C-1 Etanercept (Enbrel ® ) for the Treatment of Ankylosing Spondylitis FDA Arthritis Advisory Committee June 24, 2003

C-1

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

C-2

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

C-3

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

C-4

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

C-5

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

C-6

Family of SpondyloarthropathiesFamily of Spondyloarthropathies

AS UndifferentiatedSpondylo-

arthropathy

JuvenileSpondylo-

arthropathy

IBD Associated

Arthritis

PsoriaticArthritis

ReactiveArthritis

C-7

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

C-8


~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

C-9

Progression of Ankylosing SpondylitisProgression of Ankylosing Spondylitis

C-10

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.

C-11

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

C-12

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

C-13







C-14

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

C-15

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

C-16

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

C-17

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

C-18

Updated Core Set for SMARD in ASUpdated Core Set for SMARD in AS


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

C-19

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)


C-20

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

C-21

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

C-22

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

C-23

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

C-24


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

C-25


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

C-26

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

C-27

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

C-28

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

C-29

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

C-30

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

C-31

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?

C-32

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

C-33

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

C-34

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

C-35

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

C-36







C-37

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

C-38

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)


Study 47687*Multi-center (14 EU)


*Wyeth 0881A3-311-EU CSR 47687

C-39

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

C-40

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

C-41

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

C-42

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

C-43


Amgen Study 016.0037Amgen Study 016.0037

Wyeth Study 47687Wyeth Study 47687

C-44

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

C-45

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

C-46

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

C-47

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

C-48

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


C-49

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


C-50

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


Pivotal Program

C-51

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


Placebo(N = 39)

Etanercept(N = 45)

C-52

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

C-53

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



C-54

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)

C-55

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




*P < 0.0001

C-56

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




C-57

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

C-58

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

C-59

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




C-60

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


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


FDA Arthritis Advisory CommitteeFDA Arthritis Advisory Committee

June 24, 2003June 24, 2003

Documents

C-1 Etanercept (Enbrel ® ) for the Treatment of Ankylosing Spondylitis FDA Arthritis Advisory Committee June 24, 2003