1 Arthritis Advisory Committee Meeting April 19th, 2001 NDA
21-239: GL701 for Systemic Lupus Erythematosus Genelabs
Technologies, Incorporated 5465.01
Slide 2
2 Presentation Outline 5466.02
Slide 3
3 Consultants 5467.03
Slide 4
4 GL701 (prasterone) Prasterone is the USAN designation for
DHEA Prasterone is the synthetic equivalent of DHEA GL701 is the
Genelabs formulation of Prasterone 5468.01
Slide 5
5 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
Slide 6
6 Background Robert Lahita, MD PhD 5470.01
Slide 7
7 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
Slide 8
8 Damage within SLE SLICC/ACR Damage Index 1 5472.01
Slide 9
9 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
Slide 10
10 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
Slide 11
11 Study GL95-02 Baseline Endogenous DHEA-S and Testosterone
Levels with and without Corticosteroid Treatment 5478.02 Baseline
TestosteroneBaseline DHEA-S
Slide 12
12 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 IL
4, IL 5, IL 6 (TH2) cytokines and increase of IL2 (TH2)
5710.01
Slide 13
13 Efficacy Michelle Petri, MD 5479.01
Slide 14
14 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
Slide 15
15 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
Slide 16
16 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
Slide 17
17 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
Slide 18
18 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
Slide 19
19 GL701 Principal SLE Clinical Trials 5489.02
Slide 20
20 Study GL94-01 Objective Reduction in Corticosteroid
Requirements 5490.01
Slide 21
21 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
Slide 22
22 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
Slide 23
23 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
26 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
Slide 27
27 GL94-01: Corticosteroid Reduction Blinded Analysis of
Patients by Baseline SLEDAI N=28 N=26 N=42 N=53 N=42 5497.01
Slide 28
28 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) 5575.03 Therefore,
the SLEDAI 0-2 subgroup differed in clinical characteristics, not
just in response
Slide 29
29 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
33 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 5648.02
Slide 34
34 GL94-01: Corticosteroid Reduction Mean Prednisone Reduction
at Last Visit 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
Slide 35
35 GL94-01: Corticosteroid Reduction Individual Patient Example
of Prednisone Dose Changes from Baseline to Last Visit 5632.03
Slide 36
36 GL94-01: Corticosteroid Reduction Number of Days Prednisone
7.5 mg/day 5503.01 * 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
Slide 37
37 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
Slide 38
38 Study GL95-02 Objective Improvement or stabilization in SLE
5506.01
Slide 39
39 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
Slide 40
40 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
Slide 41
41 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
Slide 42
42 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
Slide 43
43 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
Slide 44
44 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
Slide 45
45 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: 5511.04 This agrees well with the
pre-defined window
Slide 46
46 Example of a Patient Classified as a Responder when Using
the Window 5653.02
Slide 47
47 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
Slide 48
48 GL95-02: Improvement in SLE Baseline Demographics: All
Randomized (ITT) 5520.02
Slide 49
49 GL95-02: Improvement in SLE Baseline Characteristics: All
Randomized (ITT) 5521.02
Slide 50
50 GL95-02: Improvement in SLE Patient Disposition: All
Randomized (ITT) 5519.03
Slide 51
51 GL95-02: Improvement in SLE Percent Responders: ITT 5584.01
P = 0.438 52/192 58/18965/146 86/147 * P = 0.017
Slide 52
52 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
Slide 53
53 GL95-02: Improvement in SLE Reasons for Withdrawal for
Patients Excluded from Per-Protocol Population Excluded Patients N
= 35 Possibly Related AEs GL701 N = 4 Placebo N = 3 Lack of
Efficacy GL701 N = 4 Placebo N = 2 Unrelated to Safety or Efficacy
GL701N = 8 Placebo N = 7 No Information GL701 N = 3 Placebo N = 4
5574.02
Slide 54
54 GL95-02: Improvement in SLE Baseline Characteristics of
Excluded Patients from Per-Protocol Analysis 5449.01
Slide 55
55 GL95-02: Improvement in SLE Percent Responders: Per-Protocol
(With Window) * P = 0.018 80/17699/17065/133 87/132 ** P = 0.005
5522.01
57 GL95-02: Improvement in SLE Patients with Baseline SLEDAI
Scores 0-2 Are a Different Population (Inactive Disease) Baseline
SLEDAI ScoreStudy GL94-01Study GL95-02 028 (51%)38 (43%) 1-2 due to
serologies20 (38%)25 (28%) 1-2 due to other 6 (11%)25 (28%)
5610.01
Slide 58
58 GL95-02: Improvement in SLE Mean Changes in Scoring
Instruments* (Per-protocol) *Baseline SLEDAI > 2 5525.02
Slide 59
59 GL95-02: Improvement in SLE Flare Definition* Any one of the
following: *Definition of definite flare adapted from SELENA (NIH)
study 5517.01
Slide 60
60 GL95-02: Improvement in SLE Percent of Patients with Flares
P = ns 47/17637/17041/133 31/132 5526.01
Slide 61
61 Study GL95-02 Selected Baseline Characteristics of Patients
Assessed for BMD 5315.04
Slide 62
62 GL95-02: Improvement in SLE Percent Change in BMD at 1-year
(N = 37) 5527.02 *P = 0.004**P = 0.080 ***
Slide 63
63 GL95-02: Improvement in SLE Percent of Patients with >3%
Gain or Loss in BMD at 1 Year 5444.01
Slide 64
64 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
Slide 65
65 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
Slide 66
66 GBL96-01: Taiwan Study Demographic & Baseline
Characteristics 5530.01
Slide 67
67 GBL96-01: Taiwan Efficacy Results: ITT 5532.02
Slide 68
68 GBL96-01: Taiwan Time to First Flare GL701 Placebo Days
Percent without Flares 5533.02 P = 0.044
Slide 69
69 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
Slide 70
70 Statistical Discussion Frank Hurley, PhD 5654.01
Slide 71
71 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
Slide 72
72 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
Slide 73
73 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
Slide 74
74 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
Slide 75
75 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, Patient VAS, KFSS) A too wide
window turns the majority into responders. This is not Clinically
Meaningful 5739.01
Slide 76
76 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
Slide 77
77 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
Slide 78
78 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
Slide 79
79 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
Slide 80
80 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
Slide 81
81 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
Slide 82
82 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
Slide 83
83 Safety Michelle Petri, MD 5536.02
Slide 84
84 Presentation of Safety Data 5537.02
Slide 85
85 Duration of Exposure to GL701 5538.01
Slide 86
86 All Reported Deaths: GL701 Group (N = 495) 5554.01
Slide 87
87 All Reported Deaths: Placebo Patients who Never Received
GL701 (N = 77) 5555.01
Slide 88
88 Reported Serious Adverse Events from Studies GL94-01 and
GL95-02 5631.01
Slide 89
89 Studies GL94-01 & GL95-02 Withdrawals Due to Medically
Serious Adverse Events GL701 Hepatitis C GI bleed Psychosis
Pulmonary edema Renal deterioration Placebo 2 Septicemia Hepatitis
Suicidal depression Pneumonia Coronary artery spasm Carcinoma of
the lung Pseudotumor cerebri 5573.01
Slide 90
90 Premature Withdrawals: Total and Due to Androgenic
Complaints from Studies GL95-02 and GL94-01 5541.01
Slide 91
91 Adverse Events with a Frequency of 10% 5539.01
Slide 92
92 Selected Adverse Events with a Frequency of
114 24 Hour Urine Protein at Last Visit: Patients with Doubling
of Protein for at least 2 Visits 5463.01 GL701 N = 23 Placebo N =
14 Normal GL701 N = 7 Placebo N = 2 Modest (300-1,000) GL701 N = 5*
Placebo N = 4 Mild (1,000) GL701 N = 0 Placebo N = 0 Normal at
Baseline *348, 424, 303, 404, 325
Slide 115
115 Study GL94-01 Renal Analysis per Patients Identified by FDA
Reviewer Any Two Abnormalities* 5697.01 * 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
Complement 3: from normal at BL to < lower limits of normal
Slide 116
116 Study GL95-02 Renal Analysis per Patients Identified by FDA
Reviewer Any Two Abnormalities* 5698.01 * 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
Complement 3: from normal at BL to < lower limits of normal
Slide 117
117 Signs of Renal Flare 5647.02
Slide 118
118 Signs of Renal Flare 5707.01 Medical Reviewers definition
of a renal signal, except decrease in C3, C4, or increase in dsDNA
counted only once.
Slide 119
119 DHEA Administration in Severe SLE 1 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
Slide 120
120 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
Slide 121
121 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
123 Review of GL701 Clinical Designs and Outcomes Rationale
Challenges in study design Advantage Outcomes: Important Findings
5757.01
Slide 124
124 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
Slide 125
125 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
Slide 126
126 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
5569.01
Slide 127
127 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
5570.01
Slide 128
128 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 5571.01
Slide 129
129 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 5572.01
