Etanercept (Enbrel

1
Etanercept (Enbrel) for the Treatment of
Ankylosing Spondylitis

• FDA Arthritis Advisory Committee
• June 24, 2003

2
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
• Amgen
• Benefit/Risk Assessment Daniel Burge, M.D.
• V.P. Clinical Development
• Amgen

3
Consultants

• Désirée van der Heijde, M.D., Ph.D.Professor of
  RheumatologyUniversity Hospital
  MaastrichtMaastricht, The Netherlands
• Daniel O. Clegg, M.D.Professor of
  MedicineDivision of RheumatologyUniversity of
  UtahSalt Lake City, UT

4
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

5
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
6
Family of Spondyloarthropathies
7
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

8
Ankylosing Spondylitis

• 350,000 patients in US
• Onset typically before age 45
• Males more commonly affected
• Inflammatory back pain

Khan 2003Carter 1979
9
Progression of Ankylosing Spondylitis
10
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 1992. 3Clegg 1996. 2Dougados
1995. 4Altan 2001.
11
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, 1994. Gratacos,
1994.2Canete et al, 1997. Grom et al,
1996.3Braun et al, 1995.
12
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

13
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
• Amgen
• Benefit/Risk Assessment Daniel Burge, M.D.
• V.P. Clinical Development
• Amgen

14
Formation of the ASessments in Ankylosing
Spondylitis (ASAS) Working Group

• Started in 1995
• At inception, gt120 instruments published in the
  literature
• Organization of international experts in the
  field of AS
• Several meetings yearly

15
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

16
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 signs and symptoms
• Effects on physical function/disability
• Effects on structural damage
• Clinical record keeping

17
ASAS/OMERACT Core Domains for Ankylosing
Spondylitis
DCART
Clinical Record Keeping
SMARD/Physical Therapy
physical function
spinal stiffness
patient global assessment
acutephase reactants
spinal mobility
fatigue
pain
peripheral joints/entheses
hip radiograph
spine radiograph
van der Heijde et al. J Rheumatol 199926951-4
ASAS workshop Gent, Oct 2002
18
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 199926951-4
ASAS workshop Gent, Oct 2002
19
Updated Core Set for DCART in AS
(Domains/instruments in addition to core set for
SMARD)
Domain Instrument Peripheral joints/entheses Numbe
r 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 199926951-4
ASAS workshop Gent, Oct 2002
20
Instruments for Assessment
Use either a NRS or VAS for all core set variables
0
1
3
4
5
6
7
8
9
2
10
No pain
Unbearable pain
No pain
Unbearable pain
21
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
22
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

23
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

24
Development of Response Criteria

• 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

25
Development of Response Criteria

• 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

26
ASAS 20Preliminary 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 2001441876-886
27
Performance of ASAS 20 Response Criteria

• NSAIDs 49 responders
• Placebo 24 responders

NB in a flare design!
28
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

29
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

30
ASAS - Partial Remission Criteria AS
A value below 20 units in each of the 4 domains
Patient global Pain Function Stiffness
31
ASAS 20 Improvement Criteria

• Based on NSAIDs trials signs and symptoms
• Same criteria to assess DCART such as
  TNF-blocking agents?

32
Development of Response Criteriafor DCART

• Addition of 2 extra DCART domains
• Comparison with existing ASAS criteria and BASDAI
  - improvement
• With many different cut-off values in many
  combinations

33
Development of Response Criteriafor 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

34
Response Criteria for DCART

• Development in 1 trial
• Validation in other trials
• Opinion based final selection

35
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
36
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
• Amgen
• Benefit/Risk Assessment Daniel Burge, M.D.
• V.P. Clinical Development
• Amgen

37
Clinical Development Program Objectives

• Establish efficacy and safety profile of
  etanercept in treatment of AS
• Confirm role of TNF in the pathophysiologyof AS

38
Clinical Development Program in AS

• 401 subjects evaluated in 3 randomized, double
  blind, placebo-controlled trials

Proof-of-Principle Study
Study 016.0626 Single Center (U.S.) 40 subjects
for 16 weeks
Pivotal Program
Study 016.0037 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
39
Proof-of-PrincipleStudy 016.0626
The New England Journal of Medicine
TREATMENT OF ANKYLOSING SPONDYLITIS BY INHIBITION
OF TUMOR NECROSIS FACTOR ?
GORMAN, SACK, DAVIS. 20023461349-56
40
Study Design
Study 016.0626

• 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

41
Primary Efficacy Assessment
Study 016.0626

• 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
42
Proof of Principle Established Primary Endpoint
Achieving Response
Study 016.0626
Placebo (N 20)
Etanercept (N 20)
P 0.0038
75
80
70
70
55
55
60
Subjects
50
35
40
25
25
30
20
10
10
0
4
8
12
16
Week
43
Pivotal Program

• Amgen Study 016.0037
• Wyeth Study 47687

44
Study Design
Pivotal Program

• Two randomized, double-blind, placebo-controlled,
  multi-center (placebo vs etanercept 25 mg BIW)
• 277 subjects for 24 weeks (Study 016.0037)
• 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

45
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

46
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 Schobers
• Chest expansion
• Occiput-to-wall
• Markers of systemic inflammation
• CRP, ESR
• Peripheral joint counts

47
Baseline Demographics
Pivotal Program
Study 47687
Study 016.0037
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 93 Other 9 6 5 7 HLA-B27 positive,
84 84 87 88
48
Baseline Therapy
Pivotal Program
Study 47687
Study 016.0037
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
49
Baseline Disease Activity
Pivotal Program
Study 47687
Study 016.0037
Placebo Etanercept Placebo EtanerceptASAS 20
components, mean N 139 N 138 N 39 N
45 Stiffness, duration and intensity 64.3 61.4 6
2.9 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 5
6.3 51.7 57.2 60.2
All measures on 0-100 scale Bath Ankylosing
Spondylitis Functional Index
50
Disposition
Pivotal Program
Study 47687
Study 016.0037
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 0 4 0 0 Lack of efficacy 2 1 0 0 Other 3
1 0 2 24 weeks Completed, n () 120 (86) 126
(91) Discontinued due to, n Adverse
event 1 7 Lack of efficacy 13 3 Other 5 2

51
Primary Endpoint Achieved in Both Studies ASAS 20
at 12 Weeks
Pivotal Program
Study 016.0037
Study 47687
100
100
P lt 0.0001
P 0.0008
80
80
60
60
60
60
Subjects
40
40
27
23
20
20
0
0
Placebo(N 139)
Etanercept(N 138)
Placebo(N 39)
Etanercept(N 45)
52
Rapid and Durable EffectASAS 20 Over Time
Study 016.0037
100
Placebo (N 139)
90
Etanercept (N 138)
80
70
60
59
58
60
50
46
50
Subjects
40
27
27
24
30
23
22
20
10
0
0
4
8
12
16
20
24
2
Weeks
P lt 0.0001
53
ASAS 20, 50, and 70 at Week 12
Pivotal Program
Study 016.0037
Study 47687
100
100
80
80
P 0.0008
P lt 0.0001
60
60
P 0.0002
P lt 0.0001
Subjects
60
60
49
45
P lt 0.0001
40
40
P 0.0973
27
29
23
24
13
20
20
10
10
7
0
0
ASAS 20
ASAS 50
ASAS 70
ASAS 20
ASAS 50
ASAS 70
54
Partial Remission at 12 Weeks
Pivotal Program
Study 016.0037
Study 47687
50
50
P 0.0020
P 0.3457
40
40
30
30
Subjects
21
18
20
20
10
8
10
10
0
0
Placebo(N 139)
Etanercept(N 138)
Placebo(N 39)
Etanercept(N 45)
55
Consistent DCART Response inBoth Studies at 12
Weeks
Pivotal Program
Study 016.0037
Study 47687
P lt 0.0001
P lt 0.0001
58
Subjects
44
43
37
15
15
13
8
DCART 20
DCART 40
DCART 20
DCART 40
56
Consistent Response Across All ASAS 20
Components Improvement at 12 Weeks
Pivotal Program
Study 016.0037
Study 47687
100
100
P lt 0.0001
P ? 0.02
80
80
64
54
60
60
55
56
Median Improvement
51
48
40
40
33
32
20
20
9
10
8
5
4
3
0
1
0
0
PatientGlobal
Pain
BASFI
PatientGlobal
Pain
BASFI
Stiffness
Stiffness
57
Study 016.0037Significant Improvement in Spinal
Mobility
Median Percent Improvement from Baseline
Placebo Etanercept P-valueParameter N
139 N 138 Schobers Test 12 weeks 0
8.6 0.0359 24 weeks 0 9.7 0.0014 Chest
Expansion 12 weeks 0 4.8 0.0026 24 weeks 0
16.7 lt0.0001 Occiput-to-Wall Measurements 12
weeks 0 15.7 0.0034 24 weeks 0 25.0 lt0.0001
58
Study 016.0037Peripheral Tender and Swollen
Joint Counts
Placebo Etanercept P-valueParameter N 139 N
138
Median Tender Joint Count Baseline 4.0 3.0 12
weeks 2.0 1.0 0.0061 24 weeks 2.0 1.0 0.0014 Medi
an Swollen Joint Count Baseline 0 1.0 12
weeks 0 0 0.1263 24 weeks 0 0 0.8384
Based on improvement
59
Markers of Systemic Inflammation ReducedAcute
Phase Reactants at Week 12
Pivotal Program
Study 016.0037
Study 47687
100
P lt 0.0001
P lt 0.0001
80
80
69
70
60
60
Median Improvement
40
20
0
0
0
0
-5.4
-20
ESR
CRP
ESR
CRP
60
Study 016.0037Favorable Etanercept Responsesin
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 (lt 5 years vs 510 years vs gt 10
  years)
• HLA-B27

• History of uveitis/iritis
• History of psoriasis
• History of Crohns 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

61
ASAS 20 in HLA-B27 Positive and Negative Subjects
Study 016.0037
Week 12
Week 24
80
80
65
HLA-B27Positive
62
60
60
Subjects
40
40
27
23
20
20
0
0
(N 109)
(N 108)
(N 109)
(N 108)
80
80
HLA-B27Negative
60
60
Subjects
40
40
20
20
0
0
(N 20)
(N 21)
(N 20)
(N 21)
62
Study 016.0037ASAS 20 by Gender Over Time
Week 12
Week 24
80
80
65
Men
63
60
60
Subjects
40
40
27
25
20
20
0
0
(N 105)
(N 105)
(N 105)
(N 105)
80
80
60
60
Women
45
42
Subjects
40
40
29
18
20
20
0
0
(N 34)
(N 33)
(N 34)
(N 33)
63
Study 016.0037ASAS 20 by Age Over Time
Week 12
Week 24
80
80
70
64
?42 years
60
60
Subjects
40
40
29
27
20
20
0
0
(N 66)
(N 74)
(N 66)
(N 74)
80
80
60
60
52
?42 years
48
Subjects
40
40
26
19
20
20
0
0
(N 73)
(N 64)
(N 73)
(N 64)
64
Study 016.0037ASAS 20 Response by Psoriasis
History
Week 12
Week 24
80
80
61
Withoutpsoriasis
60
60
60
Subjects
40
40
27
23
20
20
0
0
(N 124)
(N 127)
(N 124)
(N 127)
80
80
60
60
Withpsoriasis
45
Subjects
36
40
40
33
20
20
15
0
0
(N 15)
(N 11)
(N 15)
(N 11)
65
Subgroup Summary

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

66
Etanercept in AS Robust Efficacy Demonstrated
Study 016.0037
Results at Week 12
Placebo () Etanercept ()
P-valueParameter N 139 N 138 ASAS
20 27 60 lt0.0001 ASAS 50 13 45 lt0.0001 ASAS
70 7 29 lt0.0001 DCART 20 8 37 lt0.0001 DCART
40 15 43 lt0.0001 Partial Remission 8 21 0.0020
67
Consistent Efficacy in All DomainsMedian
Percent Improvement
Study 016.0037
Placebo Etanercept P-value
Physical function BASFI (0-100 scale) 3
32 lt0.0001 Pain 100-mm VAS (past week) 9
53 lt0.0001 Spinal mobility Schober test 0
9 0.0359 Chest expansion 0 5 0.0026 Occiput-to-
wall distance 0 16 0.0034 Patient Global
Assessment VAS 9 51 lt0.0001 Inflammation Nigh
t pain VAS (past 48 hours) 6 58 lt0.0001 BASDAI
morning stiffness duration VAS 3
50 lt0.0001 BASDAI morning stiffness intensity
VAS 13 58 lt0.0001 C-reactive protein -5
69 lt0.0001
van der Heijde 1999
68
Safety
Pivotal Program

• All adverse events
• Serious adverse events
• Withdrawals due to adverse events
• Laboratory abnormalities
• Antibodies

69
Adverse Events (gt10 in any treatment group)
Pivotal Program
Study 016.0037
Study 47687
Placebo Etanercept Placebo Etanerceptn () 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 lt 0.05
70
Serious Adverse Events
Study 016.0037
Placebo Accident / injury (2) Viral
infection Suicide attempt Chest pain
Etanercept Bone fracture (3) Soft tissue
infection (2) Fever/Rash Lymphadenopathy Intest
inal obstruction Ulcerative colitis
71
Withdrawals Due to Adverse Events
Study 016.0037
Placebo Suicide attempt
Etanercept Bone fracture (2) Fever Intestinal
obstruction Ulcerative colitis Hemorrhoidal
bleeding Ileitis
72
Grade 3 Laboratory Results in Etanercept Subjects
Pivotal Program

• Study 016.0037
• 1 transient ANC (500-1000)
• 1 transient lymphocyte (lt500)
• Study 47687
• 1 transient elevated AST, ALT, and bilirubin
• All were at a single time point
• All patients continued on etanercept

73
Anti-etanercept Antibodies
Pivotal Program

• 3 patients with non-neutralizing antibodies
• No effect on safety and efficacy

74
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

75
Presentations

• Introduction Daniel Burge, M.D.
• 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
• Amgen Corporation
• Benefit/Risk Assessment Daniel Burge, M.D.
• V.P. Clinical Development
• Amgen Corporation

76
Benefit/Risk Overview

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

77
Study 016.0037Etanercept 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

78
Inflammatory Bowel Disease
AS Pivotal Program
Number of Subjects
Study 016.0037
Study 47687
Placebo Etanercept Placebo Etanercept N
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
79
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

80
Immunex StudyEtanercept Study in Crohns Disease
Placebo Etanercept N 14 35 Response
Rate 50 66 Withdrawals due to 14 6
exacerbations
Response defined as decrease of ?75 units in
CDAIDose range up to 32 mg/m2 twice weekly
81
Sandborn StudyEtanercept Study in Crohns Disease
Crohns Disease Activity Index Over Time
350
300
250
Mean CDAI Score
200
150
100
50
0
2
4
8
0
Weeks of treatment
Gastroenterology 2001
82
Inflammatory Bowel Disease Experience Conclusion

• Data from overall etanercept trial experience (N
  80), including 2 randomized, placebo-controlled
  trials in Crohns disease, do not support an
  association between etanercept therapy and IBD
  exacerbation.

83
Etanercept Experience in Rheumatic Diseases

• Patients Patient-Years
• Commercial gt182,000 gt341,000
• Clinical Trials 3389 8336 in 5th year of
  therapy 1084 in 6th year of therapy 390

Through April 2003 Through December 2002
84
Adverse Events Rates in AS Comparable to Other
Rheumatic Diseases
Controlled Studies
Rheumatoid Arthritis PsA AS Mono- Proto
colEvent 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 1.2
0 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
Advanced Disease
Events per patient-year Infection associated
with hospitalization or IV antibiotics
85
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

86
Consistent Efficacy with Etanercept in Rheumatic
Diseases
AS ASAS 20
RA ACR 20
PsA ACR 20
JRA DOI
745
751
713
694
622
607
596
608
Responders
1Moreland et al 19972Moreland et al
19993Weinblatt et al 19994Bathon et al 2000
6Mease et al 2001
7Study 016.00378Study 47687
5Lovell et al 2000
87
Etanercept in AS Robust Efficacy Demonstrated
Study 016.0037
Results at Week 12
Parameter
P-value ASAS 20 lt0.0001 ASAS 50 lt0.0001 ASAS
70 lt0.0001 DCART 20 lt0.0001 DCART
40 lt0.0001 Partial Remission 0.0020
88
Etanercept in AS Consistent Efficacy in All
Domains
Study 016.0037
P-value
Physical function BASFI (0-100
scale) lt0.0001 Pain 100-mm VAS (past
week) lt0.0001 Spinal mobility Schober
test 0.0359 Chest expansion 0.0026 Occiput-to-wa
ll distance 0.0034 Patient Global
Assessment VAS lt0.0001 Inflammation Night pain
VAS (past 48 hours) lt0.0001 BASDAI morning
stiffness duration VAS lt0.0001 BASDAI morning
stiffness intensity VAS lt0.0001 C-reactive
protein lt0.0001
van der Heijde 1999
89
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

90
Etanercept (Enbrel) for the Treatment of
Ankylosing Spondylitis

• FDA Arthritis Advisory Committee
• June 24, 2003