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Etanercept (Enbrel ® ) for the Treatment of Ankylosing Spondylitis. FDA Arthritis Advisory Committee June 24, 2003. Introduction Daniel Burge, M.D. V.P. Clinical Development Amgen Assessments in D é sir é e van der Heijde, M.D., Ph.D. Ankylosing Spondylitis Professor of Rheumatology

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etanercept enbrel for the treatment of ankylosing spondylitis

Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis

FDA Arthritis Advisory Committee

June 24, 2003

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

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

1998 FDA approval for RA (alone or with MTX)

1999 FDA approval for JRA

2000 FDA approval as initial therapy for RA FDA approval for inhibition of radiographic progression

2002 FDA approval for psoriatic arthritis (alone or with MTX)

2002 Application for approval for inhibition of radiographic progression in PsA

2003 Application for approval for AS

family of spondyloarthropathies

ReactiveArthritis

JuvenileSpondylo-arthropathy

PsoriaticArthritis

AS

UndifferentiatedSpondylo-arthropathy

IBD AssociatedArthritis

Family of Spondyloarthropathies
features of spondyloarthropathies
Features of Spondyloarthropathies
  • Sacroiliitis +/- spondylitis
  • Enthesitis
  • Variable involvement with peripheral arthritis
  • Associated with uveitis
  • No association with rheumatoid factor
  • Strong association with the genetic marker, HLA-B27
ankylosing spondylitis
Ankylosing Spondylitis
  • ~350,000 patients in US
  • Onset typically before age 45
  • Males more commonly affected
  • Inflammatory back pain

Khan 2003Carter 1979

traditional therapies are inadequate
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.

pathophysiology of as role of tnf
Pathophysiology of AS: Role of TNF
  • TNF is implicated in pathogenesis of AS
    • TNF levels are elevated in serum1
    • TNF levels are elevated in synovial tissue2

Sacroiliac biopsy; TNF mRNA3

1Toussirot and Wendling, 1994. Gratacos, 1994.2Canete et al, 1997. Grom et al, 1996.3Braun et al, 1995.

challenges in as clinical trials
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
presentations13
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

Presentations
formation of the asessments in ankylosing spondylitis asas working group
Formation of the ASessments in Ankylosing Spondylitis (ASAS) Working Group
  • Started in 1995
  • At inception, >120 instruments published in the literature
  • Organization of international experts in the field of AS
  • Several meetings yearly
mission statement of asas
Mission Statement of ASAS
  • The mission of ASAS is to support and promote the study of ankylosing spondylitis. This includes:
    • Increasing awareness and early diagnosis of the disease
    • Development and validation of assessment tools
    • The evaluation of treatment modalities in order to promote clinical research with the ultimate goal to improve outcome of the disease
disease activity
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
asas omeract core domains for ankylosing spondylitis
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

hip

radiograph

peripheral joints/entheses

spine radiograph

van der Heijde et al. J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002

updated core set for smard in as
Updated 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

van der Heijde et al. J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002

updated core set for dcart in as domains instruments in addition to core set for smard
Updated Core Set for DCART in AS (Domains/instruments in addition to core set for SMARD)

Domain Instrument

Peripheral joints/entheses Number of swollen joints (44 joint count)/validated enthesitis score

Acute phase reactants ESR

X-ray spine/hips Anterior-posterior and lateral lumbar and lateral cervical spine and pelvis (SI and Hips)

van der Heijde et al. J Rheumatol 1999;26:951-4; ASAS workshop Gent, Oct 2002

instruments for assessment
Instruments for Assessment

Use either a NRS or VAS for all core set variables

0

1

2

3

4

5

6

7

8

9

10

No pain

Unbearable pain

No pain

Unbearable pain

basdai
BASDAI
  • Fatigue
  • Pain in neck, back, hips
  • Pain and swelling other joints
  • Sites painful by pressure
  • Severity of morning stiffness
  • Duration of morning stiffness

Average 1- 5/6; range 0-10

average

domains and instruments for response criteria
Domains and Instruments for Response Criteria
  • Patient global - VAS
  • Pain - VAS
  • Function – BASFI
  • Stiffness – average of morning stiffness duration and intensity (BASDAI q 5 and 6) OR duration of morning stiffness (120 minutes = maximum)
  • Spinal mobility – chest expansion, modified Schober, fingers to floor
development of response criteria
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
development of response criteria24
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
development of response criteria25
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
asas 20 preliminary response criteria as
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 2001:44:1876-886

performance of asas 20 response criteria
Performance of ASAS 20 Response Criteria
  • NSAIDs 49% responders
  • Placebo 24% responders

NB in a flare design!

performance of asas 20 response criteria28
Performance of ASAS 20 Response Criteria
  • Criteria are strict and highly specific
  • Sensitivity 62%, specificity 89%
  • Agreement with experts opinion and end of trial judgment by patient and physician: 70%
  • Responders defined by ASAS 20 are true responders acknowledged both by patient and physician
caveats in comparing trials assessing nsaids and anti tnf therapy
NSAID trials

Flare design

Proven efficacy of NSAIDs

Inclusion of patients with mild and severe disease

Anti-TNF trials

No flare design

Proven inefficacy of NSAIDS

Inclusion of patients with severe disease

Caveats in Comparing Trials Assessing NSAIDs and Anti-TNF Therapy
asas partial remission criteria as
ASAS - Partial Remission Criteria AS

A value below 20 units in each of the 4 domains

Patient global

Pain

Function

Stiffness

asas 20 improvement criteria
ASAS 20 Improvement Criteria
  • Based on NSAIDs trials – signs and symptoms
  • Same criteria to assess DCART such as TNF-blocking agents?
development of response criteria for dcart
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
development of response criteria for dcart33
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
response criteria for dcart
Response Criteria for DCART
  • Development in 1 trial
  • Validation in other trials
  • Opinion based final selection
preliminary response criteria for dcart
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

presentations36
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

Presentations
clinical development program objectives
Clinical Development Program Objectives
  • Establish efficacy and safety profile of etanercept in treatment of AS
  • Confirm role of TNF in the pathophysiologyof AS
clinical development program in as
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

proof of principle study 016 0626

Proof-of-PrincipleStudy 016.0626

The New England Journal of Medicine

TREATMENT OF ANKYLOSING SPONDYLITIS BY INHIBITION

OF TUMOR NECROSIS FACTOR 

GORMAN, SACK, DAVIS. 2002;346:1349-56

study design
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
primary efficacy assessment
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

proof of principle established primary endpoint achieving response

Study 016.0626

Proof of Principle Established Primary Endpoint: % Achieving Response

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

pivotal program

Pivotal Program

Amgen Study 016.0037

Wyeth Study 47687

study design44
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
primary efficacy endpoints
Primary Efficacy Endpoints

Pivotal Program

  • ASAS 20 at week 12
    • Improvement of 20% and absolute improvement of 10 units in at least 3 of following domains:
      • Patient global assessment
      • Pain = average of total spinal pain and nocturnal spinal pain
      • Function = BASFI
      • Stiffness = average of last two questions in BASDAI regarding morning stiffness
    • Absence of deterioration in the potential remaining domain
  • ASAS 20 at week 24
other efficacy endpoints
ASAS 50, ASAS 70

Partial remission

DCART

Elements of the ASAS Response Criteria

Pain

Stiffness

Function

Global assessment

Spinal mobility

Modified Schober’s

Chest expansion

Occiput-to-wall

Markers of systemic inflammation

CRP, ESR

Peripheral joint counts

Other Efficacy Endpoints

Pivotal Program

baseline demographics
Baseline Demographics

Pivotal Program

Study 016.0037

Study 47687

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

baseline therapy
Baseline Therapy

Pivotal Program

Study 016.0037

Study 47687

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

baseline disease activity
Baseline Disease Activity

Pivotal Program

Study 016.0037

Study 47687

Placebo Etanercept Placebo EtanerceptASAS 20 components*, mean N = 139 N = 138 N = 39 N = 45

Stiffness, duration and 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

disposition
Disposition

Pivotal Program

Study 016.0037

Study 47687

Placebo EtanerceptPlaceboEtanerceptN = 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

primary endpoint achieved in both studies asas 20 at 12 weeks

Pivotal Program

Primary Endpoint Achieved in Both StudiesASAS 20 at 12 Weeks

Study 016.0037

Study 47687

100

100

P < 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)

rapid and durable effect asas 20 over time

Study 016.0037

Rapid and Durable EffectASAS 20 Over Time

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

2

4

8

12

16

20

24

Weeks

*P < 0.0001

asas 20 50 and 70 at week 12

Placebo (N = 139)

Placebo (N = 39)

Etanercept (N = 138)

Etanercept (N = 45)

ASAS 20, 50, and 70 at Week 12

Pivotal Program

Study 016.0037

Study 47687

100

100

80

80

P = 0.0008

P < 0.0001

60

60

P = 0.0002

P < 0.0001

% Subjects

60

60

49

45

P < 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

partial remission at 12 weeks
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)

consistent dcart response in both studies at 12 weeks

100

100

80

80

60

60

40

40

20

20

0

0

Placebo (N = 139)

Placebo (N = 39)

Etanercept (N = 138)

Etanercept (N = 45)

Pivotal Program

Consistent DCART Response inBoth Studies at 12 Weeks

Study 016.0037

Study 47687

*P < 0.0001

*P < 0.0001

58*

% Subjects

44*

43*

37*

15

15

13

8

DCART 20

DCART 40

DCART 20

DCART 40

consistent response across all asas 20 components improvement at 12 weeks

Placebo (N = 139)

Placebo (N = 39)

Etanercept (N = 138)

Etanercept (N = 45)

Pivotal Program

Consistent Response Across All ASAS 20 Components% Improvement at 12 Weeks

Study 016.0037

Study 47687

100

100

*P < 0.0001

†P  0.02

80

80

64†

54*

60

60

55*

56†

Median % Improvement

51*

48†

40

40

32*

33†

20

20

9

10

8

5

4

3

0

1

0

0

PatientGlobal

Pain

BASFI

Stiffness

PatientGlobal

Pain

BASFI

Stiffness

study 016 0037 significant improvement in spinal mobility
Study 016.0037Significant Improvement in Spinal Mobility

Median

Percent Improvement from Baseline

Placebo Etanercept P-valueParameter N = 139 N = 138

Schober’s 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 <0.0001

Occiput-to-Wall Measurements 12 weeks 0 15.7 0.0034 24 weeks 0 25.0 <0.0001

study 016 0037 peripheral tender and swollen joint counts
Study 016.0037Peripheral Tender and Swollen Joint Counts

Placebo Etanercept P-value*Parameter 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

Median Swollen Joint Count Baseline 0 1.0 12 weeks 0 0 0.1263 24 weeks 0 0 0.8384

*Based on % improvement

markers of systemic inflammation reduced acute phase reactants at week 12

100

80

60

40

20

0

-20

Placebo (N = 139)

Placebo (N = 39)

Etanercept (N = 138)

Etanercept (N = 45)

Pivotal Program

Markers of Systemic Inflammation ReducedAcute Phase Reactants at Week 12

Study 016.0037

Study 47687

100

P < 0.0001

P < 0.0001

80

80

70

69

60

60

Median % Improvement

40

20

0

0

0

0

-5.4

-20

ESR

CRP

ESR

CRP

study 016 0037 favorable etanercept responses in all subgroups
Age

Gender

Weight

Race (Caucasian vs non-Caucasian)

Site (North American vs European)

Patient Global Assessment

Average Back Pain

Average of last 2 BASDAI questions(stiffness)

BASDAI

BASFI

Disease Duration (< 5 years vs 5–10 years vs > 10 years)

HLA-B27

History of uveitis/iritis

History of psoriasis

History of Crohn’s disease or UC

History of bacterial dysentery, urethritis, chlamydia, or other STD

History of urethritis and conjunctivitis

Presence of hip disease

Presence of hip disease or limited range of hip motion

NSAIDs within 6 mo. of screening

Steroids within 6 mo. of screening

Concomitant sulfasalazine

Concomitant methotrexate

Injection site reaction during study

Study 016.0037Favorable Etanercept Responsesin All Subgroups
asas 20 in hla b27 positive and negative subjects

Placebo

Etanercept

38

35

48

20

Study 016.0037

ASAS 20 in HLA-B27 Positive and Negative Subjects

Week 24

Week 12

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)

study 016 0037 asas 20 by gender over time

Placebo

Etanercept

Study 016.0037ASAS 20 by Gender Over Time

Week 24

Week 12

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)

study 016 0037 asas 20 by age over time

Placebo

Etanercept

Study 016.0037ASAS 20 by Age Over Time

Week 24

Week 12

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)

study 016 0037 asas 20 response by psoriasis history

Placebo

Etanercept

Study 016.0037ASAS 20 Response by Psoriasis History

Week 24

Week 12

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)

subgroup summary
Subgroup Summary
  • Broad group of subjects enrolled and benefited from etanercept
    • Multiple analyses performed
    • Many subgroups have small sample size
  • All subgroups demonstrate response
etanercept in as robust efficacy demonstrated

Study 016.0037

Etanercept in AS: Robust Efficacy Demonstrated

Results at Week 12

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

consistent efficacy in all domains median percent improvement

Study 016.0037

Consistent Efficacy in All Domains*Median Percent Improvement

Placebo Etanercept P-value

Physical function BASFI (0-100 scale) 3 32 <0.0001

Pain 100-mm VAS (past week) 9 53 <0.0001

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 <0.0001

Inflammation Night pain VAS (past 48 hours) 6 58 <0.0001 BASDAI morning stiffness duration VAS 3 50 <0.0001 BASDAI morning stiffness intensity VAS 13 58 <0.0001 C-reactive protein -5 69 <0.0001

*van der Heijde 1999

safety
Safety

Pivotal Program

  • All adverse events
  • Serious adverse events
  • Withdrawals due to adverse events
  • Laboratory abnormalities
  • Antibodies
adverse events 10 in any treatment group
Adverse Events (>10% 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 < 0.05

serious adverse events
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

Intestinal obstruction

Ulcerative colitis

withdrawals due to adverse events
Withdrawals Due to Adverse Events

Study 016.0037

Placebo

Suicide attempt

Etanercept

Bone fracture (2)

Fever

Intestinal obstruction

Ulcerative colitis

Hemorrhoidal bleeding

Ileitis

grade 3 laboratory results in etanercept subjects

Pivotal Program

Grade 3 Laboratory Results in Etanercept Subjects
  • Study 016.0037
    • 1 transient ANC (500-1000)
    • 1 transient lymphocyte (<500)
  • Study 47687
    • 1 transient elevated AST, ALT, and bilirubin
  • All were at a single time point
  • All patients continued on etanercept
anti etanercept antibodies
Anti-etanercept Antibodies

Pivotal Program

  • 3 patients with non-neutralizing antibodies
  • No effect on safety and efficacy
etanercept provides clinically important benefit in as
Etanercept 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
presentations75
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

Presentations
benefit risk overview
Benefit/Risk Overview
  • Additional considerations regarding inflammatory bowel disease
  • Broader rheumatic disease experience
  • Overall benefit/risk assessment for ankylosing spondylitis
study 016 0037 etanercept withdrawals due to gastrointestinal adverse events
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

inflammatory bowel disease
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

ibd experience from etanercept studies in rheumatic diseases
IBD Experience from Etanercept Studies in Rheumatic Diseases
  • 14 subjects with pre-existing IBD
    • 7 were treated in short term studies and all completed without exacerbation of disease
    • 7 were treated with etanercept for up to 5 years
    • None developed adverse events related to inflammatory bowel disease
  • No flares of inflammatory bowel disease
immunex study etanercept study in crohn s disease
Immunex StudyEtanercept Study in Crohn’s Disease

Placebo Etanercept†

N 14 35

Response Rate* 50% 66%

Withdrawals due to 14% 6% exacerbations

*Response defined as decrease of 75 units in CDAI†Dose range up to 32 mg/m2 twice weekly

sandborn study etanercept study in crohn s disease

Etanercept (N = 23)

Placebo (N = 20)

Sandborn StudyEtanercept Study in Crohn’s Disease

Crohn’s Disease Activity Index Over Time

350

300

250

200

Mean CDAI Score

150

100

50

0

0

2

4

8

Weeks of treatment

Gastroenterology 2001

inflammatory bowel disease experience conclusion
Inflammatory Bowel Disease Experience Conclusion

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

etanercept experience in rheumatic diseases
Etanercept: Experience in Rheumatic Diseases

Patients Patient-Years

Commercial* >182,000 >341,000

Clinical Trials† 3389 8336in 5th year of therapy 1084 in 6th year of therapy 390

*Through April 2003

†Through December 2002

adverse events rates in as comparable to other rheumatic diseases

Controlled Studies

Adverse Events Rates* in AS Comparable to Other Rheumatic Diseases

Rheumatoid Arthritis PsA ASMono-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

Advanced Disease

*Events per patient-year

†Infection associated with hospitalization or IV antibiotics

summary of safety
Summary of Safety
  • Etanercept generally safe and well-tolerated in patients with AS
  • Experience in AS comparable to the well-established safety profile from experience in other rheumatic diseases
consistent efficacy with etanercept in rheumatic diseases
Consistent Efficacy with Etanercept in Rheumatic Diseases

AS

ASAS 20

RA

ACR 20

JRA

DOI

PsA

ACR 20

745

751

713

694

622

607

596

608

% Responders

1Moreland et al 19972Moreland et al 19993Weinblatt et al 19994Bathon et al 2000

5Lovell et al 2000

6Mease et al 2001

7Study 016.00378Study 47687

etanercept in as robust efficacy demonstrated87

Study 016.0037

Etanercept in AS: Robust Efficacy Demonstrated

Results at Week 12

Parameter P-value

ASAS 20 <0.0001

ASAS 50 <0.0001

ASAS 70 <0.0001

DCART 20 <0.0001

DCART 40 <0.0001

Partial Remission 0.0020

etanercept in as consistent efficacy in all domains

Study 016.0037

Etanercept in AS: Consistent Efficacy in All Domains*

P-value

Physical function BASFI (0-100 scale) <0.0001

Pain 100-mm VAS (past week) <0.0001

Spinal mobility Schober test 0.0359 Chest expansion 0.0026 Occiput-to-wall distance 0.0034

Patient Global Assessment VAS <0.0001

Inflammation Night pain VAS (past 48 hours) <0.0001 BASDAI morning stiffness duration VAS <0.0001 BASDAI morning stiffness intensity VAS <0.0001 C-reactive protein <0.0001

*van der Heijde 1999

benefit risk of etanercept is highly favorable
Benefit/Risk of Etanercept is Highly Favorable
  • AS causes significant morbidity and disability
  • Substantial unmet medical need due to limitation of traditional therapies
  • Etanercept:
    • Dramatically improves patients’ lives
    • Favorable safety experience
etanercept enbrel for the treatment of ankylosing spondylitis90

Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis

FDA Arthritis Advisory Committee

June 24, 2003