Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis

Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis
FDA Arthritis Advisory Committee June 24, 2003 Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis

Presentations Introduction Daniel Burge, M.D.
V.P. Clinical Development Amgen Assessments in Désirée van der Heijde, M.D., Ph.D. Ankylosing Spondylitis Professor of Rheumatology University of Maastricht Maastricht, NL Clinical Program and Results Wayne Tsuji, M.D. Associate Medical Director Benefit/Risk Assessment Daniel Burge, M.D.

Consultants Désirée van der Heijde, M.D., Ph.D. Professor of Rheumatology University Hospital Maastricht Maastricht, The Netherlands Daniel O. Clegg, M.D. Professor of Medicine Division of Rheumatology University of Utah Salt Lake City, UT

Etanercept Properties
Only soluble receptor TNF antagonist Fully human protein Binds TNF, soluble and cell bound No neutralizing antibodies; low immunogenicity Does not bind complement; no cell lysis Well characterized pharmacokinetic profile

Etanercept History 1998 FDA approval for RA (alone or with MTX)
1999 FDA approval for JRA 2000 FDA approval as initial therapy for RA FDA approval for inhibition of radiographic progression 2002 FDA approval for psoriatic arthritis (alone or with MTX) 2002 Application for approval for inhibition of radiographic progression in PsA 2003 Application for approval for AS

Family of Spondyloarthropathies
AS Undifferentiated Spondylo- arthropathy Juvenile Spondylo- arthropathy IBD Associated Arthritis Psoriatic Arthritis Reactive Arthritis

Features of Spondyloarthropathies
Sacroiliitis +/- spondylitis Enthesitis Variable involvement with peripheral arthritis Associated with uveitis No association with rheumatoid factor Strong association with the genetic marker, HLA-B27

Ankylosing Spondylitis
~350,000 patients in US Onset typically before age 45 Males more commonly affected Inflammatory back pain Khan 2003 Carter 1979

Progression of Ankylosing Spondylitis

Traditional Therapies are Inadequate
NSAIDs: the only approved therapies for AS Improves pain and stiffness Limited effect on spinal mobility and acute phase reactants Corticosteroids: Oral: limited effect Systemic: temporary benefit/toxic1 Sulfasalazine: improves peripheral but not axial disease2,3 Methotrexate: limited benefit in controlled trial4 1Peters Clegg Dougados Altan 2001.

Pathophysiology of AS: Role of TNF
Sacroiliac biopsy; TNF mRNA3 TNF is implicated in pathogenesis of AS TNF levels are elevated in serum1 TNF levels are elevated in synovial tissue2 1Toussirot and Wendling, Gratacos, Canete et al, Grom et al, Braun et al, 1995.

Challenges in AS Clinical Trials
AS causes pain, stiffness, disability, decreased spinal mobility and decreased quality of life Multiple instruments assess different aspects of disease activity in AS No widely accepted primary measure of response

Formation of the ASessments in Ankylosing Spondylitis (ASAS) Working Group
Started in 1995 At inception, >120 instruments published in the literature Organization of international experts in the field of AS Several meetings yearly

Mission Statement of ASAS
The mission of ASAS is to support and promote the study of ankylosing spondylitis. This includes: Increasing awareness and early diagnosis of the disease Development and validation of assessment tools The evaluation of treatment modalities in order to promote clinical research with the ultimate goal to improve outcome of the disease

Disease Activity Core sets for assessment of:
Symptom Modifying Anti-Rheumatic Drugs (SMARD) and physical therapy Effects on signs and symptoms Disease Controlling Anti-Rheumatic Therapy (DCART) Effects on physical function/disability Effects on structural damage Clinical record keeping

ASAS/OMERACT Core Domains for Ankylosing Spondylitis
DCART Clinical Record Keeping SMARD/ Physical Therapy physical function spinal stiffness patient global assessment acute phase reactants spinal mobility fatigue pain peripheral joints/ entheses hip radiograph spine radiograph van der Heijde et al. J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002

Updated Core Set for SMARD in AS
Domain Instrument Function BASFI or Dougados FI Pain VAS-last week-spine-at night-due to AS and VAS-last week-spine-due to AS Spinal mobility Chest expansion and modified Schober and occiput to wall and (lateral spinal flexion or BASMI) Patient global VAS-last week Stiffness Duration of morning stiffness Fatigue Fatigue question BASDAI van der Heijde et al. J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002

Updated Core Set for DCART in AS (Domains/instruments in addition to core set for SMARD)
Domain Instrument Peripheral joints/entheses Number of swollen joints (44 joint count)/validated enthesitis score Acute phase reactants ESR X-ray spine/hips Anterior-posterior and lateral lumbar and lateral cervical spine and pelvis (SI and Hips) van der Heijde et al. J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002

Instruments for Assessment
Use either a NRS or VAS for all core set variables 1 2 3 4 5 6 7 8 9 10 No pain Unbearable pain No pain Unbearable pain

BASDAI Fatigue Pain in neck, back, hips Pain and swelling other joints
Sites painful by pressure Severity of morning stiffness Duration of morning stiffness Average 1- 5/6; range 0-10 average

Domains and Instruments for Response Criteria
Patient global - VAS Pain - VAS Function – BASFI Stiffness – average of morning stiffness duration and intensity (BASDAI q 5 and 6) OR duration of morning stiffness (120 minutes = maximum) Spinal mobility – chest expansion, modified Schober, fingers to floor

Development of Response Criteria
Definition of most reliable and sensitive instruments within each domain List of improvement definitions Sensitivity and specificity of selected candidate response definitions in 2/3 of the sample Validation in remaining 1/3 of the sample

Based on the best discrimination between NSAIDs and placebo Validated by comparison with experts opinion (Delphi exercise ASAS working group) Validated by end of trial judgment by patient and physician

5 randomized NSAID-placebo controlled trials Short-term (up to 6 weeks) Flare design Axial disease 684 patients treated with NSAIDs 346 patients treated with placebo

ASAS 20 Preliminary Response Criteria AS
Improvement of 20% AND 10 units in at least 3 domains Patient global Pain Function Stiffness No worsening in remaining domain Anderson et al Arthritis Rheum 2001:44:

Performance of ASAS 20 Response Criteria
NSAIDs 49% responders Placebo 24% responders NB in a flare design!

Performance of ASAS 20 Response Criteria
Criteria are strict and highly specific Sensitivity 62%, specificity 89% Agreement with experts opinion and end of trial judgment by patient and physician: 70% Responders defined by ASAS 20 are true responders acknowledged both by patient and physician

Caveats in Comparing Trials Assessing NSAIDs and Anti-TNF Therapy
NSAID trials Flare design Proven efficacy of NSAIDs Inclusion of patients with mild and severe disease Anti-TNF trials No flare design Proven inefficacy of NSAIDS Inclusion of patients with severe disease

ASAS - Partial Remission Criteria AS
A value below 20 units in each of the 4 domains Patient global Pain Function Stiffness

ASAS 20 Improvement Criteria
Based on NSAIDs trials – signs and symptoms Same criteria to assess DCART such as TNF-blocking agents?

Development of Response Criteria for DCART
Addition of 2 extra ‘DCART domains’ Comparison with existing ASAS criteria and BASDAI - improvement With many different cut-off values in many combinations

Development of Response Criteria for DCART
Extra domains in DCART core set Spinal mobility Acute phase reactants Joints - very low responsiveness; minority of patients Entheses - instruments still under development (Radiographs) – assess structural damage

Response Criteria for DCART
Development in 1 trial Validation in other trials Opinion based final selection

Preliminary Response Criteria for DCART
ASAS 40% and 20 units response 20% improvement in 5 out of 6 domains: Patient global Pain Function Stiffness Spinal mobility Acute phase reactants ASAS workshop Gent, October 2002

Clinical Development Program Objectives
Establish efficacy and safety profile of etanercept in treatment of AS Confirm role of TNF in the pathophysiology of AS

Clinical Development Program in AS
401 subjects evaluated in 3 randomized, double blind, placebo-controlled trials Proof-of-Principle Study Study Single Center (U.S.) 40 subjects for 16 weeks Pivotal Program Study Multi-center (25 NA and 3 EU) 277 subjects for 24 weeks Study 47687* Multi-center (14 EU) 84 subjects for 12 weeks *Wyeth 0881A3-311-EU CSR 47687

Proof-of-Principle Study 016.0626
The New England Journal of Medicine TREATMENT OF ANKYLOSING SPONDYLITIS BY INHIBITION OF TUMOR NECROSIS FACTOR  GORMAN, SACK, DAVIS. 2002;346:

Study Design Single center
Randomized, double-blind, placebo controlled 40 subjects for 16 weeks (placebo vs etanercept 25 mg BIW) Active AS with stable background NSAIDs, steroids (10 mg/d prednisone), and/or DMARDs Excluded if: Features of other spondyloarthropathy Previous TNF inhibitor therapy Rheumatoid factor positive

Primary Efficacy Assessment
Study 20% improvement in 3 of 5 parameters without worsening in the remaining 2 measures Nocturnal spinal pain* Duration of morning stiffness* Patient global assessment BASFI Swollen joint score *At least one must improve

Proof of Principle Established Primary Endpoint: % Achieving Response
Study Proof of Principle Established Primary Endpoint: % Achieving Response Placebo (N = 20) Etanercept (N = 20) P = 75 80 70 70 55 55 60 % Subjects 50 35 40 25 25 30 20 10 10 4 8 12 16 Week

Amgen Study 016.0037 Wyeth Study 47687
Pivotal Program Amgen Study Wyeth Study 47687

Study Design Pivotal Program Two randomized, double-blind, placebo-controlled, multi-center (placebo vs etanercept 25 mg BIW) 277 subjects for 24 weeks (Study ) 84 subjects for 12 weeks (Study 47687) Definite AS (modified NY criteria) with active disease Stable background NSAIDs, steroids (10 mg/d prednisone) Stable hydroxychloroquine, sulfasalazine or methotrexate permitted Excluded for: Complete ankylosis of spine Prior TNF inhibitor therapy

Primary Efficacy Endpoints
Pivotal Program ASAS 20 at week 12 Improvement of 20% and absolute improvement of 10 units in at least 3 of following domains: Patient global assessment Pain = average of total spinal pain and nocturnal spinal pain Function = BASFI Stiffness = average of last two questions in BASDAI regarding morning stiffness Absence of deterioration in the potential remaining domain ASAS 20 at week 24

Other Efficacy Endpoints
Pivotal Program ASAS 50, ASAS 70 Partial remission DCART Elements of the ASAS Response Criteria Pain Stiffness Function Global assessment Spinal mobility Modified Schober’s Chest expansion Occiput-to-wall Markers of systemic inflammation CRP, ESR Peripheral joint counts

Baseline Demographics
Pivotal Program Study Study 47687 Placebo Etanercept Placebo Etanercept Baseline characteristic N = 139 N = 138 N = 39 N = 45 Mean age, years Male, % Mean duration of disease, years Race, %: Caucasian Other HLA-B27 positive, %

Baseline Therapy Pivotal Program Study 016.0037 Study 47687
Placebo Etanercept Placebo Etanercept Baseline therapy, %: N = 139 N = 138 N = 39 N = 45 NSAIDs* Corticosteroids* Any DMARD Sulfasalazine Methotrexate Hydroxychloroquine *Taken within 6 months of screening for

Baseline Disease Activity
Pivotal Program Study Study 47687 Placebo Etanercept Placebo Etanercept ASAS 20 components*, mean N = 139 N = 138 N = 39 N = 45 Stiffness, duration and intensity Patient global assessment Total back pain BASFI† *All measures on scale †Bath Ankylosing Spondylitis Functional Index

Disposition Pivotal Program Study 016.0037 Study 47687
Placebo Etanercept Placebo Etanercept N = 139 N = 138 N = 39 N = 45 12 weeks Completed, n (%) 134 (96) 132 (96) 39 (100) 43 (96) Discontinued due to, n: Adverse event Lack of efficacy Other 24 weeks Completed, n (%) 120 (86) 126 (91) Discontinued due to, n: Adverse event Lack of efficacy Other 5 2

Primary Endpoint Achieved in Both Studies ASAS 20 at 12 Weeks
Pivotal Program Primary Endpoint Achieved in Both Studies ASAS 20 at 12 Weeks Study Study 47687 100 100 P < P = 80 80 60 60 60 60 % Subjects 40 40 27 23 20 20 Placebo (N = 139) Etanercept (N = 138) Placebo (N = 39) Etanercept (N = 45)

Rapid and Durable Effect ASAS 20 Over Time
Study Rapid and Durable Effect ASAS 20 Over Time 100 Placebo (N = 139) 90 Etanercept (N = 138) 80 70 59* 60* 58* 60 50* 46* 50 % Subjects 40 27 27 30 24 22 23 20 10 2 4 8 12 16 20 24 Weeks *P <

ASAS 20, 50, and 70 at Week 12 Study 016.0037 Study 47687
Pivotal Program Study Study 47687 100 100 80 80 P < P = 60 60 P = P < % Subjects 60 60 49 45 P < 40 40 P = 27 29 23 24 20 13 20 10 10 7 ASAS 20 ASAS 50 ASAS 70 ASAS 20 ASAS 50 ASAS 70 Placebo (N = 139) Etanercept (N = 138) Placebo (N = 39) Etanercept (N = 45)

Partial Remission at 12 Weeks
Pivotal Program Study Study 47687 50 50 40 P = 40 P = 30 30 % Subjects 21 20 20 18 10 10 8 10 Placebo (N = 139) Etanercept (N = 138) Placebo (N = 39) Etanercept (N = 45)

Consistent DCART Response in Both Studies at 12 Weeks
Pivotal Program Consistent DCART Response in Both Studies at 12 Weeks Study Study 47687 20 40 60 80 100 20 40 60 80 100 *P < *P < 58* % Subjects 43* 44* 37* 15 15 13 8 DCART 20 DCART 40 DCART 20 DCART 40 Placebo (N = 139) Etanercept (N = 138) Placebo (N = 39) Etanercept (N = 45)

Pivotal Program Consistent Response Across All ASAS 20 Components % Improvement at 12 Weeks Study Study 47687 100 100 *P < †P  0.02 80 80 64† 60 54* 55* 60 56† Median % Improvement 51* 48† 40 32* 40 33† 20 20 9 10 5 8 3 4 1 Patient Global Pain BASFI Stiffness Patient Global Pain BASFI Stiffness Placebo (N = 139) Etanercept (N = 138) Placebo (N = 39) Etanercept (N = 45)

Study 016.0037 Significant Improvement in Spinal Mobility
Median Percent Improvement from Baseline Placebo Etanercept P-value Parameter N = 139 N = 138 Schober’s Test weeks weeks Chest Expansion 12 weeks weeks <0.0001 Occiput-to-Wall Measurements 12 weeks weeks <0.0001

Study 016.0037 Peripheral Tender and Swollen Joint Counts
Placebo Etanercept P-value* Parameter N = 139 N = 138 Median Tender Joint Count Baseline weeks weeks Median Swollen Joint Count Baseline weeks weeks *Based on % improvement

Pivotal Program Markers of Systemic Inflammation Reduced Acute Phase Reactants at Week 12 Study Study 47687 100 -20 20 40 60 80 100 P < P < 80 80 69 70 60 60 Median % Improvement 40 20 -5.4 -20 ESR CRP ESR CRP Placebo (N = 139) Etanercept (N = 138) Placebo (N = 39) Etanercept (N = 45)

Study 016.0037 Favorable Etanercept Responses in All Subgroups
Age Gender Weight Race (Caucasian vs non-Caucasian) Site (North American vs European) Patient Global Assessment Average Back Pain Average of last 2 BASDAI questions (stiffness) BASDAI BASFI Disease Duration (< 5 years vs 5–10 years vs > 10 years) HLA-B27 History of uveitis/iritis History of psoriasis History of Crohn’s disease or UC History of bacterial dysentery, urethritis, chlamydia, or other STD History of urethritis and conjunctivitis Presence of hip disease Presence of hip disease or limited range of hip motion NSAIDs within 6 mo. of screening Steroids within 6 mo. of screening Concomitant sulfasalazine Concomitant methotrexate Injection site reaction during study

ASAS 20 in HLA-B27 Positive and Negative Subjects
Study ASAS 20 in HLA-B27 Positive and Negative Subjects Week 12 Week 24 80 80 65 HLA-B27 Positive 62 60 60 % Subjects 40 40 27 23 20 20 Placebo Etanercept (N = 109) (N = 108) (N = 109) (N = 108) 80 80 35 38 20 48 HLA-B27 Negative 60 60 % Subjects 40 40 20 20 (N = 20) (N = 21) (N = 20) (N = 21)

Study 016.0037 ASAS 20 by Gender Over Time
Week 12 Week 24 80 80 Men 65 63 60 60 % Subjects 40 40 27 25 20 20 Placebo Etanercept (N = 105) (N = 105) (N = 105) (N = 105) 80 80 60 60 Women 45 % Subjects 42 40 40 29 20 20 18 (N = 34) (N = 33) (N = 34) (N = 33)

Study 016.0037 ASAS 20 by Age Over Time
Week 12 Week 24 80 80 70 42 years 64 60 60 % Subjects 40 40 29 27 20 20 Placebo Etanercept (N = 66) (N = 74) (N = 66) (N = 74) 80 80 60 60 42 years 52 48 % Subjects 40 40 26 20 20 19 (N = 73) (N = 64) (N = 73) (N = 64)

Study 016.0037 ASAS 20 Response by Psoriasis History
Week 12 Week 24 80 80 Without psoriasis 61 60 60 60 % Subjects 40 40 27 23 20 20 Placebo Etanercept (N = 124) (N = 127) (N = 124) (N = 127) 80 80 60 60 With psoriasis 45 % Subjects 36 40 33 40 20 20 15 (N = 15) (N = 11) (N = 15) (N = 11)

Subgroup Summary Broad group of subjects enrolled and benefited from etanercept Multiple analyses performed Many subgroups have small sample size All subgroups demonstrate response

Etanercept in AS: Robust Efficacy Demonstrated
Study Etanercept in AS: Robust Efficacy Demonstrated Results at Week 12 Placebo (%) Etanercept (%) P-value Parameter N = 139 N = 138 ASAS <0.0001 ASAS <0.0001 ASAS <0.0001 DCART <0.0001 DCART <0.0001 Partial Remission

Consistent Efficacy in All Domains* Median Percent Improvement
Study Consistent Efficacy in All Domains* Median Percent Improvement Placebo Etanercept P-value Physical function BASFI (0-100 scale) <0.0001 Pain 100-mm VAS (past week) <0.0001 Spinal mobility Schober test Chest expansion Occiput-to-wall distance Patient Global Assessment VAS <0.0001 Inflammation Night pain VAS (past 48 hours) < BASDAI morning stiffness duration VAS < BASDAI morning stiffness intensity VAS < C-reactive protein <0.0001 *van der Heijde 1999

Safety All adverse events Serious adverse events
Pivotal Program All adverse events Serious adverse events Withdrawals due to adverse events Laboratory abnormalities Antibodies

Adverse Events (>10% in any treatment group)
Pivotal Program Study Study 47687 Placebo Etanercept Placebo Etanercept n (%) N = 139 N = 138 N = 39 N = 45 Injection site reactions 13 (9) 41 (30)* 6 (15) 15 (33)* Injection site ecchymosis 23 (17) 29 (21) 4 (10) 8 (18) Upper respiratory infection 16 (12) 28 (20)* 3 (8) 4 (9) Headache 16 (12) 19 (14) 4 (10) 6 (13) Accident/injury 6 (4) 17 (12)* 2 (5) 0 Nausea 7 (5) 7 (5) 4 (10) 3 (7) Asthenia 7 (5) 5 (4) 1 (3) 5 (11) *P < 0.05

Serious Adverse Events
Study Placebo Accident / injury (2) Viral infection Suicide attempt Chest pain Etanercept Bone fracture (3) Soft tissue infection (2) Fever/Rash Lymphadenopathy Intestinal obstruction Ulcerative colitis

Withdrawals Due to Adverse Events
Study Placebo Suicide attempt Etanercept Bone fracture (2) Fever Intestinal obstruction Ulcerative colitis Hemorrhoidal bleeding Ileitis

Grade 3 Laboratory Results in Etanercept Subjects
Pivotal Program Grade 3 Laboratory Results in Etanercept Subjects Study 1 transient ANC ( ) 1 transient lymphocyte (<500) Study 47687 1 transient elevated AST, ALT, and bilirubin All were at a single time point All patients continued on etanercept

Anti-etanercept Antibodies
Pivotal Program 3 patients with non-neutralizing antibodies No effect on safety and efficacy

Etanercept Provides Clinically Important Benefit in AS
Etanercept effective in AS Rapid onset of effect Reduces disease activity by multiple measures Relieves spinal pain and stiffness Improves spinal mobility Improves function Improves markers of systemic inflammation Etanercept safety profile in AS is favorable

V.P. Clinical Development Amgen Corporation Assessments in Désirée van der Heijde, M.D., Ph.D. Ankylosing Spondylitis Professor of Rheumatology University of Maastricht Maastricht, NL Study Results: Efficacy and Safety Wayne Tsuji, M.D. Associate Medical Director Benefit/Risk Assessment Daniel Burge, M.D.

Benefit/Risk Overview
Additional considerations regarding inflammatory bowel disease Broader rheumatic disease experience Overall benefit/risk assessment for ankylosing spondylitis

Intestinal obstruction Due to adhesions
Study Etanercept Withdrawals Due to Gastrointestinal Adverse Events Event Comment Intestinal obstruction Due to adhesions Hemorrhoidal bleeding No IBD (colonoscopy) Ulcerative colitis Pre-existing disease Ileitis History suggests IBD

Inflammatory Bowel Disease
AS Pivotal Program Number of Subjects Study Study 47687 Placebo Etanercept Placebo Etanercept N = 139 N = 138 N = 39 N = 45 Baseline History New Diagnosis Flare During Study

IBD Experience from Etanercept Studies in Rheumatic Diseases
14 subjects with pre-existing IBD 7 were treated in short term studies and all completed without exacerbation of disease 7 were treated with etanercept for up to 5 years None developed adverse events related to inflammatory bowel disease No flares of inflammatory bowel disease

Immunex Study Etanercept Study in Crohn’s Disease
Placebo Etanercept† N 14 35 Response Rate* 50% 66% Withdrawals due to 14% 6% exacerbations *Response defined as decrease of 75 units in CDAI †Dose range up to 32 mg/m2 twice weekly

Sandborn Study Etanercept Study in Crohn’s Disease
Crohn’s Disease Activity Index Over Time 350 300 250 Mean CDAI Score 200 150 100 50 2 4 8 Weeks of treatment Etanercept (N = 23) Placebo (N = 20) Gastroenterology 2001

Inflammatory Bowel Disease Experience Conclusion
Data from overall etanercept trial experience (N = 80), including 2 randomized, placebo- controlled trials in Crohn’s disease, do not support an association between etanercept therapy and IBD exacerbation.

Etanercept: Experience in Rheumatic Diseases
Patients Patient-Years Commercial* >182,000 >341,000 Clinical Trials† in 5th year of therapy in 6th year of therapy 390 *Through April 2003 †Through December 2002

Adverse Events Rates* in AS Comparable to Other Rheumatic Diseases
Controlled Studies Adverse Events Rates* in AS Comparable to Other Rheumatic Diseases Rheumatoid Arthritis PsA AS Mono- Protocol Event therapy w/ MTX Early RA Phase Any non-infectious AE Any infectious AE Upper respiratory infection Serious AE Serious infection† Advanced Disease *Events per patient-year †Infection associated with hospitalization or IV antibiotics

Summary of Safety Etanercept generally safe and well-tolerated in patients with AS Experience in AS comparable to the well- established safety profile from experience in other rheumatic diseases

Consistent Efficacy with Etanercept in Rheumatic Diseases
RA ACR 20 JRA DOI PsA ACR 20 AS ASAS 20 751 745 713 694 622 596 607 608 % Responders 1Moreland et al Moreland et al Weinblatt et al Bathon et al 2000 5Lovell et al 2000 6Mease et al 2001 7Study Study 47687

Etanercept in AS: Robust Efficacy Demonstrated
Study Etanercept in AS: Robust Efficacy Demonstrated Results at Week 12 Parameter P-value ASAS 20 <0.0001 ASAS 50 <0.0001 ASAS 70 <0.0001 DCART 20 <0.0001 DCART 40 <0.0001 Partial Remission

Etanercept in AS: Consistent Efficacy in All Domains*
Study Etanercept in AS: Consistent Efficacy in All Domains* P-value Physical function BASFI (0-100 scale) <0.0001 Pain 100-mm VAS (past week) <0.0001 Spinal mobility Schober test Chest expansion Occiput-to-wall distance Patient Global Assessment VAS <0.0001 Inflammation Night pain VAS (past 48 hours) < BASDAI morning stiffness duration VAS < BASDAI morning stiffness intensity VAS < C-reactive protein <0.0001 *van der Heijde 1999

Benefit/Risk of Etanercept is Highly Favorable
AS causes significant morbidity and disability Substantial unmet medical need due to limitation of traditional therapies Etanercept: Dramatically improves patients’ lives Favorable safety experience

Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis
FDA Arthritis Advisory Committee June 24, 2003 Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis

Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis

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