1. Achieving remission in early RA Dubai, United Arab Emirates 19. January 2009 Professor Joachim Kalden Friedrich-Alexander University Erlangen-Nuremberg Erlangen, Germany

2. 2 Achieving remission in early RA Overview Definition of remission Why early treatment. Window of opportunity Using DMARDs to induce remission Using TNF antagonists to induce remission The COMET study

3. 3 Definition of Remission Clinical Remission ACR/DAS criteria, or normal acute phase response, no clinical synovitis Imaging Remission No radiographic damage progression No significant synovitis on sensitive imaging True Remission A state of low disease activity with no progression of structural damage

4. 4 Clinical Remission by DAS28 Based on VAS of 100mm Prevoo MLL et al. Arthritis Rheum 1995;38:44-8. van Gestel AM et al. J Rheumatol 1999;26:705-11. DAS28 Score 5.1 3.2 2.6 Severe Moderate Low Remission Disease Activity DAS28 <2.6

5. 5 For achieving remission early treatment for RA is necessary Since: Damage is an early feature of RA (93 % of Ra patients have radiographic damage within less than two years) Erosions can be demonstrated within four months after the onset of symptoms by MRI or ultrasound The rate of progression is significantly faster within the first year as compared to the second and third year Osteoclasts are involved in early tissue destruction Plant. J. Rheumatol. 1998 Brook. Ann Rheum Dis. 1977 Wolfe. Arthritis Rheum. 1998 Molenaar et al. Arthritis Rheum. 2004;50:35-42

6. 6 Erosion MTP I Onset Respiratory Infection NSAR Single shot steroid 0 2 4 6 8 10 weeks CASE 31y female 1 690 60 4 1050 95 2 1 380 77 TJC SJC RF ESR Non- destructive phase Destructive phase Kinetics of bone destruction in arthritis I By the courtesy of Georg Schett

7. 7

8. 8 Early treatment reduces disability 5 years later according to: Wiles NJ, et al. Arthritis Rheum 2001; 44: 1033 - 42 * Odds ratio of HAQ ≥1 0.0 0.5 1.0 1.5 2.0 2.5 3.0 Degree of Disability* after 5 Years <6 months (n = 60) 6-12 months (n = 47) >12 months (n = 76) 0.9 2.4 2.3

9. 9 Schematic Representation of the Course of RA Over 30 Years Inflammation Disability Radiographic Scores Kirwan J. J Rheumatol. 1999;26:720-5.

10. 10 Relationship Between X-ray Progression and Physical Function - TEMPO Trial X-ray progression and HAQ scores were determined at baseline, Year 1 and Year 2 After adjustment for co- variates, Sharp-score was a statistically significant determinant of HAQ-score (P<0.0001) Progression of radiographic damage over a relatively short period of time leads to deterioration of physical function van der Heijde D, et al. Abstract 1456, ACR 2005. Negative Zero Mild Severe Progression

11. 11 Therapeutic options for early RA* Steroids systemical intraarticular in combination with DMARD‘s * Besides NSAID‘s DMARD‘s as monotherapy as combination therapy Biologics in combination with MTX

12. 12 Using DMARDS to Induce Remission Have we reached the limit of conventional therapies?

13. 13 Combination DMARD step-down therapy: COBRA trial (6 months) Boers M et al. Lancet. 1997;350:309-318. Pooled Index SSZ alone SSZ with MTX + Pred MTX 7.5 mg/week Weeks 16280 0.0 0.4 0.8 1.2 1.6 Prednisolone 7.5 mg/day Prednisolone 60 mg/day SSZ 2000 mg/day

14. 14 Early combination DMARD therapy led to sustained slowing of progression in early RA P =0.008 0 10 20 30 40 012345 Radiographic progression (Mean  VdH TSS) Years COBRA: 5.4 points/year SSZ alone: 8.6 points/year Landewe RB et al. Arthritis Rheum 2002:46:347-356 COBRA SSZ alone SSZ vs. COBRA

15. 15 3 4 7 12 8 0 4 3 0 4 1 3 5 7 6 5 3 3 0 2 4 6 8 10 12 14 16 18 012345678 Total no. of joints with US synovitis Brown, Arthritis Rheum 2006; 54: 3761 Patients (n) Patients NOT satisfying ACR Remission Criteria (n) Patients satisfying ACR Remission Criteria (n) Clinical Remission on DMARDs in 100 RA patients: # of Patients with US Synovitis (ACR Remission vs non ACR Remission)

16. 16 Grigor C et al. Lancet 2004; 364: 263 NO:Tight Control in RA 6 5 4 3 2 1 0 0369121518 Month Disease activity score Intensive Routine The TICORA Trial

17. 17 * P<0.02, ** P<0.002, Mann-Whitney Radiographic Progression: 0 and 18 Months 3 4.5 8.5 0.5 3.25 4.5 0 1 2 3 4 5 6 7 8 9 Erosion scoreNarrowing scoreTotal Sharp score RoutineIntensive ** * Median change in erosion, joint space narrowing and total Sharp score Grigor C et al. Lancet 2004; 364: 263

18. 18 Lessons from DMARD studies MTX is more efficacious at higher than lower dosages DMARDs are efficacious, but do not completely arrest radiographic progression Combination DMARD therapy is more efficacious than monotherapy Radiographic progression is reduced the most effectively, over the long-term, when DMARD therapy is initiated: Early Intensively

19. Targeting Remission with Biologic Therapy

20. 20 Biologics in combination with MTX in early RA PERMIER trial ASPIRE trial TEMPO trial BEST trial MTX + Adalimumab vs. either drug alone MTX + infliximab vs. MTX alone MTX + Etanercept vs. either drug alone 4 treatment strategies including MTX + infliximab St. Clair et al. Arthritis Rheum 2004, 50:3432 Klareskog et al. Arthritis Rheum 2004, 50:238 Breedveld et al. Arthritis Rheum 2005, 54:26 Goekoop-Ruiterman et al. Arthritis Rheum 2005, 52:3381

21. 21 Breedveld FC, et al. Arthritis Rheum 2006;54:26-37 The PREMIER trial: Remission as measured by DAS28 ≤2.6 23* 21 25*25 43* 49* 0 10 20 30 40 50 60 Adalumimab + MTX Adalumimab alone MTX alone Pts w/DAS28 <2.6 (%) Wk 52 Wk 104 *P <.001 ADA + MTX alone and ADA alone.

22. 22 ASPIRE: Proportion of Patients Achieving Remission at Week 54 MTX alone IFX 3 mg/kg + MTX IFX 6 mg/kg + MTX St Clair W, et al. Arthritis Rheum. 2004;50:3432-43. DAS28 <2.6 15.0% 21.2% 31.0% 0% 5% 10% 15% 20% 25% 30% 35% P=0.065 P <0.001 Median baseline: 6.8

23. The COMET Trial Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Emery P et al., Lancet. 2008; 372-382.

24. 24 The COMET Trial The COmbination of Methotrexate and Etanercept in early rheumatoid arthriTis (RA) trial compared the effects of a combination of etanercept (ETN) and methotrexate (MTX) with MTX alone in patients with early RA (≥3 months and ≤2 years) COMET is a 24-month, double-blind, randomised, parallel-group, multicentre, outpatient study The aim was to investigate aggressive early combination therapy as the regimen of choice to achieve clinical and radiographic targets and normalisation of function Emery P et al. Lancet. 2008;372:375-382.

25. 25 Key End Points Primary clinical end point: DAS28 remission (<2.6) at week 52 Primary radiographic end point: Change in modified Total Sharp Score (mTSS) from baseline to week 52 Secondary end points DAS44 remission (<1.6) ACR 20%, 50%, and 70% responses HAQ-DI Employment questionnaire/stopping working ACR, American College of Rheumatology DAS, disease activity score HAQ-DI, Health Assessment Questionnaire – Disability Index Emery P et al. Lancet. 2008;372:375-382.

26. 26 Study Design for COMET Trial Double-blind randomised clinical trial ETN + MTX (n=274) Period 1 ETN (1b) MTX (2b) 104 wk Randomise (n=542) Placebo ETN + MTX (n=268) 52 wk ETN + MTX (1a) ETN + MTX (2a) Period 2 Emery P et al. Lancet. 2008;372:375-382.

27. Results

28. 28  92% of patients were considered to have severe rheumatoid arthritis (DAS28 >5.1) Patient Baseline Disease Characteristics Modified ITT Population MTX n=263 ETN + MTX n=265 Total n=528 Disease duration (months)9.38.89.0 DAS286.5 No. of total swollen joints (0-68)17.617.117.3 No. of total tender joints (0-71)24.825.125.0 HAQ (0-3)1.61.7 ESR (mm/h)49.347.848.5 CRP (mg/L)36.537.036.7 Anti-CCP positive (%)706769 Anti-CCP, anticyclic citrullinated peptide Emery P et al. Lancet. 2008;372:375-382.

29. 29 *After titration Patient Disposition MTX n=268 ETN + MTX n=274 Total n=542 Completed 52 wks, n (%)189 (70.5)221 (80.7)410 (75.6) Total withdrawals, n (%)79 (29.5)53 (19.3)132 (24.4) Adverse event, n (%)34 (12.7)28 (10.2)62 (11.4) Lack of efficacy, n (%)24 (9.0)9 (3.3)33 (6.1) Protocol violation, n (%)9 (3.4)4 (1.5)13 (2.4) Patient request, n (%)8 (3.0)9 (3.3)17 (3.1) Other, n (%)4 (1.5)3 (1.1)7 (1.3) Median MTX dose at 8 weeks, mg/wk * 19.616.8— Emery P et al. Lancet. 2008;372:375-382.

30. DAS28 Remission

31. 31 DAS28 Remission Over Time * P=0.002; † P<0.0001; LOCF 50% 28% † † † † † † † * 0 20 40 60 0481216202428323640444852 Time (weeks) Proportion with DAS28 remission (%) MTX (n=263) ETN + MTX (n=265) A significant difference between the study groups was seen as early as 2 weeks Emery P et al. Lancet. 2008;372:375-382. Data on file, Wyeth Pharmaceuticals. † 2

32. 32 DAS28 Remission *P<0.0001; LOCF DAS28 remission=DAS28 <2.6; DAS44 remission=DAS<1.6; DAS28 LDA=≤3.2; DAS LDA=DAS<2.4 28% 41% 49% 50% 51% 64% 73% 0 20 40 60 80 100 Patients (%) MTX (n=263) ETN + MTX (n=265) * * DAS28 LDA DAS44 Remission DAS44 LDA * * DAS28 and DAS44 Remission and Low Disease Activity (LDA) at Week 52 Emery P et al. Lancet. 2008;372:375-382.

33. ACR Responses

34. 34 ACR Responses at Week 52 67% 49% 28% 86% 71% 48% 0 20 40 60 80 100 ACR20ACR50ACR70 Patients (%) (mITT) MTX (n=243) ETN + MTX (n=256) *P<0.0001; LOCF * * * Emery P et al. Lancet. 2008;372:375-382.

35. Radiographic Progression

36. 36 Radiographic Changes at Week 52 2.4 4 0.27 0 0.5 1 1.5 2 2.5 3 Change from baseline in mTSS MTX (n=230) ETN + MTX (n=246) Emery P et al. Lancet. 2008;372:375-382.

37. 37 * mTSS Definition of Nonprogression *P<0.001 Radiographic Nonprogression at Week 52 * 59% 54% 80% 75% 0 20 40 60 80 100 ≤0.5≤0 Patients (%) MTX (n=230)ETN+MTX (n=246) Adapted from Emery P et al. Lancet. 2008;372:375-382.

38. Quality of Life

39. 39 39% 55% 0 10 20 30 40 50 60 Week 52 Patients (%) MTX (n=241) ETN + MTX (n=256) * *P=0.0004 HAQ-DI Scores Comparable to a Healthy Population (≤0.5) Emery P et al. Lancet. 2008;372:375-382.

40. Work Productivity

41. 41 1. Puolakka K et al. Arthritis Rheum. 2004;50:55-62. 2. Verstappen SMM et al. Arthritis Rheum. 2004;51:488-497. 3. Data on file, Wyeth Pharmaceuticals. 4. Emery P et al. Lancet. 2008;372:375-382. Work Productivity in RA – Background Background Absence from work and job loss can occur relatively early in RA 1,2 A patient who stops work due to arthritis is unlikely to return 3 Work productivity data is important for estimating economic burden of disease Objective of the Work Productivity Analysis in COMET To compare the secondary end point impact of combination ETN and MTX vs. MTX alone on work stoppage among MTX naïve patients with active early RA 4

42. 42 How Many Patients With RA Are Unable to Work Over Time? Rates of Work Disability in RA: ~20% the first year 32% to 50% after 10 years Up to 90% after 30 years Lacaille D. J Rheumatol 2005; 32: 42-45 Puolakka K. Arthritis Rheum 2005; 52: 36 Eberhardt K et al. J Rheumatol 2007; 34: 481 Working part-time Working full-time Work disabled 100 20 60 0 80 40 90 10 30 50 70 123456157891011121314 0 Development of work disability over 15 years in 148 patients with early RA

43. 43 Methods Used for Work Productivity Analysis Employment questionnaire administered at weeks 12, 24, 36, and 52 Analyses restricted to patients who reported working part- time or full-time at baseline Assumed that once patients reported stopping work, they did not restart working First-time work stoppage was compared using Fisher’s exact test with LOCF Emery P et al. Lancet. 2008;372:375-382.

44. 44 Work Disability: Proportion of Patients Reporting First-time Work Stoppage Patients stopping work (%) *P=0.004 0 5 10 15 20 25 30 * 24% 9% Week 52 MTX (n=100) ETN + MTX (n=105) Emery P et al. Lancet. 2008;372:375-382.

45. Safety Data

46. 46 Safety Summary Through Year 1 The most common AE was nausea (19% in both groups) The second most common AE was nasopharyngitis (16% in both groups) The proportion of patients experiencing serious AEs was similar between the 2 groups No malignant diseases were considered related to the treatments received There were no new safety signals reported Emery P et al. Lancet. 2008;372:375-382.

47. Summary & Conclusions

48. 48 COMET Summary 50% of patients treated with ETN + MTX achieved DAS28 remission A significantly greater proportion achieved remission at Week 2 than those receiving MTX alone Almost two thirds achieved low disease activity 80% of patients receiving ETN + MTX achieved radiographic non- progression compared with 59% of those in the MTX-alone group HAQ-DI scores within the norm were achieved by 55% of patients treated with ETN + MTX Treatment with ETN + MTX significantly reduced first-time work stoppage The safety profile of combination treatment was comparable to the safety profile of MTX alone Emery P et al. Lancet. 2008;372:375-382.

49. 49 COMET Conclusions ETN in combination with MTX was superior to MTX-alone in providing Clinical remission Radiographic nonprogression Normalised function Remission is an achievable therapeutic goal when combination therapy is initiated early in the RA disease process © 2008, Wyeth PharmaceuticalsSeptember 2008235993-02 Emery P et al. Lancet. 2008;372:375-382.