Etanercept Immunex BLA 103795/5123. Arthritis Advisory Committee Bethesda, Maryland June 24, 2003. Review Committee. William Tauber, M.D. Chair, Clinical Chao Wang, PhD Biostatistics Karen Jones Project Manager Debra Bower Bioresearch Monitoring
EtanerceptImmunexBLA 103795/5123 Arthritis Advisory Committee Bethesda, Maryland June 24, 2003
Review Committee • William Tauber, M.D. Chair, Clinical • Chao Wang, PhD Biostatistics • Karen Jones Project Manager • Debra Bower Bioresearch Monitoring • Daniel Kearns Facility Review
Indications proposed in current BLA • Enbrel® is indicated for reducing signs and symptoms of ankylosing spondylitis
Rationale for Etanercept in AS: I • Ankylosing Spondylitis (AS) is a chronic inflammatory rheumatic disease unknown etiology • Non-Steroidal Anti-inflammatory drugs (NSAIDS) are FDA approved for treatment of signs and symptoms of Ankylosing Spondylitis • Disease Modifying anti-rheumatic drugs (DMARDS(RA)) used for Rheumatoid Arthritis are used in AS but are not FDA approved for use in AS. • Neither NSAIDS nor DMARDS (RA) have been demonstrated to affect the progression of disability with AS.
Rationale for Etanercept in AS:II • Tumor necrosis factor (TNF) levels have been shown to be elevated in serum and synovial tissue of patients with AS. • Etanercept is licensed for the treatment of Rheumatoid Arthritis, Juvenile Rheumatoid Arthritis, Psoriatic Arthritis. • AS may share pathogenic mechanisms with these other disorders.
Outline of Discussion Topics • Methodology for assessment of short term therapeutic benefit in AS • Phase III trials to investigate the safety and efficacy of etanercept in patients with ankylosing spondylitis • Phase II proof-of-concept trial
Ankylosing Spondylitis: Assessment of Short Term Therapeutic Benefit • Assessments in Ankylosing Spondylitis (ASAS) Working Group • 5 domains most important in assessment of short term benefit in AS: • physical function • pain • spinal mobility • spinal stiffness and inflammation • patient’s global assessment.
Derivation of ASAS Response Criteria • Analysis of 5 randomized trials of NSAIDS in AS enrolling 1030 patients 6 weeks treatment performed • 4 domains differentiated drug effect from placebo: • Combined into ASAS 20 response criteria • spinal mobility excluded because of lack of responsiveness
Phase 3 Protocols: Assessment of Response • Primary Endpoint at end of treatment -ASAS Response Criteria (ASAS 20) at 12/24 wks -An improvement of at least 20%/ 10units Visual Analog Scale (VAS) (0-100mm) in at least 3 of the following domains: o Patient Global Assessment o Average of total and nocturnal pain o BASFI average of 10 questions o BASDAI- average of last 2 questions -Absence of deterioration (20%/10units) in remaining domain
Secondary and Other Endpoints • Secondary Endpoints • ASAS 50/70 at 12/24 weeks* • Highest ASAS response achieved • Partial Remission • Other Outcome Endpoints • Individual components of ASAS Instrument • Acute Phase Reactants: ESR, CRP • Spinal Mobility Parameters • Peripheral tender/swollen joint count • Assessor Global Assessment
Phase II and III Studies • Phase II • 016.0626 Randomized, double blinded, single center • etanercept 25mg biw vs placebo, 16 weeks (N=40) • Phase III • 016.0037 Randomized, double blinded, multi-center • etanercept 25mg biw vs placebo, 24 weeks (N=277) • 47687 Randomized, double blinded, multi-center etanercept 25 mg biw vs placebo, 12 weeks (N=84)
Phase 3 Protocols: Study Population • Inclusion - Men and Women 18-70 years of age -Diagnosis of Ankylosing Spondylitis- mod NY criteria -Active Disease at baseline using (VAS) VAS 30 for avg duration and intensity morning stiffness PLUS VAS 30 for 2 of 3 parameters: -pt global assessment -nocturnal and total back pain -Bath Ankylosing Spondylitis Functional Index (BASFI) 10 question avg VAS
Phase 3 Protocols: Study Population • Exclusion -Complete Ankylosis of Spine -DMARDs other than Sulfasalazine, MTX or Hydroxychloroquine -Prednisone >10mg/d or changed w/i 2 weeks baseline -NSAIDS changing
CSR 016.0037 Clinical Protocol Study Design - n= 277 active AS patients randomized 1:1 Etanercept or placebo for 24 weeks -Randomization stratified for presence of DMARDs (Sulfasalazine, Methotrexate, and Hydroxychloroquine) Dosing -Etanercept 25 mg sc biw or Placebo sc biw
CSR 016.0037 Clinical Protocol Primary efficacy analysis - MITT population ( all randomized and 1+ dose given) - ASAS 20 at 12 (and 24 wks) compare etanercept with placebo Cochran-Mantel-Haenszel Test with stratification for DMARDs
ASAS 50 and ASAS 70 • ASAS 50 response computed and analyzed similar to ASAS 20 except that a 50% improvement in 3 of 4 components in addition to 10mm point absolute improvement. Deterioration rules same as ASAS 20 • ASAS 70 similar rules to ASAS 50 except that a 70% improvement needed
ASAS 20/50/70 at 12 and 24 weeks 12 weeks 24 weeks
Partial Remission • Criteria proposed by ASAS Working Group • Value of <20 (on a VAS scale of 0-100) in each of the four ASAS Response Criteria: • Patient Global Assessment • Average of Nocturnal/total back pain • BASFI • Last 2 questions of BASDAI
ASAS Individual ComponentsMean Percent Improvement from baseline at 12 wks
Acute Phase Reactants Mean (median) values during treatment * P value <0.001
DCART 20 and DCART 40 • DCART 20= 4 criteria of ASAS Response Criteria + chest expansion( spinal mobility) and CRP( acute phase reactants). DCART 20 same requirements ASAS20 for first 4, the other two 20% improvement relative to baseline w/o absolute numeric change. DCART 20=5 of 6 improvement, no worsening remaining domain. • DCART 40= uses 4 ASAS Response Criteria but requires 40% improvement relative to baseline plus absolute 20 unit(mm) improvement 3 of 4 w/o worsening remaining domain
ASAS DCART 20/40 Exploratory Analysis * P value <0.001
ASAS 20/12 weeks Non-Skeletal Inflammatory Condition • Similar response rates to etanercept for patients subsetted by whether they did or did not have a history of: • uveitis or iritis( n= 82) • Inflammatory bowel disease(n=13) • bacterial dysentery, urethritis, Chlamydial infection or sexually transmitted disease(n= 24)
ASAS 20 at 12weeks: Subsetted by Baseline Variables • Similar ASAS 20 response rates at 12 weeks in patients subsetted by : • Race • Weight • Disease Duration • Geographic site
Impact of Age upon ASAS 20 at 12 wks Quartiles
ASAS 20 at 12 weeks: Subsetted by Baseline Disease Severity • Similar effect size for ASAS 20 response rates at 12 weeks for patients above or below the median at baseline for: • Average back pain • Patient global assessment • BASFI • BASDAI • Same effect size in presence or absence of Hip Disease
ASAS 20 at 12 weeks prior or concomitant meds • Effect size for etanercept at 12 weeks did not appear to be affected by concomitant use of the following medications: • NSAIDS (n=247) • Corticosteroids (n=36) • DMARDs (n=87) • Sulfasalazine (n=59) • Methotrexate (n=32)
Summary: Efficacy • Etanercept 25mg sc biw was superior to placebo in achievement of ASAS 20 Response Criteria at both 12 and 24 weeks. • Treatment difference is 33% • DMARDS did not appear to affect difference • Prognostic factors potentially associated with lower response • Older Age • Female gender • HLA-B27 antigen negative • Concomitant Psoriasis
Summary of Safety • Etanercept 25 mg sc biw: higher observed incidence of certain adverse events compared to placebo • Serious adverse events (7% vs 4%) • Withdrawals for Safety (5% vs 1%) • Grade 3 /4 Adverse Events/ Infections (10% vs 3%) • Of the 7 safety withdrawals among etanercept recipients, 4 were for bowel symptoms, of which 2 were Inflammatory Bowel Disease, one a new diagnosis, the other a recurrence.
CSR: 47687 Clinical Protocol • Study Design • N=84 active AS patients randomized 1:1 Etanercept or placebo for 12 weeks • Randomization stratified for DMARDs (Sulfasalazine,Methotrexate,Hydroxychloroquine) • Dosing:Etanercept 25mg sc biw or Placebo • Primary efficacy analysis • MITT population (all randomized and one dose given) • ASAS 20 at 12 wks compare etanercept/placebo Cochran-Mantel-Haenszel test with stratification for DMARDs
Study 2 Population : Comparison with Study 1 Population • Study 2 population balanced between study arms, comparable with Study 1 population except : • Lower mean weight 75kg vs 82 kg • Prior use of DMARDs 69% vs 31% in study population 1 • Lower incidence of ocular inflammation16% vs 30%, uveitis 22% vs 30%, higher psoriasis 15% vs 10% study1. The incidence of patients with history of IBD was similar at 6% study 2 vs 5% in study 1