1 / 129

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

sandra_john
Télécharger la présentation

Arthritis Advisory Committee Meeting

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related