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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. 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

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

  2. 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

  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. ReactiveArthritis JuvenileSpondylo-arthropathy PsoriaticArthritis AS UndifferentiatedSpondylo-arthropathy IBD AssociatedArthritis 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 • 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.

  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. 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

  14. 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

  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 hip radiograph peripheral joints/entheses spine radiograph van der Heijde et al. J Rheumatol 1999;26:951-4; 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 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

  19. 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

  20. 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

  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 2001:44:1876-886

  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. 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

  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. 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

  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. 2002;346:1349-56

  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. 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

  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. 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

  47. 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

  48. 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

  49. 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

  50. 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

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