
– Similar to modified ITT population, excludes 3 more patients: 2
for less then 60 days of treatment, 1 for a major protocol violation

5744.01
80
GL95-02: Improvement in SLE
All Randomized ITT vs. Modified ITT vs. Per-
Protocol Population (Continued)

• Results of Modified ITT and per-protocol results

closely similar
• No apparent bias observed using either
population
• No evidence that excluded patients are non-
random: test of null-hypothesis is valid

5745.01
81
Conclusion

• For the target population (SLEDAI>2) using the

defined windows for stabilization, all analyses
show highly significant responder rates for
GL701 200mg compared to placebo
• Use of target population and tolerance window
are matters of clinical judgment, not statistical
principle

5746.01
82
 Safety
Michelle Petri, MD

5536.02 83
Presentation of Safety Data
Safety Data Studies
Deaths, SAE’s, Pooled AE’s and GL94-01
Withdrawals GL95-02
GL95-01*

Hormone Changes and Review of GL94-01

Reported Breast Cancers GL95-02
GL95-01

Changes in Laboratory Values GL94-01

GL95-02
GL95-01
*GL95-01: Open-label Safety Study with GL701
5537.02
84
Duration of Exposure to GL701

<6  6  12  18
mos. mos. mos. mos.
Number of female 641 387 242 138
patients/healthy volunteers

Duration of treatment by menopausal status:

Number Pre-menopausal 229 150 86
Number Post-menopausal 158 92 52

5538.01
85
All Reported Deaths: GL701 Group (N = 495)
Cause of Death Age On/off Study
Respiratory failure 39 Off (14 wks.)

Pancreatitis 32 Off (9 mos.)

Cardiac arrest 46 Off (35 days)

SLE Complications 43 On
Cerebrovascular complications 50 On

Respiratory insufficiency 67 Off (24 days)

Metastatic carcinoid tumor 68 On
recurrence

Breast cancer 49 Off (15 mos.)

5554.01
86
All Reported Deaths: Placebo Patients who
Never Received GL701 (N = 77)
Cause of Death Age On/Off
Study
Pulmonary hypertension 35 On

Sudden death 65 On

Suicide 56 On

Suicide 47 On

Non-Hodgkin’s lymphoma 47 Off (6 wks)

Respiratory failure 34 Off (2 mos)

5555.01
87
Reported Serious Adverse Events from
Studies GL94-01 and GL95-02

Treatment Total SAE’s SAE’s Reported as

Reported Possibly related

Placebo (N = 256) 47 2
GL701 100 mg (N = 63) 7 0
GL701 200 mg (N = 253) 39 1

5631.01
88
Studies GL94-01 & GL95-02
Withdrawals Due to Medically Serious
Adverse Events
GL701 Placebo
• Hepatitis C • 2 Septicemia
• GI bleed • Hepatitis
• Psychosis • Suicidal depression
• Pulmonary edema • Pneumonia
• Renal deterioration • Coronary artery spasm
• Carcinoma of the lung
• Pseudotumor cerebri

5573.01
89
Premature Withdrawals: Total and Due to
Androgenic Complaints from Studies
GL95-02 and GL94-01

Placebo GL701 200 mg

N = 256 (%) N = 253 (%)
Total Withdrawals 65 (25%) 82 (32%)

All Safety Withdrawals 21 (8%) 37 (15%)

Androgenic Complaints* 2 (<1%) 12 (5%)

*Androgenic complaints defined as acne and hirsutism

5541.01
90
Adverse Events with a Frequency of  10%
COSTART Term Placebo GL701 200mg
N = 256 N = 253
Rash 77 (30.1%) 93 (36.8%)
Acne 39 (15.2%) 91 (36.0%)*
Arthralgia 95 (37.1%) 88 (34.8%)
Asthenia 70 (27.3%) 68 (26.9%)
Headache 76 (29.7%) 60 (23.7%)
Arthritis 58 (22.7%) 57 (22.5%)
Myalgia 79 (30.9%) 55 (21.7%)*
Abdominal Pain 34 (13.3%) 41 (16.2%)
Flu Syndrome 46 (18.0%) 40 (15.8%)
Stomatitis Ulcer 50 (19.5%) 38 (15.0%)
Hirsutism 6 (2.3%) 36 (14.2%)*
Fever 39 (15.2%) 36 (14.2%)
Depression 33 (12.9%) 35 (13.8%)
Alopecia 48 (18.8%) 35 (13.8%)
Infection 37 (14.5%) 26 (10.3%)
Sinusitis 33 (12.9%) 22 (8.7%)
Chest Pain 27 (10.5%) 22 (8.7%)
5539.01 *P<0.05, Placebo vs. GL701 200mg
91
Selected Adverse Events with a Frequency
of <10%**
Placebo GL701 200 mg
N = 256 N = 253
Back pain 16 (6.3%) 24 (9.5%)
Hypertension 7 (2.7%) 20 (7.9%)*
Lymphadenopathy 21 (8.2%) 12 (4.7%)
Dyspnea 22 (8.6%) 11 (4.3%)
Hematuria 1 (0.4%) 9 (3.6%)*
Pharyngitis 14 (5.5%) 6 (2.4%)
Creatinine increase 0 (0.0%) 6 (2.4%)*
Nasal ulcers 14 (5.5%) 5 (2.0%)*
Joint disorder 14 (5.5%) 4 (1.6%)*
Lupus rash 13 (5.1%) 4 (1.6%)*
Anorexia 10 (3.9%) 2 (0.8%)*
*P< 0.05, Placebo vs. GL701 200 mg
**Absolute difference of 3% or a statistically significant difference
5540.01
92
Mean Testosterone Pre and Post Treatment
Pooled Data GL94-01 and GL95-02
Pre-menopausal Post-menopausal
Upper limit of normal* Upper limit of normal*
100 100
Total Testosterone (ng/ml)

Total Testosterone (ng/ml)

Pre Treatment Pre Treatment
80 80
Last Visit Last Visit
60 60

40 40

20 20

0 0
Placebo 100 mg 200 mg Placebo 100 mg 200 mg
*Williams Textbook of Endocrinology, 1998
5542.01
93
Mean Estradiol Pre and Post Treatment
Pooled Data GL94-01 and GL95-02
Pre-menopausal Patients

120 Pre Treatment

Last Visit
Total Estradiol (pg/ml)

100

80

60

40

20

0
Placebo 100 mg 200 mg
N = 101 N = 41 N = 115
5543.01
94
Mean / Median Estradiol Pre and Post
Treatment Pooled Data GL94-01 and GL95-02
Post-menopausal Women* Not on Hormone Replacement Therapy

80

60
Estradiol (pg/ml)

40
Normal Median
Postmenopausal

20

0
Placebo 100 mg 200 mg
pre post pre post pre post
(N=26) (N=14) (N=23)
* Defined as women with estradiol levels of < 25 pg/ml
5544.01
95
Mean / Median Estradiol Pre and Post
Treatment Pooled Data GL94-01 and GL95-02
Post-menopausal Women on Hormone Replacement Therapy

160

140

120
Estradiol (pg/ml)

100
Median
80

60 Normal
Post-
40 Menopausal

20

0
Placebo 200 mg
pre post pre post
(N=40) (N=34)
5545.02
96
Breast Cancer
Age 45 48 49 61
Treatment Placebo GL701 GL701 GL701
Duration of 0 362 days 730 days 455 days
exposure

On/off study On study Off (15 mos.) Off (4 mos.) On study

Menopausal Pre Pre Pre Post

status

HRT use No No No Yes

E/P Receptor Unknown –/– +/+ –/–

Morphology Infiltrating Infiltrating Infiltrating Infiltrating

lobular ductal ductal ductal

5548.02
97
Breast Cancer Incidence*
Normalized for Period of Observation for all
Patients and for those  45 years of age

Treatment Cases/Pt-Years Cases/1000 Pt-Yrs

All Patients:
GL701 3/1573 1.9
Placebo 1/336 2.9

 45 years:
GL701 3/206 4.6
Placebo 1/24 6.5
*Control rates (no HRT) reported as 3.9 per 1000 women years and
unopposed estrogen use rates reported 4.4 per 1000 women years1
1. Schairer et al., 2000
5549.02
98
Implications:
Effects on Hormones
• Testosterone levels increased
– Androgenic effects observed were acne and hirsutism
• Estradiol levels increased in post-menopausal women
– Increases consistent with those reported for hormone
replacement therapy
– No increase in breast carcinoma – one to two years
observation
– No significant increase in vaginal bleeding
– No endometrial hyperplasia observed

• Increased bone mineral density

5553.02
99
Routine Clinical Laboratories

• No evidence of significant effects on:

– CBC
– Liver function tests
– BUN and Creatinine
– Routine serum chemistries

5556.01
100
Mean Changes in Serum Lipids

25
20 placebo
Mean (SEM) Change (mg/dl)

GL701 100 mg
15 GL701 200 mg
10
* * * * *
5
0
-5
-10
-15
Mean Baseline:
-20
196 214 195 56 52 52 117 136 120 138 161 145
-25
Tot-C HDL-C LDL-C Tot-TG
* P<0.05 GL701 vs. placebo
5557.01
101
HDL-Cholesterol Change
Double-Blind Open-Label
2
Change from Baseline (mg/dl)

-2
Baseline means
Placebo 56.0 mg/dl
-4 GL701 52.3 mg/dl

-6

-8

-10
0 3 6 9 12 15 18 21 24
Month
Placebo to GL701 (N=255)
GL701 to GL701 (N=251)
5558.01
102
Possible Mechanisms of Decrease in HDL
and Triglycerides
• Testosterone increases hepatic lipase activity
• Increased hepatic lipase activity enhances HDL
clearance, and possibly affects reverse
cholesterol transport (removal of cholesterol
from tissues)
• Experimental evidence suggests an increase in
hepatic lipase activity may be anti-atherogenic
• Rabbit studies with DHEA indicate anti-
atherogenic effects 1-4; mechanism unknown
1. Alexandersen et al., 1999; 2. Arad et al.,1989; 3. Eich et al., 1993; 4. Gordon et al.,
1988

5559.01
103
 Serum Complement

5756.01 104
Study GL96-02
Percent Change in Serum C3 Complement
in Normal Premenopausal Women (N=14)

20%
in C3 Complement
Percent Change

10%

0%

-10%

Mean -2.3%
-20%
Median -1.4%
-30%
Baseline Day 28 GL701 200 mg

5446.01
105
Studies GL96-02 and GL94-01: Mean C3 Complement
Percent Change from Baseline
C3 Complement in Normal
% Change from Baseline Women
in Normal Women during GL701 and SLE Patients
and SLE Patients During GL701 Treatment
Study GL96-02 Study GL94-01
Normal Female Volunteers SLE Patients
6%
Month 1
% Change from Baseline

Month 1 Month 2
4%

2%

0%

-2%

-4%

-6%
200 mg
GL701 Pla
Placebo 100 mg 200
GL701 mg Placebo
GL701 Pla 100 mg 200
GL701 mg
GL701
200 mg 100 mg 200 mg 100 mg 200 mg

5639.01
106
Shift Table: Change in C3 from Baseline to
Last Visit

Low* to Normal to
Normal Low

Placebo (N=256) 16 (6.7%) 14 (5.8%)

GL701 200 mg (N = 253) 8 (3.4%) 36 (15.5%)

*Less than 85 mg/dl

5561.01
107
Patients with C3 Normal to Low
• Of 14 placebo with decrease in C3:
– 2 had isolated new onset hematuria

• Of 36 GL701 200 mg with decrease in C3:

– 3 had isolated new onset hematuria
– 2 had isolated increased proteinuria
• 2592  24,062 mg/24 hr
• 2420  4648 mg/24 hr
– 2 had increase in serum creatinine ( 0.3 mg/dl)
• 2.2  2.6 mg/dl
• 4.2  5.2 mg/dl

• None of these patients (placebo or GL701 200 mg)

received immunosuppressive therapy for renal lupus.
5562.04
108
Possible Mechanism of Action:
Effects on C3 Complement
• Mechanism may be decreased production rather
than increased consumption
– DHEA decreases IL-6 production, which may mediate
hepatic complement synthesis
– DHEA may decrease hepatic production of some
proteins including complement
– Testosterone therapy for Klinefelter’s has been shown
to decrease serum complement - no autoimmune
manifestations1
1. Yesilova, et al. 2000

5563.01
109
Implications:
Effects on C3

• Decrease in C3 did not appear to correlate with

increased disease activity
• Appears not to be associated with worsening
renal disease

5564.01
110
Patients with Hematuria as an Adverse Event
Placebo GL701 100 mg GL701 200 mg
N = 256 N = 63 N = 253

Menses or UTI (no RBC 1 0 3

in urine at last visit)

Hematuria  5 RBC/HPF 0 1 3

Hematuria > 5 RBC/HPF 0 0 2

without renal changes

Hematuria > 5 RBC/HPF 0 1 1

with renal changes

Total 1 (0.4%) 2 (3.2%) 9 (3.6%)

5546.03
111
Patients with Creatinine Increase of
 0.3 mg/dl from Baseline to Last Visit

Placebo 100 mg 200 mg

(N=256) (N=63) (N=253)
Increase in Creatinine 4 (1.6%) 3 (4.8%) 6 (2.4%)
> 0.3 mg/dl
New hematuria, proteinuria, 2 (0.8%) 3 (4.8%) 2 (0.8%)
or immunosuppressive
therapy

5547.03
112
Patients with Clinically Meaningful Increases
in 24 Hour Urine Protein at Last Visit
Placebo 100 mg 200 mg
(N = 256) (N = 63) (N = 253)
Proteinuria at Baseline 126 (49.2%) 43 (68.3%) 141 (55.7%)
>150 mg/24h
Increase in Proteinuria 7/126 6/43 11/141
 If baseline > 1000 mg/24h, then (5.6%) (14.0%) (7.8%)
approximate doubling (>70%) of
baseline 5 1 5
 If baseline < 1000 mg/24h, then 
> 500 mg/24h 2 5 6
Siginificant renal AE, > 0.3 mg/dl 4 1 6
increase in serum creatinine, or new
immunosuppressive therapy
No Proteinuria at Baseline 130 (50.8%) 20 (86.0%) 112 (44.3%)
< 150 mg/24h
Increase in Proteinuria 1 (0.8%) 0 0
  > 500 mg/24h

5578.02
113
24 Hour Urine Protein at Last Visit:
Patients with Doubling of Protein for at least
2 Visits
GL701 N = 23
Normal at Baseline Placebo N = 14

Normal Mild Modest Moderate

(<300) (300-1,000) (>1,000)
GL701 N = 7 GL701 N = 11 GL701 N = 5* GL701 N = 0
Placebo N = 2 Placebo N = 8 Placebo N = 4 Placebo N = 0
*348, 424, 303,
404, 325

5463.01
114
Study GL94-01
Renal Analysis per Patients Identified by
FDA Reviewer Any Two Abnormalities*
Patient # CCr Proteinuria RBCs C3 to Renal Conclusion
low AE
GL94-01
Placebo
(N=2)
20155 X Inc Proteinuria
GL701 100
mg (N=2)
17332 X Inc Proteinuria
18217 X X Decreased CCr
GL701 200
mg (N=7)
3149 X
14111 X X
18140 X X SLE nephritis
18143 X
20156 X X Inc protein/rbcs

* C3 and/or C4 counted as one

Decreased CCr: from normal to abnormal; any decrease from abnormal BL
Increased Total proteinuria: from none to 500; from abnormal to  1000
Rbcs: from 0 to 10; from abnormal at BL to 25
5697.01 Complement 3: from normal at BL to < lower limits of normal
115
Study GL95-02
Renal Analysis per Patients Identified by
FDA Reviewer Any Two Abnormalities*
Patient # CCr Proteinuria RBCs C3 Renal Conclusion
to AE
low
GL95-02
Placebo
(N=5)
14483 X X X X SLE nephritis
14551
46643 X X
46696 X X Decreased CCr
48819
GL701 200
mg (N=8)
15521
18724 X
19454 X X Inc Proteinuria, rbcs
20770 X X X X SLE nephritis
41535
* C3 and/or C4 counted as one
Decreased CCr: from normal to abnormal; any decrease from abnormal BL
Increased Total proteinuria: from none to 500; from abnormal to  1000
Rbcs: from 0 to 10; from abnormal at BL to 25
5698.01 Complement 3: from normal at BL to < lower limits of normal 116
Signs of Renal Flare
Study GL94-01 Placebo 100 mg 200 mg
(N=64) (N=63) (N=64)
Baseline hematuria 17 (26.6%) 15 (23.8%) 13 (20.3%)
Baseline proteinuria (mg/24 hr) 33 (51.6%) 44 (69.4%) 42 (65.6%)
Patients meeting criteria of 14 (21.8%) 28 (44.4%) 22 (34.4%)
renal flare

Study GL95-02 Placebo – 200 mg

(N=192) (N=189)
Baseline hematuria 38 (20.0%) – 41 (21.7%)
Baseline proteinuria (mg/24 hr) 94 (49.0%) – 99 (52.4%)
Patients meeting criteria of 23 (12.0%) – 23 (12.2%)
renal flare
Definition of renal flare: Met two or more of the following criteria during the study:
1. > 5 RBC/hpf
2. 24h urine protein: > 500 mg/24h increase from baseline
3. Serum creatinine: > 0.3 mg/dl increase from baseline
4. Serum complement or dsDNA: 25% decrease in C3 or C4, or doubling of dsDNA
5647.02
117
Signs of Renal Flare
Study GL94-01 Placebo 100 mg 200 mg
(N = 64) (N = 63) (N = 64)
Normal at baseline
Patients meeting at least one criterion for renal signal 11 12 12
Patients meeting at least 2 criteria for renal signal 1 0 3
Abnormal at baseline
Patients meeting at least one criterion for renal signal 17 27 23
Patients meeting at least 2 criteria for renal signal 2 8 2

Study GL95-02 Placebo 200 mg

(N = 192) (N = 189)
Normal at baseline
Patients meeting at least one criterion for renal signal 21 – 33
Patients meeting at least 2 criteria for renal signal 2 – 2
Abnormal at baseline
Patients meeting at least one criterion for renal signal 10 – 13
Patients meeting at least 2 criteria for renal signal 0 – 2

Medical Reviewer’s definition of a renal signal, except decrease in C3, C4, or

5707.01 increase in dsDNA counted only once.
118
DHEA Administration in Severe SLE1
Responders at 6 Months
• Responder definition
– Creatinine clearance stable
– >50% reduction proteinuria
– Inactive urinary sediment

• Responders (patients with nephritis):

– DHEA 6/8
– Placebo 4/6

1. van Vollenhoven et al, 1999

5693.01
119
Implications:

Renal Safety
• Signal for renal safety in GL94-01 is not confirmed in
GL95-02
• The reduction in C3 appears to be a marker of reduced
hepatic synthesis, not a renal safety signal
• Androgens may increase renal plasma flow but do not
cause glomerular hypertension. This may explain the
few patients who had mild to modest increases in
proteinuria on GL701, without overt evidence of
nephritis.
• DHEA administration to severely ill lupus patients with
nephritis led to improvement in 6 out of 8, with none
worsening

5576.03
120
Overall Safety Summary
• Majority of adverse events are androgenic (acne and
hirsutism) and only led to a small number of withdrawals
• Clinical laboratory changes reflect known hormonal
effects, primarily androgenic
– Increase in testosterone
– Decrease in triglycerides, HDL-C
– Increase in estradiol

• Decrease in C3, without adverse clinical consequences

• Modest increase in proteinuria observed in some GL701-
treated patients, but without any signal of renal flares,
including decreased creatinine clearance
5565.04
121
 Clinical Perspective
Murray Urowitz, MD

5566.01 122
Review of GL701 Clinical Designs and
Outcomes

• Rationale
• Challenges in study design
• Advantage
• Outcomes: Important Findings

5757.01
123
GL94-01: Corticosteroid Reduction
• Rationale
– Large body of patients are on long-term use of
steroids to control disease activity
• This contributes to additional, and potentially significant,
damage in SLE

• Challenges in study design

– Forced titration of steroids inherently difficult
– Other efficacy variables expected to remain stable
– Some patients, assumed to be steroid dependent, are
mistakenly kept on unnecessarily high doses of
steroids: this affected the entry criteria for steroid
dependence
5567.01
124
GL94-01: Corticosteroid Reduction
• Advantage
– Clinically meaningful and practical objective
• Outcomes: Important Findings
– Correlation between disease activity and steroid
dependency
• Most patients with SLEDAI  2 were clinically inactive and
capable of prednisone reduction
– Greater treatment effect (i.e., steroid reduction)
demonstrated in SLEDAI > 2 subgroup
– Treatment effect was present in those receiving high
doses [>15-30 mg/d] as well as low doses [10-15 mg/d]
of prednisone at study entry
5568.01
125
GL95-02: Improvement in SLE
• Rationale for Study Design
– A significant number of SLE patients flare or deteriorate
over a 1-year period
• Challenges
– Defining an appropriate endpoint
• Incorporating multiple instruments into one composite
“responder” endpoint
• Characterizing stable disease as a responder endpoint:

“Window” concept developed to account for instrument variability

• Responder definition previously untested in lupus clinical trials

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 GL95-02: Improvement in SLE (cont)
• Challenges (cont)
– Identifying the patient population that could be treated
over 1-year
• Mild to Moderate SLE
• Patients needed to be on stable doses of steroids, yet active
• Maintaining patients in study for 1-year

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GL95-02: Improvement in SLE
• Advantage
– Responder integrated 3 domains of SLE over a 1-year
period to fully assess the impact on lupus
– Deterioration was captured at any time during study,
not just at the pre-determined visits

• Outcomes
– “Responder” composite endpoint proved successful
– Use of flare to assess efficacy at any time point
– Importance of identifying active SLE patient
population (i.e.,SLEDAI > 2) confirmed
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Potential Role of GL701 in the Management
of SLE Patients
• For Mild to Moderate Lupus
– Effective in controlling disease manifestations
– Positive impact on health related quality of life
• Patient self assessment of global impact of disease
• Ability to allow withdrawal of steroids while preventing
worsening of disease activity
– Benefits greater than risks
• Benefit has been demonstrated for all disease domains
• Possible long term benefits include improved BMD
• Important immediate risks not identified in clinical trials
• Possibility of synergy with other lupus drugs

• Place in Lupus therapy armamentarium

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