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Arthritis Advisory Committee Meeting

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

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Arthritis Advisory Committee Meeting

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  1. Arthritis Advisory Committee Meeting April 19th, 2001 NDA 21-239: GL701 for Systemic Lupus Erythematosus Genelabs Technologies, Incorporated 5465.01

  2. Presentation Outline 5466.02

  3. Consultants 5467.03

  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

  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

  6. Background Robert Lahita, MD PhD 5470.01

  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

  8. Damage within SLESLICC/ACR Damage Index1 5472.01

  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

  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

  11. Study GL95-02Baseline Endogenous DHEA-S and Testosterone Levels with and without Corticosteroid Treatment Baseline DHEA-S Baseline Testosterone 5478.02

  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 IL4, IL5, IL6 (TH2) cytokines and increase of IL2 (TH2) 5710.01

  13. Efficacy Michelle Petri, MD 5479.01

  14. Stanford University Phase I/II StudiesDHEA 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

  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

  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

  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

  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

  19. GL701 Principal SLE Clinical Trials 5489.02

  20. Study GL94-01Objective Reduction in Corticosteroid Requirements 5490.01

  21. GL94-01: Corticosteroid ReductionStudy 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

  22. GL94-01: Corticosteroid ReductionEntry 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

  23. GL94-01: Corticosteroid ReductionPrimary Efficacy Endpoint (Responder) Sustained prednisone reduction: • Prednisone decreased to  7.5 mg/day • For  2 consecutive months • Including last visit 5493.01

  24. GL94-01: Corticosteroid ReductionBaseline Demographics 5494.02

  25. GL94-01: Corticosteroid ReductionBaseline Characteristics 5495.02

  26. GL94-01: Corticosteroid ReductionImpact 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

  27. GL94-01: Corticosteroid ReductionBlinded Analysis of Patients by Baseline SLEDAI N=28 N=26 N=42 N=53 N=42 5497.01

  28. Study GL94-01: Corticosteroid ReductionAnalysis of the54 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

  29. GL94-01: Corticosteroid ReductionImpact 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

  30. GL94-01: Corticosteroid ReductionPatient Disposition 5500.03

  31. GL94-01: Corticosteroid ReductionResponders 26/64 28/63 35/64 13/45 18/47 23/45 200 mg vs. placebo: ^P = 0.110 *P = 0.031 5501.01

  32. Study GL94-01Responders 12/19 3/6 3/6 5/9 12/24 10/16 2/9 1/4 8/18 7/16 13/19 2/9 2/8 5/15 4/13 5319.02

  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

  34. GL94-01: Corticosteroid ReductionMean 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

  35. GL94-01: Corticosteroid ReductionIndividual Patient Example of Prednisone Dose Changes from Baseline to Last Visit 5632.03

  36. GL94-01: Corticosteroid ReductionNumber of Days Prednisone  7.5 mg/day * 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

  37. GL94-01: Corticosteroid ReductionEfficacy 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

  38. Study GL95-02 Objective Improvement or stabilization in SLE 5506.01

  39. GL95-02: Improvement in SLEStudy 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

  40. GL95-02: Improvement in SLEEntry 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

  41. GL95-02: Improvement in SLEPrimary 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

  42. GL95-02: Improvement in SLEPrimary 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

  43. GL95-02: Improvement in SLEDevelopment 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

  44. GL95-02: Improvement in SLEDefining 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

  45. GL95-02: Improvement in SLEEvidence-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: This agrees well with the pre-defined window 5511.04

  46. Example of a Patient Classified as a Responder when Using the “Window” 5653.02

  47. GL95-02: Improvement in SLESecondary 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

  48. GL95-02: Improvement in SLEBaseline Demographics: All Randomized (ITT) 5520.02

  49. GL95-02: Improvement in SLEBaseline Characteristics: All Randomized (ITT) 5521.02

  50. GL95-02: Improvement in SLEPatient Disposition: All Randomized (ITT) 5519.03

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