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Improving outcomes in RA: Phase III results. The new OPTION in RA

Improving outcomes in RA: Phase III results. The new OPTION in RA. Professor Josef Smolen Vienna General Hospital, Medical University of Vienna, and Hietzing Hospital, Vienna, Austria. Early clinical studies with tocilizumab.

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Improving outcomes in RA: Phase III results. The new OPTION in RA

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  1. Improving outcomes in RA: Phase III results. The new OPTION in RA Professor Josef Smolen Vienna General Hospital, Medical University of Vienna, and Hietzing Hospital, Vienna, Austria

  2. Early clinical studies with tocilizumab • Successful early Phase controlled and open-label clinical trials in Japan1,2 • In Europe, the Phase II study CHARISMA confirmed efficacy of tocilizumab in combination with methotrexate and established therapeutic doses3 •  Double blind, randomised, placebo-controlled clinical trial: OPTION 1. Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167. 2. Nishimoto N, et al. Ann Rheum Dis 2006; 65(Suppl II):59. 3. Maini RN, et al. Arthritis Rheum 2006; 54:2817–2829.

  3. The OPTION study • TOcilizumab • Pivotal • Trial in methotrexate • Inadequate • RespONders

  4. Study population • Patients with moderate to severe RA with an inadequate response to MTX • Patients could have been treated with TNF- antagonists but not failed due to lack or loss of efficacy • Double-blind, randomised, controlled trial • Tocilizumab plus methotrexate (MTX) vs placebo plus MTX

  5. Main objectives • Primary endpoint: ACR20 response at Week 24 • Secondary endpoints • ACR50 and ACR70 responses • Changes in DAS28 and proportion of DAS28 remissions • Others (HAQ, fatigue, …) • Safety • Adverse events • Laboratory assessments

  6. Study design (1) • TCZ or placebo q4wk iv (6 infusions) with MTX dose maintained • A total of 623 patients randomised • Early withdrawals and patients entering rescue therapy (after Week 16) were classified as non-responders for ACR and EULAR response analyses

  7. Study design (2) Screen Randomisation Treatment period Infusions Primary endpoint TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX Placebo + MTX 0 2 4 6 8 10 12 14 16 18 20 22 24 Week Rescue therapy Primary endpoint: ACR20 response at Week 24

  8. Key inclusion criteria • Received MTX as a single DMARD for at least 12 weeks • Last 8 weeks prior to baseline at a stable dose (10 mg/wk) • All other DMARDs withdrawn at least 4 weeks prior to randomisation • All other background RA therapy stable • SJC 6 (of 66) and TJC 8 (of 68) at screening and baseline • Elevated acute phase reactant, either: • CRP 1.0 mg/dL • ESR 28 mm/h

  9. Enrolment, randomisation and study completion 623 patients enrolled 204 randomlyassigned to receiveplacebo 214 randomlyassigned to receiveTCZ 4 mg/kg 205 randomlyassigned to receiveTCZ 8 mg/kg 12 withdrew 25 withdrew 13 withdrew 68 on escapetherapy 31 on escapetherapy 19 on escapetherapy 3 withdrew 3 withdrew 1 withdrew 191 (93%) completed the study 189 (93%) completed the study 186 (87%) completed the study 537 (86%) entered long-term extension study WA18695

  10. Baseline characteristics (ITT population)

  11. MTX *** TCZ 4 mg/kg + MTX 43.9% TCZ 8 mg/kg + MTX *** 58.5% *** 47.9% *** 22.0% *** 31.5% *** 12.2% Significant clinical benefit with tocilizumab treatment 70 60 50 ***p<0.0001 40 Patients (%) 30 26.5% 20 10.8% 10 2.0% 0 ACR20 ACR50 ACR70 Cochran-Mantel-Haenszel analysis was used to calculate p-values All comparisons are to placebo + MTX Smolen J, et al.Ann Rheum Dis 2007; 66(Suppl II):87.

  12. Rapid and sustained response with tocilizumab (ACR20) MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 70 60 50 40 Patients (%) 30 20 10 0 0 2 4 8 12 16 20 24 Week Smolen J, et al.Ann Rheum Dis 2007; 66(Suppl II):87.

  13. Rapid onset and sustained action with tocilizumab (DAS28) ~50% of the improvement in DAS28 was observed at 2 weeks MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX 8 Remission (<2.6) 7 6 0.8% 5 DAS28 13.5% 4 27.5% 3 0 0 2 4 8 12 16 20 24 Week Smolen J, et al.Ann Rheum Dis 2007; 66(Suppl II):87.

  14. Rapid and sustained improvement in HAQ score with tocilizumab MTX TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX Week 0 2 4 8 12 16 20 24 0 Minimal clinically important difference (MCID) = –0.22 –0.2 Mean change in HAQ –0.4 –0.6 Alten R, et al. Ann Rheum Dis 2007; 66(Suppl II):428.

  15. TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX Rapid and sustained improvement in SF-36 physical component with tocilizumab 12 10 8 6 Change in score MCID=2.5–5.0 4 2 0 0 4 8 12 16 20 24 Week Alten R, et al. Ann Rheum Dis 2007; 66(Suppl II):428.

  16. TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX FACIT-Fatigue score improvement with tocilizumab 10 8 6 Change in score 4 MCID=4.0 2 0 0 4 8 12 16 20 24 Week Smolen J, et al.Ann Rheum Dis 2007; 66(Suppl II):87.

  17. TCZ 4 mg/kg + MTX TCZ 8 mg/kg + MTX MTX Tocilizumab induces rapid normalisation of CRP levels 3.0 2.5 2.0 Mean CRP levels (mg/dL) 1.5 1.0 0.5 ULN=0.3* 0.0 0 2 4 8 12 16 20 24 ULN = upper limit of normal Week Smolen J, et al.Ann Rheum Dis 2007; 66(Suppl II):87. *Myers GL et al.Circulation 2004;110:545–549.

  18. Adverse events (AEs)

  19. Serious adverse events (SAEs) by system organ class

  20. Safety • Both 8 mg/kg and 4 mg/kg doses of TCZ were generally well tolerated • Similar incidence of SAEs (~6%) for all study groups • Not all led to withdrawal • Frequency of infections was higher than with placebo, but no TB was observed • Increases in cholesterol, but no significant change in atherogenic indices • Transient ALT elevation – no evidence of clinical hepatitis or hepatic failure

  21. Tocilizumab plus MTX provides rapid and significant improvement in disease activity • Clinically important improvement in all signs and symptoms of RA • Clinically important improvement in physical function, fatigue, haemoglobin and DAS28 by 4 weeks • CRP normalised with 8 mg/kg dose • All primary and secondary endpoints were met

  22. Summary • This is the first TCZ study of the Phase III clinical trials programme, demonstrating efficacy and safety in MTX refractory RA patients • Four additional Phase III studies will be presented at a later date in other relevant RA patient populations (DMARD IR, TNF- IR, MTX IR, MTX naïve) • The high efficacy of TCZ confirms the important role of IL-6 receptor signalling in the pathophysiology of RA

  23. Acknowledgements Participating centres Austria: Smolen Eberl Dunky Köller Zamani Australia: Taylor Nash Smith Bulgaria: Yaneva Oparanov Karastatev Brazil: Simon Scheinberg Canada: Atkins Beaulieu Bell Haraoui Zummer Klinkhoff Martin Thorne Khraishi Mckendry Pandith Mccarthy Switzerland: Dudler Villiger Hong Kong: Lau Li Mok Germany: Alten Fiehn Heilig Lorenz Hellmich Lange Rubbert-Roth Wendler France:Kahan Bardin Nguyen Berenbaum Wendling Claudepierre Puechal Hungary: Czirjak Hodinka Szekanecz Italy: Marcolongo Bagnatoa Triolo Trotta Sechi Israel: Molad Balbir Gurman Rosner Rubinow Abu Shakra Elkayam Mexico: Ramos-Remus Lugo Silveira Abud-Mendoza Pacheco Garcia De La Torre Argentina: Tate Scali Maldonado-Cocco Singapore: Leng Koh Slovakia: Rovensky Thailand: Louthrenoo Asavatanabodee Nilganuwong Totemchokchaiyakarn

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