1. Treatment of Ankylosing Spondylitis Enbrel RA MENA Speaker Bureau Dubai, United Arab Emirates January 2009 Prof. Joachim R. Kalden Director emeritus Medical Department III Div. for Molecular Immunology University of Erlangen-Nuremberg

2. Ankylosing Spondylitis Overview –A type of arthritis that causes inflammation and eventually fusion of the spine and the spinal joints. Involvement of peripheral joints and extraarticular manifestations. –AS causes pain, stiffness, disability, decreased spinal mobility, and decreased quality of life –The prevalence ranges from 0.1 to 1 percent of the population –Men are affected three times more than women –Commonly develops between the ages of 15 and 40 –95 percent of people with AS share the genetic marker HLA-B27

3. Treatment of Ankylosing Spondylitis Overview Treatment goals Use of traditional therapies Clinical results with TNFalpha antagonists Guidelines for the management of TNFalpha antagonists

4. Treatment goals in Ankylosing Spondylitis  Reduce and or prevent deleterious effects of: Inflammation Ankylosis Abnormal posture Dougados et al. J.Rheumatol 2001;28-62:16-20. Inhibition of osteoblastogenesis

5. Development of Ankylosis in Ankylosing Spondylitis From: Cruickshank and Path, Pathology of Ankylosing Spondylitis The earliest change seen was a sub acute osteitis in the immediately adjacent bone. This was followed by extensive replacement of the fibrocartilage and adjacent bone by fibrous tissue in which there was often little remaining evidence of inflammation. The late stage of the disease in this joint consisted of assification.

6. Late Stage Reparation Mechanism - Dense Formation of Osteoblasts bone marrow bone Appel H, Loddenkemper C, Sieper J; unpublished

7. ASAS/EULAR Recommendations for the Management of AS Education, exercise, physical therapy, rehabilitation, patient associations, self help groups NSAIDs Peripheral disease Axial disease Sulfasalazine TNF blockers AnalgesicsAnalgesics Local corticosteroids SurgerySurgery Zochling J, et al. Ann Rheum Dis. 2006;65:442-52 (excerpt)

8. Celecoxib Versus Naproxen in AS: Improvements in Primary Efficacy Measures Barkhuizen et al. Ann Rheum Dis 2005;64(supplementIII);338(Abs).

9. Reduction of Radiographic Progression by NSAIDs in Ankylosing Spondylitis Wanders et al. Arthritis Rheum 2005;52:1756-65. Inhibition of proliferation and migration of osteoblasts in a rat bone healing model by diclofenac GD Krischak et al. Arch Orthop Traum Surg 2007, 127:453-458

10. Sulphasalazine in the Treatment of Spondylarthropathy 20 40 60 placebo Sulphasalazine % patients 43 40 42 59 Clegg et al. Arthritis Rheum 1999;42:2325-9. Axial n=187 Periphral n=187 Placebo (n=39)Sulphasalazine (n=45) Pain-17-26 Swollen joints-1.6-4.4 Tender joints-4.0-8.8 Dougados et al. Arthritis Rheum 2005;38:618-27.

11. 0 2 4 6 8 0481216 Week BASDAI (mean) All patients (n=20) *Braun J, …, Sieper Jl. Ann Rheum Dis 2006 Apr 10; Epub **Haibel H,..., Sieper J. Ann Rheum Dis 2005;64:124-6. † Haibel H,.... Sieper J. 2006; Aug 10; Epub. 0 2 4 6 8 04812162024 Week BASDAI (mean) All patients (n=20) Peripheral arthritis (n=10) Non-arthritis (n=10) Leflunomide** 20 mg/day Methotrexate † 20 mg/week sc 0 1 2 3 4 5 6 7 8 04812162024 Week BASDAI (mean) Placebo (n=60) Sulfasalzine (n=60) Sulfasalazine* 2 g/day P=0.03 Conventional DMARDs in the Treatment of Ankylosing Spondylitis

12. Conclusions from treatment experiences in Ankylosing Spondylitis with traditional therapies  Traditional therapy options are not sufficient to treat active disease Physiotherapy important to maintain function NSAIDs alleviate pain in some but not all patients Steroids and immunomodulators have little/no effect No drugs which impede disease progression  Unmet medical need in the treatment of severe AS

13. Infliximab Monotherapy Study In Active Ankylosing Spondylitis 54 Baseline Period 70 Patients Placebo (N=35) 0,2,6 Infliximab 5 mg/kg Q 6 Wks (N=35) Loading Period 12 Infliximab 5mg/kg Q 6 Wks Week Double-Blind Open Label Infliximab 5 mg/kg Q 6 Wks Study Design Braun et al. Lancet 2002;359:1187-93.

14. Reduction of Disease Activity Was Rapid and Durable Through 12 Weeks Weeks Percentage of Patients With Improvement of 50% in BASDAI 0 20 40 60 80 100 024681012 Patients responding, % Placebo Infliximab 5 mg / kg P<0.001 Intent-to-Treat Population Braun et al. Lancet 2002;359:1187-93.

15. Maintenance of Efficacy of Infliximab in Ankylosing Spondylitis. Two year extension of a 3 months RCT Braun et al. Ann. Rheum Dis 2005;64:229-34. BASDAI 50%ASAS 40%ASAS 20% 5 out of 6

16. Radiographic Progression in Patients with Ankylosing Spondylitis treated for 2 years with Infliximab Baraliakos et al. Ann Rheum Dis 2005;64:1462-6. Control group Progression in total group Progression in group with damage at baseline

17. Anti-TNF therapy in AS: Continuous improvement of spinal mobility and function over 2 years Placebo-patients Crossed-over 24102 2 54 2410254 Placebo-patients Crossed-over Braun J, et al. Arthritis Rheum 2008, in press

18. A randomized controlled clinical trial of infliximab shows clinical and MRI efficacy in patients with pos. HLA B27 and very early AS 49 pat. with early inflammatory back pain, HLA B27 pos. and known oedema on MRI were randomized No demographic changes between the two groups Result Infliximab appears to be an effective therapy in very early inflammatory back pain (significant change from baseline: MRI score of sacroiliac joints resolving of SI- joint lesions. Improvement of clinical parameters) N. Barkham et al. ACR 2007. L11

19. Adalimumab in Ankylosing Spondylitis. The ATLAS trial: a RPCT on 315 patients treated for 24 weeks 25 50 75 100 21 58 14 41 19 51 14 39 Davis et al. Arthritis Rheum 2005;S208 (abs.483). 12 weeks24 weeks placebo Adalimumab 40 mg eow % patients ASAS 20ASAS 40 ASAS 20

20. Adalimumab in Ankylosing Spondylitis. The ATLAS Trial: a RPCT on 315 patients Treated for 24 weeks 25 50 75 100 4 21 6 22 Davis et al. Arthritis Rheum 2005;S208 (abs.483). 12 weeks24 weeks placebo Adalimumab 40 mg eow Remission % patients

21. Adalimumab in patients with total spine ankylosis Randomized, placebo-controlled trial (ratio 2:1) In patients with TSA adalimumab treatment resulted in rapid and clinically significant improvement in signs and symptoms of active disease –At week 12: 50% of adalimumab treated patients achieved ASAS 20, 33% ASAS 40, ASAS 5/6 and BASDAI 50 as compared to non of placebo treated patients –After 1 year: 8/11 adalimumab treated patients achieved ASAS 20 –After 2 years: 6/11 adalimumab treated patients achieved ASAS10 van der Heijde D et al, Ann Rheum Dis, Dec 2007

22. Etanercept for Ankylosing Spondylitis. Results of a 24-weeks RPCT on 277 patients Davis et al. Arthritis Rheum 2003;48:3230-6.

23. Sustained Durability of Etanercept in Ankylosing Spondylitis for 96 weeks Davis et al. Ann Rheum Dis 2006;64:1557-62.

24. Longterm anti-TNF therapy in AS - persistent low disease activity over 4 years Mean BASDAI Weeks 024*487296120144168192 BASDAI (0–100) 0 10 20 30 40 50 60 70 Etanercept/Etanercept Placebo/Etanercept *Week 24 represents the baseline of the OLE as well as the point of initial etanercept treatment for the patients switched from placebo to etanercept. RCT Davis J et al. Ann Rheum Dis 2008

25. 024*487296120144168192 BASFI (0–100) 0 10 20 30 40 50 60 *Week 24 represents the baseline of the OLE as well as the point of initial etanercept treatment for the patients switched from placebo to etanercept. Etanercept/Etanercept Placebo/Etanercept Mean BASFI Weeks Long-term anti-TNF therapy in AS - continuous improvement of function Davis J et al. Ann Rheum Dis 2008

26. Assessment of Clinical Efficacy in a Randomized Double-Blind Study of Etanercept and Sulfasalazine in Patients With Ankylosing Spondylitis October 27, 2008 American College of Rheumatology Annual Scientific Meeting ACR 2008 J. Braun, 1 F. Huang, 2 R. Burgos-Vargas, 3 I.E. van der Horst-Bruinsma, 4 B. Freundlich, 5 B. Vlahos, 5 A.S. Koenig 5 1 Ruhr University, Bochum, Germany; 2 Chinese PLA General Hospital, Beijing China; 3 Hospital General de México and Universidad Nacional Autónoma de México, Mexico City, Mexico; 4 VU University Medical Center, Department of Rheumatology, Amsterdam, Netherlands; 5 Wyeth Research, Collegeville, PA, USA

27. Objective To compare the efficacy and safety of etanercept 50 mg once weekly with sulfasalazine 1.5 to 3 g daily over 16 weeks in patients with active ankylosing spondylitis (AS) 1 1 van der Linden S. et al. Arthritis Rheum 1984;27:361–8.

28. Key Endpoints Primary –Proportion of patients achieving ASAS 20 (20% improvement by Assessment of AS criteria) at 16 weeks Select Secondary –ASAS 20, ASAS 40, ASAS 5/6, partial remission 1 –BASMI (Bath Ankylosing Spondylitis Metrology Index) –BASFI (Bath Ankylosing Spondylitis Functional Index) –BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) –C-Reactive Protein through 16 weeks –Back pain –Modified Schober’s test 1 Anderson et al. Arthritis Rheum 2001; 441876-86

29. Proportion of Patients Who Achieved ASAS 20 (LOCF) *P<0.001, etanercept versus sulfasalazine Primary Endpoint: Proportion of Patients Who Achieved ASAS 20 at week 16 * * * * *

30. Proportion of Patients Who Achieved Partial Remission * (LOCF) *Anderson et al. Arthritis Rheum 2001; 441876-86; † P<0.001, etanercept versus sulfasalazine † † † † †

31. Mean BASMI Scores (LOCF) *P<0.001, etanercept versus sulfasalazine * * * * *

32. Conclusions In this 16-week study –Etanercept therapy was superior to sulfasalazine therapy in the treatment of subjects with ankylosing spondylitis. –There were no unexpected safety findings

33. Etanercept Shows Persistent clinical Efficacy over 5 Years According to: Baraliakos X et al., FRI0291, EULAR 2008 No. Achieving at 12 weeks No. Achieving at < 90% of all visits (%) Clinical Remission 65 (83) BASDAI < 3 118 (73) BASFI < 3 98 (89) BASFI < 4 1111 (100) BASDAI + global physician‘s < 4 1210 (83) At 5 Years (n = 18):  33% were in partial remission according to ASAS criteria  38% achieved a BASDAI 50% response  62% achieved a ASAS 40% response  65% achieved a ‘5 out of 6’ response

34. Effectiveness of Adalimumab after failure of infliximab or etanercept in patients with PsA and AS Open-label phase IIb studies PsA „STEREO“ 66 of 442 patients discontinued and were switched to adalimumab AS „RAPSODY“ 309 of 1186 patients discontinued and were switched to adalimumab PsA: Significant improvement in ACR 20, 50, 70 and HAQ AS: Significant improvement in ASAS 20, 50, 70 and BASDAI Burmester et al. Arthritis Rheum 2007; 56, 393

35. Rudwaleit et al. Ann Rheum Dis 2004;63:665-70. Prediction of Response to TNF Antagonists in Ankylosing Spondylitis: Infliximab n=69, Etanercept n=30 6.5 20 years

36. Median percentage change from baseline Interferon-γInterleukin-6 CRPVEGF Visvanathan Set al., Ann Rheum Dis, 2008

37. 73 58 31 0 20 40 60 80 <10 years, N=3711-20 years, N=33>20 years, N=29 % Patients with Ankylosing Spondylitis (n=99) treated with TNF  -Blockers Rudwaleit M, et al. Ann Rheum Dis. 2004; 63:665-70 Better Response if AS Patients Treated Early in the Disease Course (n=100) (as judged by BASDAI 50 response)

38. Discontinuation of anti-TNF Therapy in Ankylosing Spondylitis Baraliakos X et al., Arthritis Res Ther, 2005

39. Effects of TNFalpha antagonists on extra-articular manifestations Reduction in the number of enthesetic regions -Infliximab -Etanercept -Adalimumab Decreased incidence of anterior uveiitis -Infliximab -Adalimumab -Etanercept less effective Braun et al., Lancet 2002; 359:1187-93 Marzo-Ortego et al., Arthritis Rheum 2001; 44:2112-17 Braun et al., Arthritis Rheum 2005; 52:2447-51 Lyndell LL et al, Arthritis & Rheumatism (2007)56:3248-3252

40. 00 Proportion of Patients with Enthesopathy Weeks Percent of Patients Placebo cross-over to Infliximab * p = 0.03 * Phase II: All Patients Receive Infliximab; Original Blind Maintained 1650 0 0 0 1650 The Impact Study C. Antoni et al. Arth Rheum 2003 10 30 20 40 10

41. International ASAS Consensus Statement for the Use of anti-TNF in Patients with Ankylosing Spondylitis Indication  Definitive AS  Active disease- BASDAI ≥4 - expert opinion - acute phase response - imaging modalities  Failure of ≥2 NSAIDs  In case of peripheral arthritis failure of intraarticular corticosteroids/sulphasalazine  Absence of contraindication Monitoring  BASDAI  ASAS core set  Responder: improvement of ≥2 units on BASDAI Baeten et al. Ann Rheum Dis 2003;62:829-34..

42. News from the ACR Meeting 2008 Long-term efficacy for up to 7 years for all 3 TNF antagonists being licenzed for the treatment of AS. No new safety signals Re-Treatment of AS patients who flaired after ADA treatment was stopped is possible Early effective treatment of AS (as shown for ADA) might significantly improve the work productivity

43. Summary TNF antagonists proven in PsA, AS to have a long-term clinical efficacy and acceptable safety profile No new side effects reported in long-term clinical trials as compared to previous studies and registry data Identical recommendation for screening patients before TNFalpha antagonist should be started Psoriasis induced by TNFalpha antagonists –(Sfakis PP et al. Arthritis Rheum 2005) –(Kary S. Ann Rheum Dis 2006;65:405-407) –(Massara A et al. Rheumatology 2006;45:730-733)