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BR 8566 – 02/2009

Chapter 3 Evaluation of the efficacy and safety of RoACTEMRA ( tocilizumab): The first biologic to specifically inhibit the IL-6 receptor. BR 8566 – 02/2009. Content. RoACTEMRA - tocilizumab Preclinical evidence of IL-6 receptor inhibition Clinical trial data for tocilizumab

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BR 8566 – 02/2009

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  1. Chapter 3Evaluation of the efficacy and safety of RoACTEMRA (tocilizumab): The first biologic to specifically inhibit the IL-6 receptor BR 8566 – 02/2009

  2. Content • RoACTEMRA - tocilizumab • Preclinical evidence of IL-6 receptor inhibition • Clinical trial data for tocilizumab • Japanese Phase II data • European Phase II data • CHARISMA • Japanese Phase III data • SATORI • SAMURAI • RoACTEMRA Phase III Registration trials: efficacy and safety • OPTION • TOWARD • RADIATE • AMBITION • LITHE

  3. Tocilizumab (RoACTEMRA) • Humanised IgG1 monoclonal antibody • Binds to membrane-bound and soluble IL-6 receptors (mIL-6R and sIL-6R) • Blocks IL-6 binding to its receptor • Blocks IL-6R-mediated signalling and gene activation IL-6 RoACTEMRA SmPC RoACTEMRA 16.01.2009

  4. gp130 Tocilizumab inhibits conventional signalling and transsignalling IL-6 cannot bind sIL-6R mIL-6R Tocilizumab binds mIL-6R and sIL-6R gp130 Conventional signalling Transsignalling Adapted from Jones SA, et al. J Interferon Cytokine Res 2005;25:241-253 Adapted from Scheller J, Rose-John S. Med Microbiol Immunol 2006;195:173-183 Adapted from Mihara M, et al. Int Immunopharmacol 2005;5:1731-1740

  5. Preclinical evidence: Prevention of murine collagen-induced arthritis 15 Control • Murine collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis (RA). • In mice with collagen-induced arthritis (CIA), serum IL-6 increased in conjunction with the onset of arthritis • Anti-IL-6R antibody (MR16-1) inhibited the development of arthritis in a dose-dependent manner MR16-1 (0.5 mg) MR16-1 (2 mg) MR16-1 (8 mg) 10 Arthritis score 5 0 10 20 30 40 50 Days after first immunization Takagi N, et al. Arthritis Rheum 1998;41(12):2117–2121

  6. 0 2 4 6 8 10 12 14 Weeks after collagen immunization 50 50 40 40 30 30 Number of stiff joints Score 20 20 10 10 0 0 0 0 2 2 4 4 6 6 8 8 10 10 12 12 14 14 Weeks after collagen immunisation Weeks after collagen immunization Preclinical evidence: Cynomolgus monkey CIA treated with anti-IL-6R antibody Swelling Vehicle MRA 10 mg/kg 2.0 2.0 1.8 1.8 • MRA inhibited the development of arthritis significantly. In the MRA-treated group, four of five monkeys showed no signs of stiff joints (p<0.05 vs controls) or swelling (p<0.05 vs controls) throughout the observational period 1.6 1.6 1.4 1.4 Swelling rate Rate 1.2 1.2 1.0 1.0 p<0.05 vehicle vs 10mg/kg MRA 0.8 0.8 0.6 0.6 0 2 4 6 8 10 12 14 Weeks after collagen immunization Stiffness 50 Vehicle MRA 10 mg/kg 40 30 Score p<0.05 vehicle vs 10mg/kg MRA 20 10 0 0 2 4 6 8 10 12 14 Weeks after collagen immunization MRA = humanized anti-human IL-6 receptor antibody Each symbol indicates individual data from five monkeys (except for Weeks 12 and 14 of the vehicle group, where data from four monkeys were used). Mihara M, et al. Clin Immunol 2001;98(3):319–326

  7. Evidence for clinical efficacy of blocking IL-6 • Small open studies suggesting clinical benefit in RA patients1,2 • Single IV dose (0.1-10mg/kg or placebo) in 45 RA patients without concomitant DMARDs showed a significant ACR20 response at week 2 with 5 mg/kg3 • Phase II study in 164 Japanese RA patients at 4 or 8mg/kg or placebo every 4 weeks for 3 months as monotherapy resulting in a dose-dependent response4 • CHARISMA: Phase II study in 359 European RA patients comparing different doses of tocilizumab either as monotherapy or in combination with methotrexate (MTX) and MTX plus placebo5 1Yoshizaki K, et al. Springer Semin Immunopathol 1998;20:247-259 2Nishimoto N, et al. J Rheumatol 2003;30(7):1426-1435 3Choy EHS, et al. Arthritis Rheum 2002;46(12):3143-3150 4Nishimoto N, et al. Arthritis Rheum 2004;50(6):1761-1769 5Maini RN, et al. Arthritis Rheum 2006;54(9):2817-2829

  8. Japanese Phase II programme: Summary • Objective: Evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, tocilizumab, in patients with RA • Results: • Efficacy was dose related, and 8 mg/kg of tocilizumab provided marked clinical benefit • Tocilizumab normalised inflammation markers • IL-6 is a major cytokine responsible for acute-phase protein production in RA • Treatment with tocilizumab was generally well tolerated Nishimoto N, et al. Arthritis Rheum 2004;50:1761–1769

  9. European Phase II programme: CHARISMA • Chugai Humanized Anti-human Recombinant Interleukin-6 Monoclonal Antibody study • Objective: Establish safety and efficacy of tocilizumab, alone and in combination with MTX, in active RA patients with an inadequate response to MTX • Results at week 16: • Tocilizumab is effective in decreasing disease activity • ACR20: 63% with TCZ 8mg/kg (p<0.05) and 74% with TCZ 8mg/kg+MTX (p<0.001) vs 41% with placebo+MTX • ACR50: 53% with TCZ 8mg/kg+MTX vs 29% with placebo+MTX (p<0.05) • ACR70: 37% with TCZ 8mg/kg+MTX vs 16% with placebo+MTX (p<0.05) • DAS28 remission: 34% in TCZ 8mg/kg+MTX, 17% in TCZ 8mg/kg, 8% in placebo+MTX • Adding MTX increases the efficacy of TCZ in terms of ACR50 and ACR70 • Tocilizumab in monotherapy or in combination with MTX has a safety pattern that is line with its mechanism of action and consistent with that of other biologic and immunosupressive therapies Maini RN, et al. Arthritis Rheum 2006;54:2817–2829

  10. Japanese Phase III programme: SATORI • Study of Active controlled TOcilizumab monotherapy for Rheumatoid arthritis patients Inadequately treated with MTX • Objective: Assess the efficacy and safety of tocilizumab monotherapy vs MTX monotherapy in active RA patients with an inadequate response to low dose MTX • Primary endpoint: ACR20 response at week 24 • Secondary endpoints: • ACR50 and ACR70 responses • change in DAS28, proportion of DAS28 remissions and EULAR response criteria • Safety: • Adverse events • Laboratory assessments Nishimoto N, et al. Mod Rheumatol 2009;19:12-19

  11. Last observation Primary end-point Infusion SATORI: Study design • TCZ 8mg/kg + placebo or MTX 8mg/week + placebo every 4 weeks for a 24 week period • 127 patients enrolled, 125 of them received ≥1 dose of study medication Screen Randomization Treatment period Open label TCZ 8 mg/kg + placebo (n=61) Placebo + MTX (n=64) 0 4 8 12 16 20 24 Week Nishimoto N, et al. Mod Rheumatol 2009;19:12-19.

  12. ACR20 ACR50 ACR70 SATORI: Significant improvement in all ACR scores (ITT) TCZ superior to MTX p<0.001 100 MTX TCZ 8 mg/kg 80.3% 80 p<0.001 60 49.2% Patients (%) p<0.001 40 29.5% 25.0% 20 10.9% 6.3% 0 Nishimoto N, et al. Mod Rheumatol 2009;19:12-19.

  13. SATORI: Conclusions • Treatment with tocilizumab monotherapy for 24 weeks significantly improved the signs and symptoms of RA in patients with active disease • Significant improvement in ACR20, ACR50 and ACR70 scores • DAS28 responses significantly improved, with >40% patients achieving remission (DAS28<2.6) • Majority achieved a good or moderate outcome, according to EULAR response criteria • Tocilizumab is generally well tolerated • Similar incidence of SAEs in the TCZ and MTX groups • No tuberculosis was observed • Despite lipid increases, the atherogenic index was unchanged • Elevation of hepatic transaminases which stabilised at week 16 • Tocilizumab may be an effective treatment for patients with RA who have an inadequate response to MTX Nishimoto N, et al.Mod Rheumatol 2009;19:12-19

  14. Japanese Phase III programme: SAMURAI • Study of Active controlled Monotherapy Used for Rheumatoid Arthritis, an IL-6 inhibitor • Objective: Evaluate the ability of tocilizumab monotherapy, versus conventional DMARD therapy, to prevent progressive joint damage in active RA patients with a previous inadequate response to ≥1 DMARD or immunosuppressant • Primary endpoint: Change from baseline to week 52 in total sharp score (TSS) • Secondary endpoints: • ACR20, ACR50 and ACR70 • DAS28 • Safety DMARD = disease-modifying antirheumatic drugs, including methotrexate (MTX), salazosulfapyridine, bucillamine, mizoribine, D-penicillamineincluding combinations Nishimoto N, et al. Ann Rheum Dis 2007;66:1162-1167

  15. Last observation Infusion Primary end-point SAMURAI: Study design • Multi-centre, X-ray reader-blinded, randomised, controlled trial • TCZ 8mg/kg monotherapy or DMARDs every 4 weeks for 52 weeks • 306 patients enrolled, 302 of them received ≥1 dose of study medication Screen Randomization Treatment period Open label TCZ 8 mg/kg (n=158) Conventional DMARDs (n=148) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week Nishimoto N, et al. Ann Rheum Dis 2007;66:1162–1167

  16. –10 –20 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 SAMURAI: Significant improvement in TSS withtocilizumab (ITT) TCZ inhibits radiographic progression 70 60 50 DMARDs TCZ 8 mg/kg 40 30 Change from baseline in TSS 20 10 0 Cumulative probability Nishimoto N, et al. Ann Rheum Dis 2007;66:1162–1167

  17. DMARDs TCZ 8 mg/kg 6.1% 3.2% 2.9% P<0.001 SAMURAI: Significant improvement in radiographic outcomes with tocilizumab (ITT) P<0.01 7 6 5 P<0.05 4 Mean change from baseline 3 2.3% 1.5% 2 0.9% 1 0 Mean Total SharpScore Mean Erosion score Joint space narrowing Change in radiographic scores at 52 weeks Nishimoto N, et al. Ann Rheum Dis 2007;66:1162–1167

  18. SAMURAI: Conclusions • TCZ monotherapy improved significantly signs and symptoms of RA • Significant improvement in ACR20, ACR50 and ACR70 scores • Greater reduction in DAS28 scores and higher remission rates with DAS28<2.6 at week 52 achieved in 59% of patients receiving TCZ vs 3% in DMARDs (p<0.001) • ACR70 response for 6 consecutive months in 24% with TCZ vs 2% with DMARDs • TCZ was superior to conventional DMARDs in preventing radiographic progression • Tocilizumab was generally well tolerated • Most common AE reported was nasopharyngitis • No specific infection related to TCZ, including tuberculosis • No cardiovascular complications were associated with lipid abnormalities • These data support the use of tocilizumab for the treatment of RA Nishimoto N, et al. Ann Rheum Dis 2007;66:1162-1167

  19. Tocilizumab Phase III Programme 19

  20. Tocilizumab Phase III Programme The OPTION trial tOcilizumab Pivotal Trial in methotrexate Inadequate respONders Smolen JS, et al. Lancet 2008;371:987-997

  21. OPTION: Study objective • Phase III, three arm, randomised, double-blind, placebo-controlled, parallel group, international study • Objective: Evaluation of the efficacy and safety of tocilizumab in 623 adult patients with moderate to severe active RA who had an inadequate response to MTX • Primary endpoint: Proportion of patients with ACR20 response at week 24 • Secondary endpoints: • ACR50 and ACR70 responses at 24 weeks • Change from baseline in DAS28, DAS28 remission (DAS28<2.6) and EULAR response by 24 weeks • Others (HAQ, FACIT-Fatigue and SF-36) • Safety • Adverse events • Laboratory assessments Smolen JS, et al. Lancet 2008;371:987-997

  22. OPTION: Study population: inclusion criteria Adult patients with moderate to severe RA of more than > 6 months' duration who had an inadequate response to MTX Active disease at screening/baseline SJC  6 (of 66) + TJC  8 (of 68) + CRP 1.0 mg/dl or ESR  28 mm/h Received MTX as a single disease modifying anti-rheumatic drug (DMARD) for at least 12 weeks Last 8 weeks prior to baseline at a stable dose (10 - 25 mg/week) All other DMARDs were discontinued before start of study leflunomide for ≥ 12 weeks; anakinra for ≥ 1 week, etanercept for ≥ 2 weeks, infliximab or adalimumab for ≥ 8 weeks All other background RA therapy stable Smolen JS, et al. Lancet 2008;371:987-997

  23. OPTION: Study population: exclusion criteria • Other autoimmune diseases or significant systemic involvement secondary to RA • Functional class IV RA • Previous or current inflammatory joint disease other than RA • Currently active or previous recurrent bacterial, viral, fungal or other infections invl. tuberculosis and atypical mycobacterial disease • Clinically significant abnormalities on chest radiograph • Hepatitis B and C • Recurrent herpes zoster • Active liver disease • Previous unsuccessful treatment with an anti-TNF agent Smolen JS, et al. Lancet 2008;371:987-997

  24. OPTION: Study design TCZ 4mg/kg or TCZ 8mg/kg or placebo every 4 weeks for 24 weeks with weekly administration of a stable dose of MTX (10-25mg) Early withdrawals and patients entering rescue therapy were classified as non-responders for analyses according to ACR and EULAR response criteria Screen Randomization Treatment period Rescue therapy Infusions Primary endpoint TCZ 4 mg/kg + MTX (n=214) TCZ 8 mg/kg + MTX (n=205) Placebo + MTX (n=204) 0 2 4 6 8 10 12 14 16 18 20 22 24 Week Rescue therapy with TCZ 8mg/kg if patients did not achieve >20% improvement from baseline in both TJC and SJC at week 16 Smolen JS, et al. Lancet 2008;371:987-997

  25. OPTION: Patient disposition 623 patients enrolled 204 receivedplacebo 214 receivedtocilizumab 4 mg/kg 205 receivedtocilizumab 8 mg/kg 13 withdrew 12 withdrew 25 withdrew 68 on rescuetherapy 31 on rescuetherapy 19 on rescuetherapy 1 withdrew 3 withdrew 3 withdrew 189 (93%) completed the study 191 (93%) completed the study 186 (87%) completed the study 537 entered long-term extension study Smolen JS, et al. Lancet 2008;371:987-997 Kremer JM, et al. ACR 2008. Poster 390

  26. OPTION: Baseline demographic data (ITT) * Not counting MTX; data are mean Smolen JS, et al. Lancet 2008;371:987-997

  27. OPTION: Baseline disease characteristics (ITT) Baseline patient characteristics were much the same in all three groups. There were no important differences between the groups with respect to comorbidities Smolen JS, et al. Lancet 2008;371:987-997

  28. OPTION: Significant improvement in ACR scores with tocilizumab at week 24 (ITT) 59% Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 70 p<0.0001 p<0.0001 p<0.0001 60 p<0.0001 p<0.0001 p<0.0001 48% 50 44% 40 Patients (%) 31% 30 26% 22% 20 12% 11% 10 2% 0 ACR20 ACR50 ACR70 Smolen J, et al. Lancet 2008;371:987-997

  29. OPTION: Rapid and sustained ACR20 response with tocilizumab (ITT) Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 70 60 50 40 Patients (%) 30 20 10 0 0 4 8 12 16 20 24 Time (weeks) Numerical differences between the placebo and TCZ 8mg/kg at week 2 Smolen J, et al. Lancet 2008;371:987-997

  30. OPTION: Rapid and sustained improvements in DAS28 with tocilizumab (ITT) • DAS28 decreased rapidly with the mean improvement corresponding to at least moderate EULAR response at 2 weeks • DAS 28 continued to improve over time 8 Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 7 6 Mean DAS28 scores 5 4 3 2 0 4 8 12 16 20 24 Time (weeks) Smolen J, et al. Lancet 2008;371:987-997

  31. OPTION: Significantly increased DAS28 remission at 24 weeks with tocilizumab (ITT) p<0.0001 30 27.5% 25 p=0.0002 20 Patients (%) 15 13.0% 10 5 0.8% 0 Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX Smolen J, et al. Lancet 2008;371:987-997

  32. OPTION: Significant clinical response by EULAR response criteria at 24 weeks (ITT) Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 90 p<0.0001 79% 80 p<0.0001 70 65% 62% 60 50 Patients (%) 38% 40 35% 30 20% 20 10 0 No response Good/moderate response Smolen J, et al. Lancet 2008;371:987-997

  33. OPTION: Tocilizumab induces rapid normalisation of CRP levels (ITT) • Mean CRP concentrations normalised by week 2 with TCZ 8mg/kg • Mean CRP concentrations remained < ULN* until end of study (p<0.0001 vs baseline) 3.0 Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 2.5 2.0 1.5 Mean CRP levels (mg/dl) 1.0 0.5 ULN=0.3 0.0 0 2 4 8 12 16 20 24 Time (weeks) ULN = Upper limit of normal Smolen J, et al. Lancet 2008;371:987-997

  34. OPTION: Significant improvements in fatigue with tocilizumab (ITT) Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 10 • Clinically meaningful change from baseline of ≥4 points was observed by week 4 in both TCZ groups 8 6 Mean change in FACIT-Fatigue 4 MCID*=4.0 2 0 0 4 8 12 16 20 24 Time (weeks) MCID = Minimal clinically important difference Smolen J, et al. Lancet 2008;371:987-997 Alten R, et al. EULAR 2007 Barcelona Poster no:SAT0001 Smolen J, et al. ACR 2007 Boston Poster no 292

  35. OPTION: Rapid and sustained improvement in HAQ score with tocilizumab (ITT) Time (weeks) • Mean HAQ-DI scores improved for patients tretaed with both doses of tocilizumab, starting at week 4 with mean reductions greater than the MCID 0 4 8 12 16 20 24 0 MCID= –0.22 –0.2 Mean change in HAQ score –0.4 Placebo + MTX TCZ 4 mg/kg + MTX –0.6 TCZ 8 mg/kg + MTX Smolen J, et al. Lancet 2008;371:987-997 Alten R, et al. EULAR 2007 Barcelona Poster no:SAT0001 Smolen J, et al. ACR 2007 Boston Poster No 292

  36. OPTION: Rapid and sustained improvement in SF-36 score with tocilizumab (ITT) Placebo + MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 8 12 10 6 MCID=2.5–5.0 8 4 6 MCID=2.5–5.0 Mean change in SF-36 Mental Component Score Mean change in SF-36 Physical Component Score 4 2 2 0 0 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Time (weeks) Time (weeks) MCID = Minimal clinically important difference Smolen J, et al. Lancet 2008;371:987-997 Alten R, et al. EULAR 2007 Barcelona Poster no:SAT0001 Smolen J, et al. ACR 2007 Boston Poster no 292

  37. OPTION: Tocilizumab therapy significantly improves the signs and symptoms of RA Significantly more patients achieved ACR responses with TCZ About a quarter of patients achieved DAS28 remission with TCZ 8mg/kg Rapid and sustained improvements in CRP levels Highly significant increase in haemoglobin levels indicate tocilizumab reverses anaemia suggesting a reduction in the severity of systemic inflammation Significant improvements were also observed in: FACIT-Fatigue score HAQ score SF-36 score Smolen J, et al. Lancet 2008;371:987-997

  38. OPTION: Low incidence of serious adverse events with tocilizumab (safety population) Smolen J, et al. Lancet 2008;371:987-997

  39. OPTION: Summary of serious infections (safety population) URTI=Upper respiratory tract infection; UTI=Urinary tract infection Smolen J, et al. Lancet 2008;371:987-997

  40. OPTION: Resolution of inflammation unmasks elevated lipid levels (safety population) • Mean plasma concentrations of total cholesterol (TC), HDL and LDL cholesterol were increased from baseline in the TCZ groups at week 6 • These increases coincided with moderate to large decreases in CRP • No excess in major adverse cardiovascular events with TCZ vs placebo • Lipid-lowering agents decreased the lipid levels Smolen J, et al. Lancet 2008;371:987-997

  41. OPTION: Transient increases in concentrations of hepatic transaminases (safety population) • No concurrent increase in total bilirubin or alkaline phosphatase • No clinical signs of hepatitis or hepatic dysfunction related • Increases mostly declined or normalised spontaneously or after temporary interruption of study treatment without recurrent increases after resumption of treatment • No evidence that the 5-7% of patients with raised hepatic TA before randomisation had a higher likelihood for abnormal liver functional tests affecting adherence during the study Smolen J, et al. Lancet 2008;371:987-997

  42. OPTION: Decrease in neutrophil counts • Mean neutrophil counts decreased to within the normal range by week 2 after each infusion in TCZ groups • Effect more stable with TCZ 8mg/kg • Transient decreases < LLN more often seen with TCZ vs placebo • No apparent association between neutropenia and occurrence or intensity of infections LLN = Lower Limit of Normal Neutropenia= < 1x109 neutrophils per liter Smolen J, et al. Lancet 2008;371:987-997

  43. OPTION: Tocilizumab therapy was generally well tolerated Similar incidence of SAEs (~6%) for all study groups Frequency of infections was higher with TCZ+MTX than with placebo No cases of tuberculosis occurred during the study period Observed lipid changes with tocilizumab are consistent with other cytokine-targeted therapies in RA Transient hepatic aminotransferase elevation – no cases of clinical hepatitis or hepatic failure Smolen J, et al. Lancet 2008;371:987-997

  44. OPTION: Efficacy and safety proven in DMARD-IR patients with moderate to severe RA • Tocilizumab inhibits IL-6-mediated proinflammatory effects, IL-6 being a pleiotropic cytokine over-expressed in synovial tissue in patients with RA with raised concentrations in serum and synovial fluid • Clinically important improvement in signs and symptoms of RA with tocilizumab • RoACTEMRA delivers a combination of a rapid onset of action and an efficacy that keeps improving over time • All primary and secondary endpoints were met • Tocilizumab therapy was generally well tolerated Smolen J, et al. Lancet 2008;371:987-997

  45. Tocilizumab Phase III Programme The TOWARD trial Tocilizumab in cOmbination With traditional DMARD therapy Genovese MC, et al. Arthritis Rheum 2008; 58:2968-2980

  46. TOWARD: Study objective • Phase III, randomized, double-blind, placebo-controlled, international, multicenter study • Objective: Evaluation of the efficacy and safety of tocilizumab in combination with conventional DMARDs, in 1220 patients with moderate to severe active RA in who had an inadequate response to DMARDs • Primary endpoint: Proportion of patients with ACR20 response at week 24 • Secondary endpoints: • ACR50 and ACR70 responses at week 24 • Time to onset of ACR20/50/70 responses • Change in DAS28, proportion of DAS28 remission and EULAR response criteria by week 24 • Others (HAQ, FACIT-Fatigue and SF-36) • Safety: • Adverse events • Laboratory assessments Genovese MC, et al. Arthritis Rheum 2008; 58:2968-2980

  47. TOWARD: Study population: in- and exclusion criteria Inclusion criteria: Adult patients ≥18 years with moderate to severe RA of ≥6 months' duration who had an inadequate response to DMARDs Active disease at screening/baseline SJC 6 (of 68) + TJC 8 (of 66) + CRP 1.0 mg/dl or ESR 28 mm/h Received stable doses of permitted DMARDs (MTX, (hydroxy)chloroquine, parenteral gold, sulfasalazine, azathioprine, leflunomide) for ≥8 weeks All other background RA therapy stable ≥6 weeks Exclusion criteria: Inadequate response to anti-TNF treatment Inadequate response to any cell-depleting therapy Genovese MC, et al. Arthritis Rheum 2008; 58:2968-2980

  48. TOWARD: Study design TCZ 8mg/kg or placebo every 4 weeks combined with stable DMARDs Early withdrawals and patients entering rescue (after week 16) were classified as non-responders for ACR and EULAR response criteria 5 year open-label long-term extension study for nonresponders and patients completing the study 2 6 10 12 16 18 22 24 Rescue therapy Screen Randomization Treatment period Infusions Primary endpoint TCZ 8 mg/kg + DMARDs (n=805) Placebo + DMARDs (n=415) 0 4 8 14 20 Week Rescue therapy for patients who failed to respond to treatment at week 16 consisting of adjustment of background DMARD dosage and/or different DMARD, and/or corticoids Genovese MC, et al. Arthritis Rheum 2008; 58:2968-2980

  49. TOWARD: Patient disposition 1,220 patients enrolled 415 randomized toplacebo + DMARDs 805 randomized to TCZ 8 mg/kg +DMARDs 2 received no study medication 1 received no study medication 43 withdrew 53 withdrew 45 on rescue therapy 19 on rescue therapy 370 (89%) completed the study 751 (93%) completed the study Genovese MC, et al. Arthritis Rheum 2008; 58:2968-2980

  50. TOWARD: Overview of analysis populations *Two patients randomized to the placebo + DMARDs group received TCZ + DMARDs †Three patients randomized to the TCZ + DMARDs group received placebo + DMARDs Genovese MC, et al. Arthritis Rheum 2008; 58:2968-2980

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