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Etanercept (EnbrelEtanercept (Enbrel®®) )
for the Treatment of for the Treatment of
Ankylosing SpondylitisAnkylosing Spondylitis
FDA Arthritis Advisory CommitteeFDA Arthritis Advisory Committee
June 24, 2003June 24, 2003
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PresentationsPresentations IntroductionIntroduction Daniel Burge, M.D.Daniel Burge, M.D.
V.P. Clinical DevelopmentV.P. Clinical DevelopmentAmgenAmgen
Assessments in Assessments in DDéésirsiréée van der Heijde, M.D., Ph.D.e van der Heijde, M.D., Ph.D.Ankylosing Spondylitis Ankylosing Spondylitis Professor of RheumatologyProfessor of Rheumatology
University of MaastrichtUniversity of MaastrichtMaastricht, NL Maastricht, NL
Clinical Program and ResultsClinical Program and Results Wayne Tsuji, M.D.Wayne Tsuji, M.D.Associate Medical DirectorAssociate Medical DirectorAmgenAmgen
Benefit/Risk AssessmentBenefit/Risk Assessment Daniel Burge, M.D.Daniel Burge, M.D.V.P. Clinical DevelopmentV.P. Clinical DevelopmentAmgenAmgen
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ConsultantsConsultants
DDéésirsiréée van der Heijde, M.D., Ph.D.e van der Heijde, M.D., Ph.D.Professor of RheumatologyProfessor of RheumatologyUniversity Hospital MaastrichtUniversity Hospital MaastrichtMaastricht, The NetherlandsMaastricht, The Netherlands
Daniel O. Clegg, M.D.Daniel O. Clegg, M.D.Professor of MedicineProfessor of MedicineDivision of RheumatologyDivision of RheumatologyUniversity of UtahUniversity of UtahSalt Lake City, UTSalt Lake City, UT
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Etanercept PropertiesEtanercept 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
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1998 1998 FDA approval for RA (alone or with MTX)FDA approval for RA (alone or with MTX)
1999 1999 FDA approval for JRAFDA approval for JRA
2000 2000 FDA approval as initial therapy for RAFDA approval as initial therapy for RAFDA approval for inhibition of radiographic progressionFDA approval for inhibition of radiographic progression
2002 2002 FDA approval for psoriatic arthritis (alone or with MTX)FDA approval for psoriatic arthritis (alone or with MTX)
20022002 Application for approval for inhibition of radiographic Application for approval for inhibition of radiographic progression in PsAprogression in PsA
20032003 Application for approval for ASApplication for approval for AS
Etanercept HistoryEtanercept History
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Family of SpondyloarthropathiesFamily of Spondyloarthropathies
AS UndifferentiatedSpondylo-
arthropathy
JuvenileSpondylo-
arthropathy
IBD Associated
Arthritis
PsoriaticArthritis
ReactiveArthritis
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Features of SpondyloarthropathiesFeatures of Spondyloarthropathies
Sacroiliitis +/- spondylitisSacroiliitis +/- spondylitis
EnthesitisEnthesitis
Variable involvement with peripheral arthritisVariable involvement with peripheral arthritis
Associated with uveitisAssociated with uveitis
No association with rheumatoid factorNo association with rheumatoid factor
Strong association with the genetic marker, Strong association with the genetic marker, HLA-B27HLA-B27
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Ankylosing SpondylitisAnkylosing Spondylitis
~350,000 patients in US~350,000 patients in US
Onset typically before age 45 Onset typically before age 45
Males more commonly affectedMales more commonly affected
Inflammatory back painInflammatory back pain
Khan 2003Carter 1979
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Progression of Ankylosing SpondylitisProgression of Ankylosing Spondylitis
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Traditional Therapies are InadequateTraditional Therapies are Inadequate
NSAIDs: the only approved therapies for ASNSAIDs: the only approved therapies for AS
– Improves pain and stiffnessImproves pain and stiffness
– Limited effect on spinal mobility and acute phase reactantsLimited effect on spinal mobility and acute phase reactants
Corticosteroids:Corticosteroids:
– Oral: limited effectOral: limited effect
– Systemic: temporary benefit/toxicSystemic: temporary benefit/toxic11
Sulfasalazine: improves peripheral but not axial Sulfasalazine: improves peripheral but not axial diseasedisease2,32,3
Methotrexate: limited benefit in controlled trialMethotrexate: limited benefit in controlled trial4
1Peters 1992. 3Clegg 1996. 2Dougados 1995. 4Altan 2001.
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Pathophysiology of AS: Role of TNFPathophysiology of AS: Role of TNF
TNF is implicated in TNF is implicated in pathogenesis of ASpathogenesis of AS
– TNF levels are elevated TNF levels are elevated in serumin serum11
– TNF levels are elevated in TNF levels are elevated in synovial tissuesynovial tissue22
1Toussirot and Wendling, 1994. Gratacos, 1994.2Canete et al, 1997. Grom et al, 1996.3Braun et al, 1995.
Sacroiliac biopsy; TNF mRNA3
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Challenges in AS Clinical Trials Challenges in AS Clinical Trials
AS causes pain, stiffness, disability, AS causes pain, stiffness, disability, decreased spinal mobility and decreased decreased spinal mobility and decreased quality of lifequality of life
Multiple instruments assess different aspects Multiple instruments assess different aspects of disease activity in ASof disease activity in AS
No widely accepted primary measure of No widely accepted primary measure of responseresponse
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PresentationsPresentations IntroductionIntroduction Daniel Burge, M.D.Daniel Burge, M.D.
V.P. Clinical DevelopmentV.P. Clinical DevelopmentAmgenAmgen
Assessments in Assessments in DDéésirsiréée van der Heijde, M.D., Ph.D.e van der Heijde, M.D., Ph.D.Ankylosing Spondylitis Ankylosing Spondylitis Professor of RheumatologyProfessor of Rheumatology
University of MaastrichtUniversity of MaastrichtMaastricht, NL Maastricht, NL
Clinical Program and ResultsClinical Program and Results Wayne Tsuji, M.D.Wayne Tsuji, M.D.Associate Medical DirectorAssociate Medical DirectorAmgenAmgen
Benefit/Risk AssessmentBenefit/Risk Assessment Daniel Burge, M.D.Daniel Burge, M.D.V.P. Clinical DevelopmentV.P. Clinical DevelopmentAmgenAmgen
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Formation of the ASessments in Ankylosing Formation of the ASessments in Ankylosing Spondylitis (ASAS) Working GroupSpondylitis (ASAS) Working Group
Started in 1995Started in 1995
At inception, >120 instruments published in At inception, >120 instruments published in the literaturethe literature
Organization of international experts in the Organization of international experts in the field of ASfield of AS
Several meetings yearlySeveral meetings yearly
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Mission Statement of ASASMission Statement of ASAS
The mission of ASAS is to support and The mission of ASAS is to support and promote the study of ankylosing promote the study of ankylosing spondylitis. This includes:spondylitis. This includes:
– Increasing awareness and early diagnosis of Increasing awareness and early diagnosis of the diseasethe disease
– Development and validation of assessment toolsDevelopment and validation of assessment tools
– The evaluation of treatment modalities in order to The evaluation of treatment modalities in order to promote clinical research with the ultimate goal to promote clinical research with the ultimate goal to improve outcome of the diseaseimprove outcome of the disease
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Disease ActivityDisease Activity
Core sets for assessment of:Core sets for assessment of:
– Symptom Modifying Anti-Rheumatic Drugs (SMARD) and Symptom Modifying Anti-Rheumatic Drugs (SMARD) and physical therapyphysical therapy
Effects on signs and symptomsEffects on signs and symptoms
– Disease Controlling Anti-Rheumatic TherapyDisease Controlling Anti-Rheumatic Therapy(DCART)(DCART)
Effects on signs and symptomsEffects on signs and symptoms
Effects on physical function/disabilityEffects on physical function/disability
Effects on structural damageEffects on structural damage
– Clinical record keepingClinical record keeping
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ASAS/OMERACT ASAS/OMERACT Core Domains for Core Domains for Ankylosing Ankylosing SpondylitisSpondylitis
van der Heijde et al. J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002
SMARD/Physical Therapy
Clinical Record Keeping
DCART
physical functionspinal stiffness
pain
spinal mobility
patient global assessment
peripheral joints/entheses
acutephase
reactants
spine radiograph
hip radiograph
fatigue
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Updated Core Set for SMARD in ASUpdated Core Set for SMARD in AS
van der Heijde et al. J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002
Domain Instrument
Function BASFI or Dougados FI
Pain VAS-last week-spine-at night-due to ASand VAS-last week-spine-due to AS
Spinal mobility Chest expansionand modified Schoberand occiput to walland (lateral spinal flexion or BASMI)
Patient global VAS-last week
Stiffness Duration of morning stiffness
Fatigue Fatigue question BASDAI
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Updated Core Set for DCART in AS Updated Core Set for DCART in AS (Domains/instruments in addition to core set for SMARD)(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
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Instruments for AssessmentInstruments for Assessment
00 11 33 44 55 66 77 88 9922 1010
No pain Unbearable pain
No pain Unbearable pain
Use either a NRS or VAS for all core set variablesUse either a NRS or VAS for all core set variables
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BASDAIBASDAI
1.1. FatigueFatigue
2.2. Pain in neck, back, hipsPain in neck, back, hips
3.3. Pain and swelling other jointsPain and swelling other joints
4.4. Sites painful by pressureSites painful by pressure
5.5. Severity of morning stiffnessSeverity of morning stiffness
6.6. Duration of morning stiffnessDuration of morning stiffness
Average 1- 5/6; range 0-10Average 1- 5/6; range 0-10
averageaverage
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Domains and Instruments for Domains and Instruments for Response CriteriaResponse Criteria
Patient global - Patient global - VASVAS
Pain - Pain - VASVAS
Function – Function – BASFIBASFI
Stiffness – average of Stiffness – average of morning stiffness durationmorning stiffness duration and and intensityintensity (BASDAI q 5 and 6) OR (BASDAI q 5 and 6) OR durationduration of of morning stiffness (120 minutes = maximum)morning stiffness (120 minutes = maximum)
Spinal mobility – chest expansion, modified Spinal mobility – chest expansion, modified Schober, fingers to floorSchober, fingers to floor
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Development of Response CriteriaDevelopment of Response Criteria
Definition of most reliable and sensitive Definition of most reliable and sensitive instruments within each domaininstruments within each domain
List of improvement definitionsList of improvement definitions
Sensitivity and specificity of selected Sensitivity and specificity of selected candidate response definitions in 2/3 of candidate response definitions in 2/3 of the samplethe sample
Validation in remaining 1/3 of the sampleValidation in remaining 1/3 of the sample
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Development of Response CriteriaDevelopment of Response Criteria
Based on the best discrimination between Based on the best discrimination between NSAIDs and placeboNSAIDs and placebo
Validated by comparison with experts opinion Validated by comparison with experts opinion (Delphi exercise ASAS working group)(Delphi exercise ASAS working group)
Validated by end of trial judgment by patient Validated by end of trial judgment by patient and physicianand physician
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Development of Response CriteriaDevelopment of Response Criteria
5 randomized NSAID-placebo controlled trials5 randomized NSAID-placebo controlled trials
Short-term (up to 6 weeks)Short-term (up to 6 weeks)
Flare designFlare design
Axial diseaseAxial disease
684 patients treated with NSAIDs684 patients treated with NSAIDs
346 patients treated with placebo346 patients treated with placebo
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ASAS 20ASAS 20Preliminary Response Criteria ASPreliminary Response Criteria AS
Patient globalPatient global
PainPain
FunctionFunction
StiffnessStiffness
Improvement of 20% AND 10 units in at least 3 domainsImprovement of 20% AND 10 units in at least 3 domains
No worsening in remaining domainNo worsening in remaining domain
Anderson et al Arthritis Rheum 2001:44:1876-886
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NSAIDsNSAIDs 49% responders49% responders
Placebo 24% respondersPlacebo 24% responders
NB in a flare design!NB in a flare design!
Performance of ASAS 20 Response CriteriaPerformance of ASAS 20 Response Criteria
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Criteria are strict and highly specific Criteria are strict and highly specific
Sensitivity 62%, specificity 89%Sensitivity 62%, specificity 89%
Agreement with experts opinion and end of Agreement with experts opinion and end of trial judgment by patient and physician: 70%trial judgment by patient and physician: 70%
Responders defined by ASAS 20 are true Responders defined by ASAS 20 are true responders acknowledged both by patient and responders acknowledged both by patient and physicianphysician
Performance of ASAS 20 Response CriteriaPerformance of ASAS 20 Response Criteria
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Caveats in Comparing Trials Assessing Caveats in Comparing Trials Assessing NSAIDs and Anti-TNF TherapyNSAIDs and Anti-TNF Therapy
NSAID trialsNSAID trials
Flare designFlare design
Proven efficacy of Proven efficacy of NSAIDsNSAIDs
Inclusion of patients Inclusion of patients with mild and severe with mild and severe diseasedisease
Anti-TNF trialsAnti-TNF trials
No flare designNo flare design
Proven inefficacy of Proven inefficacy of NSAIDSNSAIDS
Inclusion of patients Inclusion of patients with severe diseasewith severe disease
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ASAS - ASAS - Partial RemissionPartial Remission Criteria AS Criteria AS
Patient globalPatient global
PainPain
FunctionFunction
StiffnessStiffness
A value below 20 units in each of the 4 domainsA value below 20 units in each of the 4 domains
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ASAS 20 Improvement CriteriaASAS 20 Improvement Criteria
Based on NSAIDs trials – signs and symptomsBased on NSAIDs trials – signs and symptoms
Same criteria to assess DCART such as TNF-Same criteria to assess DCART such as TNF-blocking agents?blocking agents?
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Development of Response CriteriaDevelopment of Response Criteriafor DCARTfor DCART
Addition of 2 extra ‘DCART domains’Addition of 2 extra ‘DCART domains’
Comparison with existing ASAS criteria and Comparison with existing ASAS criteria and BASDAI - improvementBASDAI - improvement
With many different cut-off values in many With many different cut-off values in many combinationscombinations
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Development of Response CriteriaDevelopment of Response Criteriafor DCARTfor DCART
Extra domains in DCART core setExtra domains in DCART core set
– Spinal mobility Spinal mobility
– Acute phase reactants Acute phase reactants
– Joints - very low responsiveness; minority of Joints - very low responsiveness; minority of patientspatients
– Entheses - instruments still under developmentEntheses - instruments still under development
– (Radiographs) – assess structural damage(Radiographs) – assess structural damage
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Response Criteria for DCARTResponse Criteria for DCART
Development in 1 trialDevelopment in 1 trial
Validation in other trialsValidation in other trials
Opinion based final selectionOpinion based final selection
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Preliminary Response Criteria for DCARTPreliminary Response Criteria for DCART
ASAS 40% and 20 units responseASAS 40% and 20 units response
20% improvement in 5 out of 6 domains:20% improvement in 5 out of 6 domains:
– Patient globalPatient global
– PainPain
– FunctionFunction
– StiffnessStiffness
– Spinal mobilitySpinal mobility
– Acute phase reactantsAcute phase reactants
ASAS workshop Gent, October 2002
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PresentationsPresentations IntroductionIntroduction Daniel Burge, M.D.Daniel Burge, M.D.
V.P. Clinical DevelopmentV.P. Clinical DevelopmentAmgenAmgen
Assessments in Assessments in DDéésirsiréée van der Heijde, M.D., Ph.D.e van der Heijde, M.D., Ph.D.Ankylosing Spondylitis Ankylosing Spondylitis Professor of RheumatologyProfessor of Rheumatology
University of MaastrichtUniversity of MaastrichtMaastricht, NL Maastricht, NL
Clinical Program and ResultsClinical Program and Results Wayne Tsuji, M.D.Wayne Tsuji, M.D.Associate Medical DirectorAssociate Medical DirectorAmgenAmgen
Benefit/Risk AssessmentBenefit/Risk Assessment Daniel Burge, M.D.Daniel Burge, M.D.V.P. Clinical DevelopmentV.P. Clinical DevelopmentAmgenAmgen
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Clinical Development Program ObjectivesClinical Development Program Objectives
Establish efficacy and safety profile of Establish efficacy and safety profile of etanercept in treatment of ASetanercept in treatment of AS
Confirm role of TNF in the pathophysiologyConfirm role of TNF in the pathophysiologyof ASof AS
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Clinical Development Program in ASClinical Development Program in AS401 subjects evaluated in 3 randomized, 401 subjects evaluated in 3 randomized,
double blind, placebo-controlled trialsdouble blind, placebo-controlled trials
Proof-of-Principle StudyProof-of-Principle Study
Pivotal ProgramPivotal Program
Study 016.0626Single Center (U.S.)
40 subjects for 16 weeks
Study 016.0037Multi-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
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Proof-of-PrincipleProof-of-PrincipleStudy 016.0626Study 016.0626
GORMAN, SACK, DAVIS. 2002;346:1349-56
The New England Journal of Medicine
TREATMENT OF ANKYLOSING SPONDYLITIS BY INHIBITION OF TUMOR NECROSIS FACTOR
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Study DesignStudy Design
Single centerSingle center
Randomized, double-blind, placebo controlledRandomized, double-blind, placebo controlled
40 subjects for 16 weeks (placebo vs 40 subjects for 16 weeks (placebo vs etanercept 25 mg BIW)etanercept 25 mg BIW)
Active AS with stable background NSAIDs, steroids (Active AS with stable background NSAIDs, steroids (110 0 mg/d prednisone), and/or DMARDsmg/d prednisone), and/or DMARDs
Excluded if:Excluded if:
– Features of other spondyloarthropathyFeatures of other spondyloarthropathy
– Previous TNF inhibitor therapyPrevious TNF inhibitor therapy
– Rheumatoid factor positiveRheumatoid factor positive
Study 016.0626
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Primary Efficacy AssessmentPrimary Efficacy Assessment
20% improvement in 3 of 5 parameters without 20% improvement in 3 of 5 parameters without worsening in the remaining 2 measuresworsening in the remaining 2 measures
– Nocturnal spinal pain*Nocturnal spinal pain*
– Duration of morning stiffness*Duration of morning stiffness*
– Patient global assessmentPatient global assessment
– BASFIBASFI
– Swollen joint scoreSwollen joint score
*At least one must improve
Study 016.0626
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Proof of Principle Established Proof of Principle Established Primary Endpoint: % Achieving ResponsePrimary Endpoint: % Achieving Response
Week
% S
ub
ject
s
10
35
25 25
55 55
7075
0
10
20
30
40
50
60
70
80
4 8 12 16
Placebo (N = 20) Etanercept (N = 20)P = 0.0038
Study 016.0626Study 016.0626
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Pivotal ProgramPivotal Program
Amgen Study 016.0037Amgen Study 016.0037
Wyeth Study 47687Wyeth Study 47687
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Study DesignStudy Design
Two randomized, double-blind, placebo-controlled, multi-Two randomized, double-blind, placebo-controlled, multi-center (placebo vs etanercept 25 mg BIW)center (placebo vs etanercept 25 mg BIW)– 277 subjects for 24 weeks (Study 016.0037)277 subjects for 24 weeks (Study 016.0037)
– 84 subjects for 12 weeks (Study 47687)84 subjects for 12 weeks (Study 47687)
Definite AS (modified NY criteria) with active diseaseDefinite AS (modified NY criteria) with active disease Stable background NSAIDs, steroids (Stable background NSAIDs, steroids (10 mg/d prednisone)10 mg/d prednisone) Stable hydroxychloroquine, sulfasalazine or methotrexate Stable hydroxychloroquine, sulfasalazine or methotrexate
permittedpermitted Excluded for:Excluded for:
– Complete ankylosis of spineComplete ankylosis of spine
– Prior TNF inhibitor therapyPrior TNF inhibitor therapy
Pivotal Program
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Primary Efficacy EndpointsPrimary Efficacy Endpoints
ASAS 20 at week 12ASAS 20 at week 12– Improvement of Improvement of 20% and absolute improvement of 20% and absolute improvement of 10 10
units in at least 3 of following domains:units in at least 3 of following domains: Patient global assessmentPatient global assessment PainPain = average of total spinal pain and nocturnal = average of total spinal pain and nocturnal
spinal painspinal pain FunctionFunction = BASFI = BASFI StiffnessStiffness = average of last two questions in BASDAI regarding = average of last two questions in BASDAI regarding
morning stiffnessmorning stiffness
– Absence of deterioration in the potential remaining domainAbsence of deterioration in the potential remaining domain
ASAS 20 at week 24ASAS 20 at week 24
Pivotal Program
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Other Efficacy EndpointsOther Efficacy Endpoints
ASAS 50, ASAS 70ASAS 50, ASAS 70
Partial remission Partial remission
DCARTDCART
Elements of the ASAS Elements of the ASAS Response CriteriaResponse Criteria
– PainPain
– StiffnessStiffness
– FunctionFunction
– Global assessmentGlobal assessment
Spinal mobilitySpinal mobility
– Modified Schober’s Modified Schober’s
– Chest expansionChest expansion
– Occiput-to-wallOcciput-to-wall
Markers of systemic Markers of systemic inflammationinflammation
– CRP, ESRCRP, ESR
Peripheral joint countsPeripheral joint counts
Pivotal Program
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Baseline DemographicsBaseline Demographics
Placebo Etanercept Placebo EtanerceptBaseline characteristic N = 139 N = 138 N = 39 N = 45
Mean age, years 41.9 42.1 40.7 45.3
Male, % 76 76 77 80
Mean duration of disease, years 10.5 10.1 9.7 15.0
Race, %:Caucasian 91 94 95 93Other 9 6 5 7
HLA-B27 positive, % 84 84 87 88
Study 47687Study 016.0037
Pivotal Program
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Baseline TherapyBaseline Therapy
Placebo Etanercept Placebo EtanerceptBaseline therapy, %: N = 139 N = 138 N = 39 N = 45
NSAIDs* 92 91 85 89
Corticosteroids* 14 13 15 16
Any DMARD 31 32 41 36
Sulfasalazine 22 21 28 24
Methotrexate 12 11 13 13
Hydroxychloroquine 1 2 3 0
*Taken within 6 months of screening for 016.0037
Pivotal Program
Study 47687Study 016.0037
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Baseline Disease ActivityBaseline Disease Activity
Placebo Etanercept Placebo EtanerceptASAS 20 components*, mean N = 139 N = 138 N = 39 N = 45
Stiffness, durationand intensity 64.3 61.4 62.9 67.5
Patient global assessment 62.9 62.9 63.4 65.6
Total back pain 63.5 61.1 56.5 61.9
BASFI† 56.3 51.7 57.2 60.2
*All measures on 0-100 scale†Bath Ankylosing Spondylitis Functional Index
Pivotal Program
Study 47687Study 016.0037
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DispositionDisposition
Placebo Etanercept Placebo EtanerceptN = 139 N = 138 N = 39 N = 45
12 weeksCompleted, n (%) 134 (96) 132 (96) 39 (100) 43 (96)Discontinued due to, n:
Adverse event 0 4 0 0Lack of efficacy 2 1 0 0Other 3 1 0 2
24 weeksCompleted, n (%) 120 (86) 126 (91)Discontinued due to, n:
Adverse event 1 7Lack of efficacy 13 3Other 5 2
Study 47687Study 016.0037
Pivotal Program
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Primary Endpoint Achieved in Both StudiesPrimary Endpoint Achieved in Both Studies ASAS 20 at 12 WeeksASAS 20 at 12 Weeks
Study 016.0037 Study 47687
P < 0.0001
27
60
Placebo(N = 139)
Etanercept(N = 138)
0
20
40
60
80
100
% S
ub
ject
s
23
60
0
20
40
60
80
100P = 0.0008
Pivotal ProgramPivotal Program
Placebo(N = 39)
Etanercept(N = 45)
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Rapid and Durable EffectRapid and Durable EffectASAS 20 Over TimeASAS 20 Over Time
*P < 0.0001
2327272422
58*60*59*
50*46*
0
10
20
30
40
50
60
70
80
90
100
0 4 8 12 16 20 24
Weeks
% S
ub
ject
s
Placebo (N = 139)Etanercept (N = 138)
Study 016.0037
2
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ASAS 20, 50, and 70 at Week 12ASAS 20, 50, and 70 at Week 12
Study 016.0037 Study 47687
% S
ub
ject
s
7
29
13
27
45
60
ASAS 20 ASAS 50 ASAS 70
10
24
10
23
49
60
ASAS 20 ASAS 50 ASAS 700
20
40
60
80
100
0
20
40
60
80
100
P = 0.0973
P = 0.0002
P = 0.0008P < 0.0001
P < 0.0001
P < 0.0001
Pivotal Program
Placebo (N = 139)Etanercept (N = 138)
Placebo (N = 39)Etanercept (N = 45)
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Partial Remission at 12 WeeksPartial Remission at 12 Weeks%
Su
bje
cts
P = 0.0020
Study 016.0037 Study 47687
Pivotal Program
P = 0.3457
0
20
40
50
8
2130
10
0
20
40
50
10
18
30
10
Placebo(N = 139)
Etanercept(N = 138)
Placebo(N = 39)
Etanercept(N = 45)
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Consistent DCART Response inConsistent DCART Response inBoth Studies at 12 WeeksBoth Studies at 12 Weeks
% S
ub
ject
s
*P < 0.0001
158
43*37*
DCART 20 DCART 400
20
40
60
80
100
1513
58*
44*
DCART 20 DCART 400
20
40
60
80
100Study 016.0037 Study 47687
Pivotal ProgramPivotal Program
Placebo (N = 139)Etanercept (N = 138)
Placebo (N = 39)Etanercept (N = 45)
*P < 0.0001
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Consistent Response Across All ASAS 20 ComponentsConsistent Response Across All ASAS 20 Components% Improvement at 12 Weeks% Improvement at 12 Weeks
Med
ian
% I
mp
rove
men
t
08
33†
64†
14
56†
48†
PatientGlobal
Pain BASFI0
20
40
60
80
100
310
32*
55*
59
54*51*
0
20
40
60
80
100
PatientGlobal
Pain BASFI
*P < 0.0001
Stiffness
Study 016.0037 Study 47687
†P 0.02
Stiffness
Pivotal ProgramPivotal Program
Placebo (N = 139)Etanercept (N = 138)
Placebo (N = 39)Etanercept (N = 45)
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Placebo Etanercept P-valueParameter N = 139 N = 138
Schober’s Test12 weeks 0 8.6 0.035924 weeks 0 9.7 0.0014
Chest Expansion12 weeks 0 4.8 0.002624 weeks 0 16.7 <0.0001
Occiput-to-Wall Measurements12 weeks 0 15.7 0.003424 weeks 0 25.0 <0.0001
Study 016.0037Study 016.0037
Significant Improvement in Spinal MobilitySignificant Improvement in Spinal MobilityMedian
Percent Improvement from Baseline
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Study 016.0037Study 016.0037
Peripheral Tender and Swollen Joint CountsPeripheral Tender and Swollen Joint Counts
Median Tender Joint CountBaseline 4.0 3.012 weeks 2.0 1.0 0.006124 weeks 2.0 1.0 0.0014
Median Swollen Joint CountBaseline 0 1.012 weeks 0 0 0.126324 weeks 0 0 0.8384
*Based on % improvement
Placebo Etanercept P-value*Parameter N = 139 N = 138
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Markers of Systemic Inflammation ReducedMarkers of Systemic Inflammation ReducedAcute Phase Reactants at Week 12Acute Phase Reactants at Week 12
Study 016.0037 Study 47687
-20
0
20
40
60
80
100
-5.4
0
6960
00
7080
-20
0
20
40
60
80
100
ESR CRP ESR CRP
Med
ian
% I
mp
rove
men
t P < 0.0001 P < 0.0001
Pivotal ProgramPivotal Program
Placebo (N = 139)Etanercept (N = 138)
Placebo (N = 39)Etanercept (N = 45)
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Study 016.0037Study 016.0037
Favorable Etanercept ResponsesFavorable Etanercept Responsesin All Subgroupsin All Subgroups
AgeAge
GenderGender
WeightWeight
Race (Caucasian vs non-Caucasian)Race (Caucasian vs non-Caucasian)
Site (North American vs European) Site (North American vs European)
Patient Global Assessment Patient Global Assessment
Average Back PainAverage Back Pain
Average of last 2 BASDAI questionsAverage of last 2 BASDAI questions(stiffness)(stiffness)
BASDAI BASDAI
BASFIBASFI
Disease Duration (< 5 years vs 5–10 years Disease Duration (< 5 years vs 5–10 years vs > 10 years)vs > 10 years)
HLA-B27HLA-B27
History of uveitis/iritisHistory of uveitis/iritis
History of psoriasisHistory of psoriasis
History of Crohn’s disease or UCHistory of Crohn’s disease or UC
History of bacterial dysentery, History of bacterial dysentery, urethritis, chlamydia, or other STD urethritis, chlamydia, or other STD
History of urethritis and conjunctivitisHistory of urethritis and conjunctivitis
Presence of hip diseasePresence of hip disease
Presence of hip disease or limited Presence of hip disease or limited range of hip motionrange of hip motion
NSAIDs within 6 mo. of screeningNSAIDs within 6 mo. of screening
Steroids within 6 mo. of screeningSteroids within 6 mo. of screening
Concomitant sulfasalazineConcomitant sulfasalazine
Concomitant methotrexateConcomitant methotrexate
Injection site reaction during studyInjection site reaction during study
C-61
ASAS 20 in HLA-B27 Positive and ASAS 20 in HLA-B27 Positive and Negative SubjectsNegative Subjects
PlaceboEtanercept
Study 016.0037
20
48HLA-B27Negative
HLA-B27Positive
27
65
(N = 109) (N = 108)
Week 12 Week 24
0
20
40
60
80
23
62%
Su
bje
cts
35 38
(N = 20) (N = 21)
0
20
40
60
80%
Su
bje
cts
(N = 109) (N = 108)
(N = 20) (N = 21)0
20
40
60
80
0
20
40
60
80
C-62
Study 016.0037Study 016.0037
ASAS 20 by Gender Over TimeASAS 20 by Gender Over Time
0
20
40
60
80
18
42Women
27
65
(N = 105) (N = 105)
Week 12 Week 24
20
40
60
80
25
63%
Su
bje
cts
29
45
0
20
40
60
80
(N = 34) (N = 33)
20
40
60
80%
Su
bje
cts
(N = 105) (N = 105)
(N = 34) (N = 33)
0 0
Men
PlaceboEtanercept
C-63
Study 016.0037Study 016.0037
ASAS 20 by Age Over TimeASAS 20 by Age Over Time
19
5242 years
29
70
(N = 66) (N = 74)
Week 12 Week 24
20
40
60
80
27
64%
Su
bje
cts
26
48
(N = 73) (N = 64)
20
40
60
80%
Su
bje
cts
(N = 66) (N = 74)
(N = 73) (N = 64)0
20
40
60
80
0
20
40
60
80
0 0
42 years
PlaceboEtanercept
C-64
Study 016.0037Study 016.0037
ASAS 20 Response by Psoriasis HistoryASAS 20 Response by Psoriasis History
15
36With
psoriasis
27
61
(N = 124) (N = 127)
Week 12 Week 24
20
40
60
80
23
60%
Su
bje
cts
33
45
(N = 15) (N = 11)
20
40
60
80%
Su
bje
cts
(N = 124) (N = 127)
(N = 15) (N = 11)0
20
40
60
80
0
20
40
60
80
0 0
Withoutpsoriasis
PlaceboEtanercept
C-65
Subgroup SummarySubgroup Summary
Broad group of subjects enrolled and Broad group of subjects enrolled and benefited from etanerceptbenefited from etanercept
– Multiple analyses performedMultiple analyses performed
– Many subgroups have small sample sizeMany subgroups have small sample size
All subgroups demonstrate responseAll subgroups demonstrate response
C-66
Etanercept in AS: Robust Efficacy Etanercept in AS: Robust Efficacy DemonstratedDemonstrated
Placebo (%) Etanercept (%) P-valueParameter N = 139 N = 138
ASAS 20 27 60 <0.0001
ASAS 50 13 45 <0.0001
ASAS 70 7 29 <0.0001
DCART 20 8 37 <0.0001
DCART 40 15 43 <0.0001
Partial Remission 8 21 0.0020
Results at Week 12
Study 016.0037Study 016.0037
C-67
Consistent Efficacy in All Domains*Consistent Efficacy in All Domains*Median Percent ImprovementMedian Percent Improvement
Physical functionBASFI (0-100 scale) 3 32 <0.0001
Pain100-mm VAS (past week) 9 53 <0.0001
Spinal mobilitySchober test 0 9 0.0359Chest expansion 0 5 0.0026Occiput-to-wall distance 0 16 0.0034
Patient Global AssessmentVAS 9 51 <0.0001
InflammationNight pain VAS (past 48 hours) 6 58 <0.0001BASDAI morning stiffness duration VAS 3 50 <0.0001BASDAI morning stiffness intensity VAS 13 58 <0.0001C-reactive protein -5 69 <0.0001
Study 016.0037
Placebo Etanercept P-value
*van der Heijde 1999
C-68
SafetySafety
All adverse eventsAll adverse events
Serious adverse eventsSerious adverse events
Withdrawals due to adverse eventsWithdrawals due to adverse events
Laboratory abnormalitiesLaboratory abnormalities
AntibodiesAntibodies
Pivotal Program
C-69
Adverse Events Adverse Events (>10% in any treatment group)(>10% in any treatment group)
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)
Study 016.0037 Study 47687
*P < 0.05
Pivotal Program
Placebo Etanercept Placebo Etanerceptn (%) N = 139 N = 138 N = 39 N = 45
C-70
Serious Adverse EventsSerious Adverse Events
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
Study 016.0037
C-71
Withdrawals Due to Adverse EventsWithdrawals Due to Adverse EventsStudy 016.0037
Placebo
Suicide attempt
Etanercept
Bone fracture (2)
Fever
Intestinal obstruction
Ulcerative colitis
Hemorrhoidal bleeding
Ileitis
C-72
Grade 3 Laboratory Results in Grade 3 Laboratory Results in Etanercept SubjectsEtanercept Subjects
Study 016.0037Study 016.0037
– 1 transient ANC (500-1000)1 transient ANC (500-1000)
– 1 transient lymphocyte (<500)1 transient lymphocyte (<500)
Study 47687Study 47687
– 1 transient elevated AST, ALT, and bilirubin1 transient elevated AST, ALT, and bilirubin
All were at a single time pointAll were at a single time point
All patients continued on etanerceptAll patients continued on etanercept
Pivotal Program
C-73
Anti-etanercept AntibodiesAnti-etanercept Antibodies
3 patients with non-neutralizing antibodies3 patients with non-neutralizing antibodies
No effect on safety and efficacyNo effect on safety and efficacy
Pivotal Program
C-74
Etanercept Provides Clinically Important Etanercept Provides Clinically Important Benefit in ASBenefit in AS
Etanercept effective in ASEtanercept effective in AS
– Rapid onset of effectRapid onset of effect
– Reduces disease activity by multiple measuresReduces disease activity by multiple measures
– Relieves spinal pain and stiffnessRelieves spinal pain and stiffness
– Improves spinal mobilityImproves spinal mobility
– Improves functionImproves function
– Improves markers of systemic inflammationImproves markers of systemic inflammation
Etanercept safety profile in AS is favorableEtanercept safety profile in AS is favorable
C-75
PresentationsPresentations IntroductionIntroduction Daniel Burge, M.D.Daniel Burge, M.D.
V.P. Clinical DevelopmentV.P. Clinical DevelopmentAmgen CorporationAmgen Corporation
Assessments in Assessments in DDéésirsiréée van der Heijde, M.D., Ph.D.e van der Heijde, M.D., Ph.D.Ankylosing SpondylitisAnkylosing Spondylitis Professor of RheumatologyProfessor of Rheumatology
University of MaastrichtUniversity of MaastrichtMaastricht, NLMaastricht, NL
Study Results: Study Results: Efficacy and SafetyEfficacy and Safety Wayne Tsuji, M.D.Wayne Tsuji, M.D.
Associate Medical DirectorAssociate Medical DirectorAmgen CorporationAmgen Corporation
Benefit/Risk AssessmentBenefit/Risk Assessment Daniel Burge, M.D.Daniel Burge, M.D.V.P. Clinical DevelopmentV.P. Clinical DevelopmentAmgen CorporationAmgen Corporation
C-76
Benefit/Risk OverviewBenefit/Risk Overview
Additional considerations regarding Additional considerations regarding inflammatory bowel diseaseinflammatory bowel disease
Broader rheumatic disease experienceBroader rheumatic disease experience
Overall benefit/risk assessment for Overall benefit/risk assessment for ankylosing spondylitisankylosing spondylitis
C-77
Study 016.0037Study 016.0037
Etanercept Withdrawals Due to Etanercept Withdrawals Due to Gastrointestinal Adverse EventsGastrointestinal Adverse Events
Event Comment
Intestinal obstruction Due to adhesions
Hemorrhoidal bleeding No IBD (colonoscopy)
Ulcerative colitis Pre-existing disease
Ileitis History suggests IBD
C-78
Inflammatory Bowel DiseaseInflammatory Bowel Disease
Placebo Etanercept Placebo EtanerceptN = 139 N = 138 N = 39 N = 45
Baseline History 6 7 3 3
New Diagnosis 1 1 0 0
Flare During Study 0 1 0 0
Study 016.0037 Study 47687
AS Pivotal Program
Number of Subjects
C-79
IBD Experience from Etanercept Studies IBD Experience from Etanercept Studies in Rheumatic Diseasesin Rheumatic Diseases
14 subjects with pre-existing IBD14 subjects with pre-existing IBD
– 7 were treated in short term studies and all 7 were treated in short term studies and all completed without exacerbation of diseasecompleted without exacerbation of disease
– 7 were treated with etanercept for up to 5 years7 were treated with etanercept for up to 5 years
– None developed adverse events related to None developed adverse events related to inflammatory bowel diseaseinflammatory bowel disease
No flares of inflammatory bowel diseaseNo flares of inflammatory bowel disease
C-80
Immunex StudyImmunex Study
Etanercept Study in Crohn’s DiseaseEtanercept 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
C-81
Sandborn StudySandborn Study
Etanercept Study in Crohn’s DiseaseEtanercept Study in Crohn’s Disease
Gastroenterology 2001
Crohn’s Disease Activity Index Over Time
Weeks of treatment
Mea
n C
DA
I S
core
50
100
150
200
250
300
350
2 4 800
Etanercept (N = 23) Placebo (N = 20)
C-82
Inflammatory Bowel Disease Experience Inflammatory Bowel Disease Experience ConclusionConclusion
Data from overall etanercept trial experience Data from overall etanercept trial experience (N = 80), including 2 randomized, placebo-(N = 80), including 2 randomized, placebo-controlled trials in Crohn’s disease, do not controlled trials in Crohn’s disease, do not support an association between etanercept support an association between etanercept therapy and IBD exacerbation.therapy and IBD exacerbation.
C-83
Etanercept: Experience in Rheumatic Etanercept: Experience in Rheumatic DiseasesDiseases
PatientsPatients Patient-YearsPatient-Years
Commercial*Commercial* >182,000>182,000 >341,000>341,000
Clinical TrialsClinical Trials†† 33893389 83368336
in 5in 5thth year of therapy year of therapy 10841084
in 6in 6thth year of therapy year of therapy 390390
*Through April 2003††Through December 2002
C-84
Rheumatoid Arthritis PsA AS
Mono- ProtocolEvent therapy w/ MTX Early RA Phase 3 016.0037
Any non-infectious AE 5.39 5.02 5.90 3.28 6.10
Any infectious AE 2.42 2.07 1.54 1.24 1.20
Upper respiratory infection 0.92 0.57 0.50 0.50 0.54
Serious AE 0.09 0.11 0.09 0.14 0.17
Serious infection† 0.02 0.08 0.02 0 0.03
Adverse Events Rates* in AS Comparable Adverse Events Rates* in AS Comparable to Other Rheumatic Diseasesto Other Rheumatic Diseases
*Events per patient-year†Infection associated with hospitalization or IV antibiotics
Advanced Disease
Controlled Studies
C-85
Summary of SafetySummary of Safety
Etanercept generally safe and well-tolerated in Etanercept generally safe and well-tolerated in patients with AS patients with AS
Experience in AS comparable to the well-Experience in AS comparable to the well-established safety profile from experience in established safety profile from experience in other rheumatic diseasesother rheumatic diseases
C-86
Consistent Efficacy with Etanercept in Consistent Efficacy with Etanercept in Rheumatic DiseasesRheumatic Diseases
622713
694751
RA ACR 20
1Moreland et al 19972Moreland et al 19993Weinblatt et al 19994Bathon et al 2000
% R
esp
on
der
s
596
PsAACR 20
6Mease et al 2001
607 608
ASASAS 20
7Study 016.00378Study 47687
745
JRADOI
5Lovell et al 2000
C-87
Etanercept in AS: Robust Efficacy Etanercept in AS: Robust Efficacy DemonstratedDemonstrated
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 0.0020
Results at Week 12
Study 016.0037
C-88
Etanercept in AS: Consistent Efficacy in Etanercept in AS: Consistent Efficacy in All Domains*All Domains*
Study 016.0037
Physical functionBASFI (0-100 scale) <0.0001
Pain100-mm VAS (past week) <0.0001
Spinal mobilitySchober test 0.0359Chest expansion 0.0026Occiput-to-wall distance 0.0034
Patient Global AssessmentVAS <0.0001
InflammationNight pain VAS (past 48 hours) <0.0001BASDAI morning stiffness duration VAS <0.0001BASDAI morning stiffness intensity VAS <0.0001C-reactive protein <0.0001
*van der Heijde 1999
P-value
C-89
Benefit/Risk of Etanercept is Highly Benefit/Risk of Etanercept is Highly FavorableFavorable
AS causes significant morbidity and disabilityAS causes significant morbidity and disability
Substantial unmet medical need due to Substantial unmet medical need due to limitation of traditional therapieslimitation of traditional therapies
Etanercept:Etanercept:
– Dramatically improves patients’ livesDramatically improves patients’ lives
– Favorable safety experienceFavorable safety experience
C-90
Etanercept (EnbrelEtanercept (Enbrel®®) )
for the Treatment of for the Treatment of
Ankylosing SpondylitisAnkylosing Spondylitis
FDA Arthritis Advisory CommitteeFDA Arthritis Advisory Committee
June 24, 2003June 24, 2003
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