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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

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etanercept immunex bla 103795 5123
EtanerceptImmunexBLA 103795/5123

Arthritis Advisory Committee

Bethesda, Maryland

June 24, 2003

review committee
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
Indications proposed in current BLA
  • Enbrel® is indicated for reducing signs and symptoms of ankylosing spondylitis
rationale for etanercept in as i
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
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
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
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
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
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 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 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
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 population13
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
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)


-Etanercept 25 mg sc biw or Placebo sc biw

csr 016 0037 clinical protocol16
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 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
partial remission
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
dcart 20 and dcart 40
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 20 12 weeks non skeletal inflammatory condition
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 12 weeks subsetted by baseline variables
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
asas 20 at 12 weeks subsetted by baseline disease severity
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
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
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
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
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 : 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
csr 016 0626 clinical protocol
CSR 016.0626 Clinical Protocol
  • Study Design
    • N= 40 active AS patients randomized 1:1 to Etanercept or placebo for 16 weeks
  • Dosing: Etanercept 25mg sc biw or placebo
csr 016 0626 clinical protocol54
CSR 016.0626 Clinical Protocol
  • Primary Efficacy Analysis
    • MITT population ( all randomized and one dose drug)
    • 20% response at 16 weeks in 3 of 5 Pre-specified Ankylosing Spondylitis Criteria (with one of the improved measures being spinal pain or morning stiffness without worsening in the remaining 2. For patients without joint swelling( one of the 5 measured elements) at baseline, improvement was required in 3 of the remaining 4 elements without concurrent worsening in the remaining one.
five pre specified measures
Five Pre-Specified Measures
  • Patient global assessment-5 point scale over the past week, improvement = decrease of 1
  • Nocturnal spinal pain: 100mm VAS, improvement 20% in # mm
  • Duration of morning stiffness; duration of morning stiffness in minutes on the day preceding clinic visit. 20% fewer or more minutes
five pre specified measures56
Five Pre-Specified Measures
  • BASFI 10 questions VAS average
  • Swollen joint score: peripheral joint swelling in 44 diarthrodial joints rated on 4 point scale 0=no swelling, 1=mild, 2=moderate,3 = severe. Improvement defined as decrease in joint swelling by 20% in swelling score. If the swollen joint score was 0 at baseline, any increase in score=worsening
spinal mobility study 1 mean percent improvement from baseline at 12 weeks
Spinal Mobility (Study 1)Mean Percent Improvement from baseline at 12 weeks




*=Nominal p-value <0.05

spinal mobility study 2 mean percent improvement from baseline at 12 weeks
Spinal Mobility(Study 2) Mean Percent Improvement from baseline at 12 weeks


*=Nominal p-value <0.05

tender and swollen peripheral joints study 1 median percent improvement at 12 wks
Tender and Swollen Peripheral Joints (Study 1)Median Percent Improvement at 12 wks


*=Nominal p-value <0.05

conclusions efficacy
Conclusions: Efficacy
  • Etanercept was demonstrated statistically superior to placebo in 3 trials assessing symptomatic treatment in active Ankylosing Spondylitis (AS).
  • Older age, female gender were associated with lower response rate.
    • Responses in HLA-B27- negative and concomitant psoriasis patients were also lower but the number of patients with these conditions was small.
conclusions methodology
Conclusions: Methodology
  • Results using ASAS 20 generally demonstrated responses of similar direction and magnitude to previously used measures used in the assessment of therapeutic benefit in AS.
conclusions safety
Conclusions: Safety
  • Safety profile of etanercept in ankylosing spondylitis similar to that seen in RA and other indications
  • There were more withdrawals for inflammatory bowel disease in etanercept patients compared to placebo recipients in study 1 but numbers were small.