# Presentation: 212983

## Arthritis Advisory Committee Meeting

**April 19th, 2001**
**NDA 21-239:  GL701 for **
**Systemic Lupus Erythematosus**
**Genelabs Technologies, Incorporated**

**5465.01**

## Presentation Outline

**5466.02**

## Consultants

**5467.03**

## 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**

## 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**

## Background

**Robert Lahita, MD PhD**

**5470.01**

## 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**

## Damage within SLESLICC/ACR Damage Index1

**5472.01**

## 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**

## 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**

**Notes:**
What about DHEA levels in men with SLE?

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

**5478.02**

**Baseline Testosterone**

**Baseline DHEA-S**

**Notes:**
Need help with title size

## 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**

## Efficacy

**Michelle Petri, MD**

**5479.01**

## 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**

## 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**

## 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**

**Notes:**
Need this publication by Susan Barr for Flare data.  Should also state morbidity associated with corticosteroids as a lead into the clinical study objectives.

## 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**

**Notes:**
Where do we want this slide to be.  Should it reside in two places?

## 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**

## GL701 Principal SLE Clinical Trials

**5489.02**

## Study GL94-01Objective

**Study GL94-01****Objective**

**Reduction in Corticosteroid Requirements**

**5490.01**

**Notes:**
The recommendation was to present GL95-02 before GL94-01.  Do we still want to consider this???

## GL94-01:  Corticosteroid ReductionStudy Design

**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**

**Notes:**
Consider adding that if patients required immunosuppressives during study that it was cause for withdrawal

## 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**

## 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**

## GL94-01:  Corticosteroid ReductionBaseline Demographics

**GL94-01:  Corticosteroid Reduction****Baseline Demographics**

**5494.02**

## GL94-01:  Corticosteroid Reduction Baseline Characteristics

**5495.02**

**Notes:**
Can we do mean and medians on separate lines?

## 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**

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

**N=28**

**N=26**

**N=42**

**N=53**

**N=42**

**5497.01**

## 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***

## 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**

## GL94-01:  Corticosteroid Reduction Patient Disposition

**5500.03**

**Notes:**
This table will be replaced by a disposition figure.

## GL94-01:  Corticosteroid ReductionResponders 

**26/64  28/63   35/64**

**200 mg vs. placebo:  ****	****^P = 0.110****	*****P = 0.031**

**13/45  18/47   23/45**

**5501.01**

## Study GL94-01Responders

**5319.02**

**13/19**

**10/16**

**12/19**

**5/15**

**8/18**

**5/9**

**4/13**

**7/16**

**12/24**

**2/9**

**2/9**

**3/6**

**2/8**

**1/4**

**3/6**

## 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**

## 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**

**Notes:**
Confirm the population.  Baseline SLEDAI >2?

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

**5632.03**

## 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**

**Notes:**
Need to note that this is an exploratory analysis.  Title needs to be fixed.  Do we need the parametric and nonparametric p-values.  Need to fill in the p-value column?

## 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**

**Notes:**
Need to add p-value for trend test.

## Study GL95-02 Objective

**Improvement or stabilization **
**in SLE**

**5506.01**

## 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**

## 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**

**Notes:**
Slide needs formatting help.

## 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**

**Notes:**
Focus on the original protocol and stabilization not defined and meant zero

## 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**

**Notes:**
Need back up slide providing this definition in more detail

## 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**

## 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**

## 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**

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

**5653.02**

## 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**

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

**5520.02**

**Notes:**
Table needs formatting

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

**5521.02**

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

**5519.03**

**Notes:**
This slide should supersede the slide on withdrawals

## GL95-02:  Improvement in SLE Percent Responders: ITT

**5584.01**

**P = 0.438**

**52/192        ****	****58/189**

**65/146         86/147****	**

*** P = 0.017**

## 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**

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

**5574.02**

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

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

**5449.01**

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

*** P = 0.018**

**	****80/176****	****99/170****	****65/133****	**** 87/132                  **

**** P = 0.005**

**5522.01**

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

**5320.02**

**15/43**

**12/38**

**20/36**

**15/25**

**35/62**

**43/58**

**5/22**

**27/32**

**5/13**

**8/12**

***With Window**

## 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**

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

***Baseline SLEDAI > 2**

**5525.02**

**Notes:**
Need to have this data for per-protocol as a back up

## GL95-02:  Improvement in SLE Flare Definition*

**Any one of the following:**

- *Definition of definite flare adapted from SELENA (NIH) study

**5517.01**

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

**P = ns**

**P = ns**

**	****47/176****	****37/170****	****41/133****	****   31/132                  **

**5526.01**

**Notes:**
Need to add p-values and need to change the “all patients” to “per-protocol”

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

**5315.04**

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

**5527.02**

***P = 0.004**

****P = 0.080**

*****

******

## GL95-02:  Improvement in SLE Percent of Patients with >3% Gain or Loss in BMD at 1 Year

**5444.01**

## 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**

## 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**

**Notes:**
I have not made any changes to the GBL96-01 slides.  We need to review and discuss what changes need to be made.

## GBL96-01:  Taiwan StudyDemographic & Baseline Characteristics

**5530.01**

**Notes:**
Need to add p-values

## GBL96-01:  Taiwan Efficacy Results: ITT

**5532.02**

**Notes:**
Table needs formatting.  Need to add responder rates

## GBL96-01:  TaiwanTime to First Flare

**GBL96-01:  Taiwan****Time to First Flare**

**GL701**

**Placebo**

**Days**

**Percent without Flares**

**5533.02**

**P = 0.044 **

## 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**

## Statistical Discussion

**Frank Hurley, PhD**

**5654.01**

## Statistical Issues

**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**

## Strategy in Uncharted Territory

**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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## 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**

## Safety

**Michelle Petri, MD**

**5536.02**

## Presentation of Safety Data

**5537.02**

## Duration of Exposure to GL701

**5538.01**

## All Reported Deaths:  GL701 Group (N = 495) 

**5554.01**

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

**5555.01**

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

**5631.01**

## 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**

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

**5541.01**

## Adverse Events with a Frequency of  10% 

**5539.01**

## Selected Adverse Events with a Frequency of <10%**

**5540.01**

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

***Williams Textbook of Endocrinology, 1998**

**5542.01**

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

**N = 101**

**N = 41**

**N = 115**

**5543.01**

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

*** Defined as women with estradiol levels of < 25 pg/ml  **

**5544.01**

**Median**

**Normal **
**Postmenopausal **

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

**5545.02**

**Median**

**Normal**
**Post-**
**Menopausal**

## Breast Cancer

**5548.02**

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

***Control rates (no HRT) reported as 3.9 per 1000 women years and**
** ****unopposed estrogen use rates reported 4.4 per 1000 women years****1**

**1. Schairer *****et al*****., 2000**

**5549.02**

## 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**

**Notes:**
The comments here were:

Long-term effects of testosterone exposure in women unknown
Estradiol levels increased modestly, but below those levels seen with HRT.
No adverse events suggesting estradiol effects on uterus (menometroahia)

## Routine Clinical Laboratories

**No evidence of significant effects on:**
**CBC**
**Liver function tests**
**BUN and Creatinine**
**Routine serum chemistries**

**5556.01**

## Mean Changes in Serum Lipids

**5557.01**

## HDL-Cholesterol Change

**5558.01**

## 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**

## Serum Complement

**5756.01**

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

**5446.01**

**Mean****	****-2.3%**
**Median****	****-1.4%**

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

**5639.01**

**Placebo**

**GL701**
**100 mg**

**GL701**
**200 mg**

**Placebo**

**GL701**
**100 mg**

**GL701**
**200 mg**

**GL701**
**200 mg**

**Study GL96-02**
**Normal Female Volunteers**

**Study GL94-01**
**SLE Patients**

## Shift Table: Change in C3 from Baseline to Last Visit

**5561.01**

**Notes:**
The comment was to remove the figure originally presented and replace it with a table or bar graph.  Comment was also made on showing how many patients went from normal to low.  Should we just show this data for the double-blind studies or include open-label?

## 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**

## 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 manifestations****1**
**1. Yesilova, *****et al*****. 2000**

**5563.01**

**Notes:**
The comments made here were:

For the pts that went from normal to low what happened:
Did they flare? Did they have renal flare(s)?
Did they have proteinuria?
What was the impact on C4?
How is this finding connected with IL-6 or CRP?

## 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**

## Patients with Hematuria as an Adverse Event

**5546.03**

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

**5547.03**

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

**5578.02**

## 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 **
** ****(<300)**
** ****GL701    N = 11**
** ****Placebo N =   8 **

** ****Moderate **
** ****(>1,000)**
** ****GL701    N = 0**
** ****Placebo N = 0 **

**Normal at Baseline**

***348, 424, 303, 404, 325**

## 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**

## 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**

## Signs of Renal Flare

**5647.02**

## Signs of Renal Flare

**5707.01**

**Medical Reviewer’s definition of a renal signal, except decrease in C3, C4, or increase in dsDNA counted only once.**

## 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**

## 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**

## Overall Safety Summary

**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**

## Clinical Perspective

**Murray Urowitz, MD**

**5566.01**

**Notes:**
Need to develop slides for Bob’s wrap up discussion.  

## Review of GL701 Clinical Designs and Outcomes

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

**5757.01**

## 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**

## 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**

## 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**

**Notes:**
The comment from the meeting was that a slide on the instruments should follow the Domain slide.  It was then suggested that the “burden of flares” slide follow the Domain slide.  What should we do here?

##  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**

## 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**

## 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**