# Presentation: 793662

## 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 ****	****D****é****sir****é****e 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**

## Consultants

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

## Etanercept Properties

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

## Etanercept History

**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

## Features of Spondyloarthropathies

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

## Ankylosing Spondylitis

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

**Khan 2003****Carter 1979**

## Progression of Ankylosing Spondylitis

## Traditional Therapies are Inadequate

**NSAIDs:  the only approved therapies for AS**
**Improves pain and stiffness**
**Limited effect on spinal mobility and acute phase reactants**
**Corticosteroids:**
**Oral: limited effect**
**Systemic: temporary benefit/toxic****1**
**Sulfasalazine: improves peripheral but not axial disease****2,3**
**Methotrexate: limited benefit in controlled trial****4**

**1****Peters 1992.****	****3****Clegg 1996. ****2****Dougados 1995.****	****4****Altan 2001.**

## Pathophysiology of AS: Role of TNF

**TNF is implicated in pathogenesis of AS**
**TNF levels are elevated ****in serum****1**
**TNF levels are elevated in synovial tissue****2**

**1****Toussirot and Wendling, 1994. Gratacos, 1994.****2****Canete et al, 1997. Grom et al, 1996.****3****Braun et al, 1995.**

**Sacroiliac biopsy; TNF mRNA****3**

## 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**

## Presentations

**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**
**	****	****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**

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

**Started in 1995**
**At inception, >120 instruments published in the literature**
**Organization of international experts in the field of AS**
**Several meetings yearly**

## Mission Statement of ASAS

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

## Disease Activity

**Core sets for assessment of:**
**Symptom Modifying Anti-Rheumatic Drugs (SMARD) and physical therapy**
***Effects on signs and symptoms***** **
**Disease Controlling Anti-Rheumatic Therapy****(DCART)**
***Effects on 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

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

***SMARD/******Physical Therapy****** ***

***Clinical Record Keeping****** ***

***DCART***

**physical function**

**spinal stiffness**

**pain**

**spinal mobility**

**patient global assessment**

**peripheral joints/****entheses**

**acute****phase ****reactants**

**spine****    radiograph**

**hip  **
**radiograph**

**fatigue**

## Updated Core Set for SMARD in AS

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

***Domain******	******Instrument***
**Function****	****BASFI *****or***** Dougados FI**
**Pain****	****VAS-last week-spine-at night-due to 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**

## 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

***0***

***1***

***3***

***4***

***5***

***6***

***7***

***8***

***9***

***2***

***10***

**No pain**

**Unbearable pain**

**No pain**

**Unbearable pain**

- Use either a NRS or VAS for all core set variables

## BASDAI

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

**average**

## Domains and Instruments for Response Criteria

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

## Development of Response Criteria

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

## 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 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

**Patient global**
**Pain**
**Function**
**Stiffness**

**Improvement of 20% AND 10 units in at least 3 domains**

**No worsening in remaining domain**

**Anderson et al Arthritis Rheum 2001:44:1876-886**

## NSAIDs	49% responders
Placebo 24% responders

**Placebo 24% responders**

**NB in a flare design!**

- Performance of ASAS 20 Response Criteria

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

**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**

- Performance of ASAS 20 Response Criteria

## Caveats in Comparing Trials Assessing NSAIDs and Anti-TNF Therapy

**NSAID trials**
**Flare design**
**Proven efficacy of NSAIDs**
**Inclusion of patients with mild and severe disease**

**Anti-TNF trials**
**No flare design**
**Proven inefficacy of NSAIDS**
**Inclusion of patients with severe disease**

## ASAS - Partial Remission Criteria AS

**Patient global**
**Pain**
**Function**
**Stiffness**

**A value below 20 units in each of the 4 domains**

## ASAS 20 Improvement Criteria

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

## Development of Response Criteriafor DCART

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

## Development of Response Criteriafor DCART

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

## Response Criteria for DCART

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

## Preliminary Response Criteria for DCART

**ASAS 40% and 20 units response**
**20% improvement in 5 out of 6 domains:**
**Patient global**
**Pain**
**Function**
**Stiffness**
**Spinal mobility**
**Acute phase reactants**

**ASAS workshop Gent, October 2002**** **

## Presentations

**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**
**	****	****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**

## Clinical Development Program Objectives

**Establish efficacy and safety profile of etanercept in treatment of AS**
**Confirm role of TNF in the pathophysiology****of AS**

## Clinical Development Program in AS

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

**Proof-of-Principle Study**

**Pivotal Program**

**Study 016.0626**
**Single Center (U.S.)**
**40 subjects for 16 weeks**

**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

**G****ORMAN****, S****ACK****, D****AVIS****. 2002;346:1349-56**

**The New England ****Journal of Medicine**

**TREATMENT OF ANKYLOSING SPONDYLITIS BY INHIBITION **
**OF TUMOR NECROSIS FACTOR ******

## Study Design

**Single center**
**Randomized, double-blind, placebo controlled**
**40 subjects for 16 weeks (placebo vs ****etanercept 25 mg BIW)**
**Active AS with stable background NSAIDs, steroids (********1****0 mg/d prednisone), and/or DMARDs**
**Excluded if:**
**Features of other spondyloarthropathy**
**Previous TNF inhibitor therapy**
**Rheumatoid factor positive**

**Study 016.0626**

## Primary Efficacy Assessment

**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**

**Study 016.0626**

## Proof of Principle Established Primary Endpoint: % Achieving Response

**Week**

**% Subjects**

**10**

**35**

**25**

**25**

**55**

**55**

**70**

**75**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**4**

**8**

**12**

**16**

**Placebo (N = 20)**

**Etanercept (N = 20)**

***P***** = 0.0038**

**Study 016.0626**

## Pivotal Program

**Amgen Study 016.0037**
**Wyeth Study 47687**

## Study Design

**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**

**Pivotal Program**

## Primary Efficacy Endpoints

**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**

**Pivotal Program**

## 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**

**Pivotal Program**

## Baseline Demographics

**	****	****Placebo****	****Etanercept****	****Placebo****	****Etanercept****Baseline 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**

**Study 47687**

**Study 016.0037**

**Pivotal Program**

## Baseline Therapy

**	****	****Placebo****	****Etanercept****	****Placebo****	****Etanercept****Baseline therapy, %: ****	****N = 139****	****N = 138****	****N = 39****	****N = 45**
**NSAIDs*****	**** 92****	**** 91****	**** 85****	****89**
**Corticosteroids*****	**** 14****	**** 13****	**** 15****	****16**
**Any DMARD****	**** 31****	**** 32****	**** 41****	****36**
**	****Sulfasalazine****	**** 22****	**** 21****	**** 28****	****24**
**	****Methotrexate****	**** 12****	**** 11****	**** 13****	****13**
**	****Hydroxychloroquine****	**** 1****	**** 2****	**** 3****	****0**

***Taken within 6 months of screening for 016.0037**

**Pivotal Program**

**Study 47687**

**Study 016.0037**

## Baseline Disease Activity

**	****	****Placebo****	****Etanercept****	****Placebo****	****Etanercept****ASAS 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**

**Pivotal Program**

**Study 47687**

**Study 016.0037**

## Disposition

**	****	****	****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****	****	**

**Study 47687**

**Study 016.0037**

**Pivotal Program**

## Primary Endpoint Achieved in Both Studies ASAS 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**

**% Subjects**

**23**

**60**

**0**

**20**

**40**

**60**

**80**

**100**

***P *****= 0.0008**

**Pivotal Program**

**Placebo****(N = 39)**

**Etanercept****(N = 45)**

## Rapid and Durable EffectASAS 20 Over Time

********P *****< 0.0001**

**23**

**27**

**27**

**24**

**22**

**58***

**60***

**59***

**50***

**46***

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**0**

**4**

**8**

**12**

**16**

**20**

**24**

**Weeks**

**% Subjects**

**Placebo (N = 139)**

**Etanercept (N = 138)**

**Study 016.0037**

**2**

## ASAS 20, 50, and 70 at Week 12

- Study 016.0037

- Study 47687

**% Subjects**

**7**

**29**

**13**

**27**

**45**

**60**

**ASAS 20**

**ASAS 50**

**ASAS 70**

**10**

**24**

**10**

**23**

**49**

**60**

**ASAS 20**

**ASAS 50**

**ASAS 70**

**0**

**20**

**40**

**60**

**80**

**100**

**0**

**20**

**40**

**60**

**80**

**100**

***P *****= 0.0973**

***P *****= 0.0002**

***P *****= 0.0008**

***P *****< 0.0001**

***P *****< 0.0001**

***P *****< 0.0001**

**Pivotal Program**

## Partial Remission at 12 Weeks

**% Subjects**

***P *****= 0.0020**

- Study 016.0037

- Study 47687

**Pivotal Program**

***P *****= 0.3457**

**0**

**20**

**40**

**50**

**8**

**21**

**30**

**10**

**0**

**20**

**40**

**50**

**10**

**18**

**30**

**10**

**Placebo****(N = 139)**

**Etanercept****(N = 138)**

**Placebo****(N = 39)**

**Etanercept****(N = 45)**

## Consistent DCART Response inBoth Studies at 12 Weeks

**% Subjects**

****P *****< 0.0001**

**15**

**8**

**43***

**37***

**DCART 20**

**DCART 40**

**15**

**13**

**58***

**44***

**DCART 20**

**DCART 40**

- Study 016.0037

- Study 47687

**Pivotal Program**

****P *****< 0.0001**

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

**Median % Improvement**

**0**

**8**

**33****†**

**64****†**

**1**

**4**

**56****†**

**48****†**

**Patient****Global**

**Pain**

**BASFI**

**0**

**20**

**40**

**60**

**80**

**100**

**3**

**10**

**32***

**55***

**5**

**9**

**54***

**51***

**0**

**20**

**40**

**60**

**80**

**100**

**Patient****Global**

**Pain**

**BASFI**

****P *****< 0.0001**

**Stiffness**

- Study 016.0037

- Study 47687

***†******P ********* 0.02**

**Stiffness**

**Pivotal Program**

## Study 016.0037Significant Improvement in Spinal Mobility

**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**Significant Improvement in Spinal Mobility

**Median**
**Percent Improvement from Baseline **

## Study 016.0037Peripheral Tender and Swollen Joint Counts

**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**

**	****Placebo****	****Etanercept****	**** P-value*****Parameter****	****N = 139****	****N = 138**

## Markers of Systemic Inflammation ReducedAcute Phase Reactants at Week 12

- Study 016.0037

- Study 47687

**-20**

**0**

**20**

**40**

**60**

**80**

**100**

**-5.4**

**0**

**69**

**60**

**0**

**0**

**70**

**80**

**ESR**

**CRP**

**ESR**

**CRP**

**Median % Improvement**

***P***** < 0.0001**

***P***** < 0.0001**

**Pivotal Program**

## Study 016.0037Favorable Etanercept Responsesin All Subgroups

**Age**
**Gender**
**Weight**
**Race (Caucasian vs non-Caucasian)**
**Site (North American vs European) **
**Patient Global Assessment **
**Average Back Pain**
**Average of last 2 BASDAI questions****(stiffness)**
**BASDAI **
**BASFI**
**Disease Duration (< 5 years vs 5–10 years vs > 10 years)**
**HLA-B27**

**History of uveitis/iritis**
**History of psoriasis**
**History of Crohn’s disease or UC**
**History of bacterial dysentery, urethritis, chlamydia, or other STD **
**History of urethritis and conjunctivitis**
**Presence of hip disease**
**Presence of hip disease or limited range of hip motion**
**NSAIDs within 6 mo. of screening**
**Steroids within 6 mo. of screening**
**Concomitant sulfasalazine**
**Concomitant methotrexate**
**Injection site reaction during study**

## ASAS 20 in HLA-B27 Positive and Negative Subjects

**Study 016.0037**

- HLA-B27Negative

- HLA-B27Positive

**27**

**65**

** ****(N = 109)**

**(N = 108)**

**Week 12**

**Week 24**

**0**

**20**

**40**

**60**

**80**

**23**

**62**

**% Subjects**

**(N = 20)**

**(N = 21)**

**0**

**20**

**40**

**60**

**80**

**% Subjects**

** ****(N = 109)**

**(N = 108)**

**(N = 20)**

**(N = 21)**

**0**

**20**

**40**

**60**

**80**

**0**

**20**

**40**

**60**

**80**

## Study 016.0037ASAS 20 by Gender Over Time

**0**

**20**

**40**

**60**

**80**

**18**

**42**

- Women

**27**

**65**

** ****(N = 105)**

**(N = 105)**

**Week 12**

**Week 24**

**20**

**40**

**60**

**80**

**25**

**63**

**% Subjects**

**29**

**45**

**0**

**20**

**40**

**60**

**80**

**(N = 34)**

**(N = 33)**

**20**

**40**

**60**

**80**

**% Subjects**

** ****(N = 105)**

**(N = 105)**

**(N = 34)**

**(N = 33)**

**0**

**0**

- Men

## Study 016.0037ASAS 20 by Age Over Time

**19**

**52**

- 42 years

**29**

**70**

** ****(N = 66)**

**(N = 74)**

**Week 12**

**Week 24**

**20**

**40**

**60**

**80**

**27**

**64**

**% Subjects**

**26**

**48**

**(N = 73)**

**(N = 64)**

**20**

**40**

**60**

**80**

**% Subjects**

** ****(N = 66)**

**(N = 74)**

**(N = 73)**

**(N = 64)**

**0**

**20**

**40**

**60**

**80**

**0**

**20**

**40**

**60**

**80**

**0**

**0**

- 42 years

## Study 016.0037ASAS 20 Response by Psoriasis History

**15**

**36**

- Withpsoriasis

**27**

**61**

** ****(N = 124)**

**(N = 127)**

**Week 12**

**Week 24**

**20**

**40**

**60**

**80**

**23**

**60**

**% Subjects**

**33**

**45**

**(N = 15)**

**(N = 11)**

**20**

**40**

**60**

**80**

**% Subjects**

** ****(N = 124)**

**(N = 127)**

**(N = 15)**

**(N = 11)**

**0**

**20**

**40**

**60**

**80**

**0**

**20**

**40**

**60**

**80**

**0**

**0**

- Withoutpsoriasis

## 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

**	****Placebo (%)****	****Etanercept (%)****	****      P-value****Parameter****	****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 016.0037**

## Consistent Efficacy in All Domains*Median Percent Improvement

**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**

**Study 016.0037**

**	****Placebo****	****Etanercept****	****P-value**

***van der Heijde 1999**

## Safety

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

**Pivotal Program**

## Adverse Events (>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****	****Etanercept****n (%)****	****N = 139****	****N = 138****	****N = 39****	****N = 45**

## Serious 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**

## 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

**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**

**Pivotal Program**

## Anti-etanercept Antibodies

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

**Pivotal Program**

## 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**

## Presentations

**Introduction****	****Daniel Burge, M.D.**
**	****	****V.P. Clinical Development**
**	****	****Amgen Corporation**
**Assessments in ****	****D****é****sir****é****e 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**

## 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

**Event****	****Comment**
**Intestinal obstruction****	****Due to adhesions**
**Hemorrhoidal bleeding****	****No IBD (colonoscopy)**
**Ulcerative colitis****	****Pre-existing disease**
**Ileitis****	****History suggests IBD**

## Inflammatory Bowel Disease

**	****	****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**

**Study 016.0037**

**Study 47687**

**AS Pivotal Program**

**Number of Subjects**

## IBD Experience from Etanercept Studies in Rheumatic Diseases

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

## Immunex StudyEtanercept Study in Crohn’s Disease

**	****	****Placebo****	****Etanercept****†**
**N****	****14****	****35**
**Response Rate*****	****50%****	****66%**
**Withdrawals due to****	****14%****	****6%**** ****	****exacerbations****	****	**

***Response defined as decrease of ********75 units in CDAI****†****Dose range up to 32 mg/m****2**** twice weekly**

## Sandborn StudyEtanercept Study in Crohn’s Disease

**Gastroenterology 2001**

- Crohn’s Disease Activity Index Over Time

**Weeks of treatment**

**Mean CDAI Score**

**50**

**100**

**150**

**200**

**250**

**300**

**350**

**2**

**4**

**8**

**0**

**0**

## Inflammatory Bowel Disease Experience Conclusion

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

## Etanercept: Experience in Rheumatic Diseases

**	****	****Patients****	****Patient-Years**
**Commercial*****	****>182,000****	****>341,000**
**Clinical Trials****†****	****3389****	****8336****	****in 5****th**** year of therapy****	****1084****	****in 6****th**** year of therapy****	****390**

***Through April 2003**
**†****Through December 2002**

## Adverse Events Rates* in AS Comparable to Other Rheumatic Diseases

**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**

***Events per patient-year**
**†****Infection associated with hospitalization or IV antibiotics**

**Advanced Disease**

**Controlled Studies**

## 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

**62****2**

**71****3**

**69****4**

**75****1**

**RA **
**ACR 20**

**1****Moreland et al 1997****2****Moreland et al 1999****3****Weinblatt et al 1999****4****Bathon et al 2000**

**% Responders**

**59****6**

**PsA**
**ACR 20**

**6****Mease et al 2001**

**60****7**

**60****8**

**AS**
**ASAS 20**

**7****Study 016.0037****8****Study 47687**

**74****5**

**JRA**
**DOI**

**5****Lovell et al 2000**

## Etanercept in AS: Robust Efficacy Demonstrated

**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**

## Etanercept in AS: Consistent Efficacy in All Domains*

**Study 016.0037**

**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**

**P-value**

## Benefit/Risk of Etanercept is Highly Favorable

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

## Etanercept (Enbrel®) for the Treatment of Ankylosing Spondylitis

- FDA Arthritis Advisory Committee
- June 24, 2003