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EtanerceptImmunexBLA 103795/5123Arthritis Advisory CommitteeBethesda, MarylandJune 24, 2003

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Review Committee

• William Tauber, M.D. Chair, Clinical• Chao Wang, PhD Biostatistics• Karen Jones Project Manager• Debra Bower Bioresearch

Monitoring• Daniel Kearns Facility Review

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Indications proposed in current BLA

•Enbrel® is indicated for reducing signs and symptoms of ankylosing spondylitis

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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.

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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.

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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

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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.

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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

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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 Assessmento Average of total and nocturnal paino BASFI average of 10 questionso BASDAI- average of last 2 questions-Absence of deterioration (20%/10units) in remaining domain

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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

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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)

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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 PLUSVAS 30 for 2 of 3 parameters: -pt global assessment-nocturnal and total back pain-Bath Ankylosing Spondylitis Functional Index (BASFI) 10 question avg VAS

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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

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Study 016.0037 (Study 1)

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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

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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

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Study Completion at 12 and 24 wks

Placebo N=139

Etanercept N=138

Patient Status n/(%) n/(%)Randomized no drug

3/142 (2) 4/142 (3)

Completed 12 wks 134 (96) 132 (96)Completed 24 wks 120 (86) 126 (91)D/C due AE 1(1) 7 (5)D/C due LOE 13 (9) 3 (2)Other 5 (4) 2 (1)

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Demographics 016.0037

Placebo

Etanercept

Characteristic N=139 N=138Mean Age(yrs) 42 42

Male 76% 76%Caucasian 91% 94%

Mean Weight 83.1kg 82.2kgHLA-B27+ 84% 84%Duration AS(yrs)

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Baseline Characteristics

Placebo EtanerceptCharacteris

ticN=139 N=138

Patient Global

63 63

Pain (avg n+t)

62 60

BASFI 56 52Inflammatio

n64 61

Any DMARD 31% 32%Corticosteroids

14% 12%

20 20

Extra-Spinal Inflammatory SxSymptom/

SignPlacebo N=139

Etanercept N=138

Occular Inflam

28% 32%

Conjunctivitis

8% 7%

Uveitis/iritis 31% 28%Inflammator

y Bowel Disease

4% 5%

Psoriasis 11% 8%

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Primary EndpointsNumber (%) Achieving ASAS 20

Placebo Etanercept

Parameter

N=139 N=138 P-Value

ASAS 2012

weeks

38 (27) 83 (60) <0.0001

ASAS 2024

weeks

32 (23) 80 (58) <0.0001

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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

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ASAS 20/50/70 at 12 and 24 weeks

0

20

40

60

80

100

20 50 70 20 50 70

placeboetanercept

12 weeks 24 weeks

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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

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ASAS Defined-Partial Remission

0

20

40

60

80

100

Week 12 Week 24

placeboetanercept

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ASAS Individual Components

Mean Percent Improvement from baseline at 12 wks

020406080

100

Ptglobal

Avgpain

BASFI BASDAI

placeboetanercept

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Acute Phase Reactants Mean (median) values during

treatmentPlacebo Etanercept

Parameter

N=139 N=138

ESR/ BL 25 (17) 26(23)12

weeks26(16) 13 (9)*

24 weeks

26 (19) 11 (7)*

CRP/BL 2.0(1) 1.9 (1)12

weeks2.0(1) 1(0.2)*

24 weeks

2.0 (1) <1 (0.3)*

* P value <0.001

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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

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ASAS DCART 20/40 Exploratory Analysis

Placebo EtanerceptParameter N=139 N=138DCART 20 n (%) n (%)12 weeks 11 (8) 51 (37)*24 weeks 10 (7) 46 (33)*DCART 4012 weeks 21 (15) 59 (43)*24 weeks 18 (13) 57 (41)*

* P value <0.001

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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)

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ASAS 20 at 12 weeks: Subset with Psoriasis

020406080

100

Psoriasisnegativen=251

Psoriasis positive n=26

placeboetanercept

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ASAS 20 at 12 weeks: Subsetted by Baseline Variables

• Similar ASAS 20 response rates at 12 weeks in patients subsetted by :–Race–Weight–Disease Duration–Geographic site

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Impact of Age upon ASAS 20 at 12 wks

020406080

100

<34yrs 34 to<42

42 to<50

50yrs +

PlaceboEtanercept

Quartiles

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Impact of Gender on ASAS 20 -12 wks

0

20

40

60

80

100

Male n=210 Female n=67

placeboetanercept

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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

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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)

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ASAS 20 at 12 and 24 weeks HLA B27 positive vs negative

020406080

100

B27pos

B27neg

B27pos

B27neg

PlaceboEtanercept

12 wks 24 wks

HLA B27 pos=217HLA B27 neg=40

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Adverse Events all IntensitiesProportions of Patients

(n(%)Event Placebo

N=139Etanercept

138Any Adverse Event 105 (76) 99 (72)Infections 42 (30) 57 (41)Injection site reactions 13 (9) 41 (30)Injection site ecchymosis 23 (17) 29 (21)Headache 16 (12) 19 (14)Accidental Injury 6 (4) 17 (12)Diarrhea 13 (9) 11 (8)Rash 9 (7) 11 (8)Dizziness 3 (2) 8 (6)Rhinitis 9 (7) 8 (6)Abdominal Pain 7 (5) 8 (6)Nausea 7 (5) 7 (5)Asthenia 7 (5) 5 (4)

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Important Safety Outcomes

Safety Outcomes Placebo N=139n/N %

Etanercept

N=138n/N %

Serious Adverse Events

5 (4) 9 (7)

Withdrawals for Safety

1 (1) 7 (5)

Grade 3 /4 Adverse Events/ Infections

4 (3) 14 (10)

Grade 3 /4 Abnormal Laboratory

0 (0) 2 (1)

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Percent Serious Adverse Events

PlaceboN=139

Etanercept

N=138Totals 4% 7%

Accidents 1% 2%

Infection/Fever 1% 3%Gastrointestinal 0% 1%

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Withdrawals for SafetyPlacebo Etanerc

eptTotal 1 (1%) 7 (5%)AE: Overall 1 (1%) 7 (5%)Accidents 0 (0) 2 (1%)Infections/Fever 0 (0) 1(1%)Gastrointestinal 0 (0) 4 (3%)Psychiatric 1 (1%) 0 (0)

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Infections: All IntensitiesProportions of

Patients(n [%])

Placebo Etanercept

Event N=139 N=138Any Infection 42 (30) 57 (41)Any Infection not URI

28 (20) 33 (24)

URI 16 (12) 28 (20)Flu syndrome 10 (7) 5 (4)

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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

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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.

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Study CSR-47687 (Study 2)

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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

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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

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Primary EndpointNumber (%) Achieving ASAS 20: Week

12Paramet

erPlaceboN=39

Etanercept

N=45Complete

d12 weeks

100% 96%P-Value

ASAS 20 9 (23) 27(60) 0.0008

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ASAS-Defined Partial Remission

PlaceboN=39

Etanercept

N=45Time point

n/(%) n(%) P-Value

Week 12 4 (10) 8(18) 0.3Any

time 5(13) 12 (26) 0.1

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Adverse Events all IntensitiesProportions of Patients

(n(%)Event Placebo

N=39Etanercep

t N=45Any Adverse Event 24 (62) 25 (56)Infections 13(33) 16 (36)Injection site reactions 6 (15) 15 (33)Injection site ecchymosis 4 (10) 8 (18)Headache 4(10) 6 (13)Accidental Injury 2 (4) 0 (0)Diarrhea 2 (5) 2 (4)Rash 0 (0) 2 (4)Dizziness 1 (3) 1 (2)Abdominal Pain 3 (8) 1 (2)Nausea 4(10) 3(7)Asthenia 1 (3) 5 (11)

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Important Safety OutcomesSafety Outcomes Placebo

N=39n/N %

Etanercept

N=45n/N %

Serious Adverse Events

0(0) 1 (2)

Withdrawals for Safety

0 (0) 0 (0)

Grade 3 /4 Adverse Events/ Infections

2 (5) 4 (9)

Grade 3 /4 Abnormal Laboratory

0 (0) 1 (2)

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Study CSR: 016.0626 (Study 3)

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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

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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.

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Five Pre-Specified Measures1. Patient global assessment-5

point scale over the past week, improvement = decrease of 1

2. Nocturnal spinal pain: 100mm VAS, improvement 20% in # mm

3. Duration of morning stiffness; duration of morning stiffness in minutes on the day preceding clinic visit. 20% fewer or more minutes

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Five Pre-Specified Measures

4. BASFI 10 questions VAS average5. 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

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Primary Endpoint

Primary Endpoint: Number(%) Achieving AS Response Criteria

Placebo Etanercept

P-Value

Time point N=20 N=20Week 12 5 (25) 14 (70) 0.01Week 16 5 (25) 15 (75) 0.01

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Ad hoc Analysis: Modified ASAS 20 at 12/16wks

Number(%) Achieving ASAS 20 at 12 and 16 weeks

Placebo Etanercept

Time point

N=20 N=20 P-Value

Week 12 5 (25) 13 (65) <0.05Week 16 5 (25) 17 (85) <0.05

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Other Endpoints: Pain Assessment, DSFI, Krupp’s

Fatigue Measure at 16 weeks

-200

20406080

100

Pain DSFI Krupp'sFatigue

PlaceboEtanercept

60 60

Spinal Mobility (Study 1) Mean Percent Improvement from baseline

at 12 weeks

-20

0

20

40

60

80

100

Schober's Chest exp Occiput-Wall

PlaceboEtanercept

*

*

*

*=Nominal p-value <0.05

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Spinal Mobility (Study 2) Mean Percent Improvement from baseline

at 12 weeks

-200

20406080

100

Schober'sChest exp Occiput-Wall

PlaceboEtanercept

*

*=Nominal p-value <0.05

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Spinal Mobility (Study 3) Mean % Improvement from baseline

at 12 weeks

-200

20406080

100

Schober's Chestexp

Occiput-Wall

PlaceboEtanercept

*=Nominal p-value <0.05

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Tender and Swollen Peripheral Joints (Study 1)

Median Percent Improvement at 12 wks

020406080

100

Tender joints Swollen joints

PlaceboEtanercept

*=Nominal p-value <0.05

*

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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.

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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.

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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.