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The new star on the RA horizon: Positive results from SATORI/SAMURAI monotherapy trials

The new star on the RA horizon: Positive results from SATORI/SAMURAI monotherapy trials. Professor Norihiro Nishimoto Osaka University, Osaka, Japan. MOUSE. Fab. Fc. Tocilizumab: Humanised anti-IL-6R antibody. CHIMERIC. HUMANISED. CDR. Antigenicity in human. Anti-IL-6R antibody TCZ.

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The new star on the RA horizon: Positive results from SATORI/SAMURAI monotherapy trials

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  1. The new star on the RA horizon: Positive results from SATORI/SAMURAI monotherapy trials Professor Norihiro Nishimoto Osaka University, Osaka, Japan

  2. MOUSE Fab Fc Tocilizumab: Humanised anti-IL-6R antibody CHIMERIC HUMANISED CDR Antigenicity in human Anti-IL-6R antibody TCZ Murine protein Human protein

  3. IL-6 IL-6 IL-6 signals through membrane-bound and soluble receptors sIL-6R mIL-6R gp130 gp130 Membrane signalling Trans-signalling

  4. IL-6 Tocilizumab binds mIL-6R and sIL-6R to inhibit IL-6R signalling sIL-6R mIL-6R gp130 gp130 Membrane signalling Trans-signalling

  5. The SATORI study • Study of • Active controlled • TOcilizumab monotherapy for • Rheumatoid arthritis patients • Inadequately treated with MTX

  6. TCZ 8 mg/kg + MTX placebo MTX + placebo Efficacy and safety of tocilizumab monotherapy in MTX inadequate responders • Double-blind, placebo-controlled study Screen Randomisation Treatment period Open label Infusions Primary endpoint 0 4 8 12 16 20 24 Week Last observation Primary endpoint: ACR20 response at Week 24 Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59.

  7. Major inclusion criteria • RA diagnosed according to 1987 ACR criteria • Disease duration ≥6 months • Treated with 8 mg/week of MTX for at least 8 weeks • Active disease with: • Tender joints ≥6 • Swollen joints ≥6 • ESR ≥30 mm/hr and CRP ≥1.0 mg/dL Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59.

  8. Disposition of patients Enrolled 127 MTX group 66 TCZ group 61 Not treated 2 Completed 33 Withdrawn 31 Completed 54 Withdrawn 7 LOE: 20 Pt’s requests: 3 AE: 3 Protocol violation: 4 Other: 1 LOE: 1 AE: 2 Protocol violation: 2 Other: 2

  9. Patient demographic and baseline disease characteristics Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59.

  10. *** *** Significant clinical responses with tocilizumab monotherapy *** MTX (n=64) 100 TCZ 8 mg/kg (n=61) 80.3 80 60 49.2 Patients (%) 40 29.5 25.0 20 10.9 6.3 0 ACR20 ACR50 ACR70 Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59. ***p<0.001

  11. *** *** *** Consistent improvements in disease activity with tocilizumab monotherapy MTX (n=64) 96.6 TCZ 8 mg/kg (n=61) 100 80 60 43.1 39.7 40 20 Change in DAS28 1.6 0 Good/moderate EULAR response DAS remission (DAS28 <2.6) –1 –1.1 –2 –3 –3.3 –4 Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59. ***p<0.001

  12. Tocilizumab was very well tolerated *Upper respiratory tract infection Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59.

  13. Modest laboratory elevations Nishimoto N, et al.Ann Rheum Dis 2006; 65(suppl II):59.

  14. 100 80 60 40 20 Modest lipid elevations with tocilizumab but no change in the atherogenic index Total cholesterol HDL-cholesterol 250 200 mg/dL mg/dL 150 100 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Week Week Atherogenic index* 5.0 MTX (n=64) TCZ 8 mg/kg (n=61) 4.0 Atherogenic index 3.0 Atherogenic index >4.97 = increasedrisk of IHD 2.0 0 4 8 12 16 20 24 Week *Atherogenic index = (TC-HDLC)/HDLCIHD = ischaemic heart disease Nishimoto N, et al.Ann Rheum Dis 2006; 65(suppl II):59.

  15. No significant differences between ALT levels with tocilizumab versus placebo • Largely grade 1 with no reported cases of hepatitis 30 MTX TCZ 8 mg/kg 25 ALT concentration (IU/L) 20 15 10 0 4 8 12 16 20 24 Lastobs Week Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59. Mean +/- SEM

  16. The SAMURAI study • Study of • Active controlled • Monotherapy • Used for • Rheumatoid • Arthritis, an • IL-6 inhibitor Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  17. X-ray reader-blinded study Tocilizumab monotherapy to inhibit progression of structural joint damage in RA Screen Randomisation Treatment period Open label Infusions Primary endpoint TCZ 8 mg/kg Conventional DMARDs 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week Last observation Primary endpoint: Change from baseline to Week 52 in TSS Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  18. Major inclusion/exclusion criteria • RA diagnosed according to 1987 ACR criteria • Disease duration ≥6 months and <5 years • Inadequate response to at least one DMARD or immunosuppressant • Active disease with: • Tender joints ≥6 • Swollen joints ≥6 • ESR ≥30 mm/hr and CRP ≥2.0 mg/dL • Use of anti-TNF- agents and leflunomide within 3 months of first dose not permitted Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  19. Enrolled 306 Patient disposition DMARDs 148 TCZ group 158 Not treated 3 Not treated 1 Completed 131 (88%) Withdrawn 14 (10%) Completed 134 (85%) Withdrawn 23 (15%) AE: 5 Insufficient therapeutic response: 3 Refused treatment: 4 Protocol violation: 2 AE: 17 Insufficient therapeutic response: 1 Refused treatment: 1 Protocol violation: 1 Anti-TCZ antibodies: 3

  20. Patient demographic and baseline disease characteristics

  21. DMARDs (n=145) ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 Rapid and significant clinical response to tocilizumab monotherapy 100 TCZ 8 mg/kg (n=157) 80 TCZ 60 Patients (%) 40 20 DMARDs 0 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.

  22. Rapid and sustained improvements in DAS28 DMARDs (n=145) 8 TCZ 8 mg/kg (n=157) Remission 6 3.4% DAS28 4 *** *** *** *** *** 58.6% 2 0 0 4 8 12 24 36 48 52 Week Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167. ***p<0.001

  23. TSS indicates considerable difference in favour of tocilizumab DMARDs (n=143) 70 TCZ (n=157) 60 50 40 30 Change from baseline in TSS 20 10 0 –10 –20 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Cumulative probability Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  24. Radiographic outcomes show consistent and significant improvement ** *** * 7 6 5 DMARDs (n=143) TCZ 8 mg/kg (n=157) 4 Mean change from baseline 3 2 1 0 Total Sharp Erosion score Joint space Score narrowing Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167. * p<0.05, ** p<0.01, *** p<0.001

  25. Tocilizumab monotherapy does not significantly increase the incidence of adverse events • Assessed on the basis of AEs and clinical laboratory results • Overall incidence of AEs, including laboratory abnormalities, was 89% and 82% in the TCZ and DMARD patient groups, respectively • Overall incidence of treatment-emergent serious AEs was 18% and 13% in the TCZ and DMARD patient groups, respectively Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  26. Low incidence of serious infection with tocilizumab Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  27. Adverse events were largely of mild or moderate severity • Mild, transient increases in liver function tests were frequently observed in both groups • Lipid increases were reported in the TCZ group however, atherogenic index remained unchanged Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.

  28. Conclusions • Tocilizumab monotherapy significantly improved signs and symptoms of RA • Tocilizumab monotherapy shows superiority to conventional DMARDs in inhibiting radiographic progression • Tocilizumab monotherapy was generally well tolerated with a safety profile similar to that observed in the Phase II studies • These data strongly support the use of tocilizumab for the treatment of RA

  29. Collaborators Committee MembersJ. Hashimoto (Osaka Univ) N. Miyasaka (Tokyo Medical & Dental Univ) K. Yamamoto (Univ of Tokyo） S. Kawai (Toho Univ Omori Medical Center) T. Takeuchi (Saitama Medical Center & Sch) N. Murata (Kyowakai Hosp) Investigators T. Atsumi (Hokkaido Univ) S. Majima (Hokkaido Univ) A. Sagawa (Center for Rheumatic Dis. Sapporo Yamanoue Hosp) T. Sasaki (Tohoku Univ) K. Arai (Niigata Univ Medical & Dental Hosp) S. Ohta (Taga General Hosp) T. Mimura (Saitama Medical Sch) T. Takeuchi (Saitama Medical Center & Sch) N. Miyasaka (Tokyo Medical & Dental Univ) M. Hirakata (Keio Univ) N. Kamatani (Tokyo Women’s Medical Univ) S. Ozaki (St. Marianna Univ) S. Tohma (Sagamihara National Hosp) N. Ishiguro (Nagoya Univ Sch of Medicine) A. Kaneko (Nagoya Medical Center) Y. Takagi (Tonami General Hospital) T. Tanaka (Osaka University) Y. Saeki (South Osaka Medical Center) H. Sano(Hyogo College of Medicine) T. Matsubara (Matsubara Mayflower Hosp) S. Yamana (Higashi-Hiroshima Memorial Hosp) T. Horiuchi (Kyusyu Univ) T. Syuto (Kyusyu Univ) K. Saito (Univ of Occupational & Environmental Health) H. Miyahara (Kyushu Medical Center) M. Kondo (Kondo clinic of Rheumatol & Orthopaedics) T. Matsuda (Kagoshima Red Cross Hosp) Y. Ueki (Sasebo Central Hosp) Coordinating X-Ray assessment Désirée van der Heijde (Univ Hosp Maastricht) Medical Advisor N. Nishimoto (Osaka Univ） Supervisor T. Kishimoto (Osaka Univ）

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