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

Professor Norihiro Nishimoto
Osaka University,
Osaka, Japan
Tocilizumab: Humanised anti-IL-6R antibody
             MOUSE    CHIMERIC   HUMANISED
                                     CDR



      Fab


            Fc

 Antigenicity
 in human
                             Anti-IL-6R antibody
         Murine protein
                                     TCZ
         Human protein
IL-6 signals through membrane-bound
and soluble receptors


              IL-6                          IL-6

    mIL-6R                                          sIL-6R




                       gp130   gp130




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




     mIL-6R                                          sIL-6R




                        gp130        gp130




              Membrane signalling Trans-signalling
The SATORI study
• Study of
• Active controlled
• TOcilizumab monotherapy for
• Rheumatoid arthritis patients
• Inadequately treated with MTX
Efficacy and safety of tocilizumab
monotherapy in MTX inadequate responders
• Double-blind, placebo-controlled study
   Screen   Randomisation                Treatment period                       Open label

                                          Infusions                   Primary endpoint

              TCZ 8 mg/kg +
               MTX placebo




                  MTX +
                 placebo
                              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.
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.
Disposition of patients
                                        Enrolled
                                          127



                MTX group                             TCZ group
                   66                                    61
Not treated 2


    Completed           Withdrawn              Completed      Withdrawn
       33                   31                    54              7
                                    LOE: 20                              LOE:    1
                          Pt’s requests: 3                                 AE:   2
                                      AE: 3                Protocol violation:   2
                      Protocol violation: 4                            Other:    2
                                  Other: 1
Patient demographic and baseline
disease characteristics
                                    MTX                        TCZ 8 mg/kg
Variable
                                   (n=64)                        (n=61)
Female (%)                          75.0                            90.2
Age (mean, years)                   50.8                            52.6
Disease duration (mean, years)       8.7                             8.5
Previous DMARDs (mean)               3.6                             3.3
PSL-equivalent steroid            5.4±2.9                         6.1±2.9
SJC (mean)                       12.7±7.5                        12.4±5.9
TJC (mean)                       14.2±8.6                        13.8±7.5
CRP (mean, mg/dL)                 3.2±2.6                         3.0±2.0
ESR (mean, mm/hr)                 51.9±24                       51.9±27.7
DAS28 (mean)                      6.2±0.9                         6.1±0.9




                                 Nishimoto N, et al. Ann Rheum Dis 2006; 65(Suppl II):59.
Significant clinical responses with
tocilizumab monotherapy
                100      ***                              MTX (n=64)
                                                          TCZ 8 mg/kg (n=61)
                             80.3
                80
                                        ***
 Patients (%)




                60
                                           49.2                          ***
                40
                                                                           29.5
                      25.0
                20
                                    10.9
                                                                   6.3
                 0
                        ACR20         ACR50                          ACR70

***p<0.001                          Nishimoto N, et al. Ann Rheum Dis 2006; 65(Suppl II):59.
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
                                 1.6                         DAS28
       0
             Good/moderate     DAS remission
      –1     EULAR response     (DAS28 <2.6)
                                                            –1.1
      –2

      –3
                                                                     –3.3
      –4

***p<0.001                       Nishimoto N, et al. Ann Rheum Dis 2006; 65(Suppl II):59.
Tocilizumab was very well tolerated
                                       MTX                       TCZ 8 mg/kg
 Variable
                                      (n=64)                       (n=61)
 Pts with at least 1 AE (%)          46 (71.9)                      56 (91.8)
 Nasopharyngitis                     7 (10.9)                       11 (18.0)
 Stomatitis                               –                           7 (11.5)
 Hyperlipidaemia                      1 (1.6)                         4 (6.6)
 Headache                             2 (3.1)                         4 (6.6)
 Rash                                 2 (3.1)                         4 (6.6)
 Diarrhoea                            1 (1.6)                         4 (6.6)
 URTI*                                4 (6.3)                         3 (4.9)



*Upper respiratory tract infection   Nishimoto N, et al. Ann Rheum Dis 2006; 65(Suppl II):59.
Modest laboratory elevations
                                           MTX                TCZ 8 mg/kg
Frequent findings ≥5%; n (%)
                                          (n=64)                (n=61)
Total patients                          15 (23.4)                34 (55.7)
Total cholesterol increased               2 (3.1)                22 (36.1)
LDL increased                             2 (3.1)                17 (27.9)
HDL increased                             2 (3.1)                  4 (6.6)
Triglycerides increased                   2 (3.1)                12 (19.7)
LDH increased                             4 (6.3)                  6 (9.8)
ALT increased                             7 (10.9)                 3 (4.9)
AST increased                             5 (7.8)                  2 (3.3)



                               Nishimoto N, et al. Ann Rheum Dis 2006; 65(suppl II):59.
Modest lipid elevations with tocilizumab but
no change in the atherogenic index
                      250
                            Total cholesterol                                   100
                                                                                      HDL-cholesterol
                                                                                80
                      200
  mg/dL




                                                                        mg/dL
                                                                                60
                      150
                                                                                40

                      100                                                       20
                            0   4   8 12     16    20    24                           0   4   8 12 16 20   24
                                    Week                                                       Week

                      5.0   Atherogenic index*
                                                                                      MTX (n=64)
  Atherogenic index




                                                                                      TCZ 8 mg/kg (n=61)
                      4.0


                      3.0

                                                                   Atherogenic index >4.97 =
                      2.0
                            0   4   8   12        16    20    24   increased risk of IHD
                                     Week
*Atherogenic index = (TC-HDLC)/HDLC
IHD = ischaemic heart disease                                            Nishimoto N, et al. Ann Rheum Dis 2006; 65(suppl II):59.
No significant differences between ALT
levels with tocilizumab versus placebo
• Largely grade 1 with no reported cases of hepatitis
                           30
                                    MTX
ALT concentration (IU/L)




                                    TCZ 8 mg/kg
                           25


                           20


                           15


                           10
                                0   4      8      12          16            20           24          Last
                                                       Week                                          obs
      Mean +/- SEM                                 Nishimoto N, et al. Ann Rheum Dis 2006; 65(Suppl II):59.
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.
Tocilizumab monotherapy to inhibit
progression of structural joint damage in RA
• X-ray reader-blinded study
   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.
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.
Patient disposition
                                        Enrolled
                                          306



                  DMARDs                                      TCZ group
                    148                                          158
                                   Not treated 3                                 Not treated 1




  Completed               Withdrawn                Completed              Withdrawn
  131 (88%)                14 (10%)                134 (85%)               23 (15%)

                                 AE:    5                                         AE: 17
  Insufficient therapeutic response:    3          Insufficient therapeutic response: 1
                  Refused treatment:    4                          Refused treatment: 1
                  Protocol violation:   2                          Protocol violation: 1
                                                                 Anti-TCZ antibodies: 3
Patient demographic and baseline
disease characteristics
                                 DMARDs      TCZ 8 mg/kg
Variable
                                  (n=145)      (n=157)
Female (%)                         82.1         79.6
Age (mean, years)                  53.1         52.9
Disease duration (mean, years)    2.4±1.3      2.2±1.4
Previous DMARDs (mean)              2.8          2.7
SJC (mean)                       11.9±5.5     12.5±6.4
TJC (mean)                       14.4±7.2     15.3±7.3
CRP (mg/dL)                       4.9±2.9      4.7±2.9
ESR (mm/hr)                      71.0±25.2    70.8±27.9
DAS28 (mean)                        6.4          6.5
TSS                              30.6±42.0    28.3±43.9
Rapid and significant clinical response
to tocilizumab monotherapy
                                                                              DMARDs (n=145)
                100
                                                                              TCZ 8 mg/kg (n=157)

                 80                                            ACR20
 Patients (%)




                                                               ACR50         TCZ
                 60

                                                               ACR70
                 40
                                                               ACR20
                 20
                                                               ACR50
                                                                             DMARDs

                  0                                            ACR70
                      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.
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
***p<0.001                                Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.
TSS indicates considerable difference
in favour of tocilizumab

                                70                                    DMARDs (n=143)
  Change from baseline in TSS




                                                                      TCZ (n=157)
                                60
                                50
                                40
                                30
                                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.
Radiographic outcomes show consistent
and significant improvement
                                        **             ***                     *
                                7
    Mean change from baseline




                                6

                                5                                                    DMARDs (n=143)

                                4                                                   TCZ 8 mg/kg (n=157)

                                3

                                2

                                1

                                0
                                    Total Sharp   Erosion score        Joint space
                                      Score                            narrowing

* p<0.05, ** p<0.01, *** p<0.001                        Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.
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.
Low incidence of serious infection with
tocilizumab
Infections and infestations                  Control                    TCZ
Total patients n (%)                          6 (4.1)                 12 (7.6)
Pneumonia                                     2 (1.4)                  3 (1.9)
Upper respiratory tract infection             1 (0.7)                  2 (1.3)
Cellulitis                                        –                    2 (1.3)
Gastroenteritis                               3 (2.1)                  1 (0.6)
Herpes zoster                                 1 (0.7)                  1 (0.6)
Herpes simplex                                    –                    1 (0.6)
Perianal abscess                                  –                    1 (0.6)
Sepsis                                        1 (0.7)                     –
Unidentified infection                            –                    1 (0.6)

                                    Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.
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.
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
Collaborators
Committee                           Investigators
                                    T. Atsumi   (Hokkaido Univ)         A. Kaneko    (Nagoya Medical Center)
Members                             S. Majima   (Hokkaido Univ)         Y. Takagi    (Tonami General
J. Hashimoto (Osaka Univ)           A. Sagawa   (Center for                          Hospital)
N. Miyasaka (Tokyo Medical &                    Rheumatic Dis.          T. Tanaka    (Osaka University)
             Dental Univ)                       Sapporo Yamanoue        Y. Saeki     (South Osaka Medical
K. Yamamoto (Univ of Tokyo)                     Hosp)                                Center)
S. Kawai     (Toho Univ Omori       T. Sasaki   (Tohoku Univ)           H. Sano      (Hyogo College of
             Medical Center)        K. Arai     (Niigata Univ Medical                Medicine)
T. Takeuchi (Saitama Medical                    & Dental Hosp)          T. Matsubara (Matsubara Mayflower
             Center & Sch)          S. Ohta     (Taga General Hosp)                  Hosp)
N. Murata    (Kyowakai Hosp)        T. Mimura   (Saitama Medical        S. Yamana    (Higashi-Hiroshima
                                                Sch)                                 Memorial Hosp)
Coordinating                        T. Takeuchi (Saitama Medical        T. Horiuchi (Kyusyu Univ)
                                                                        T. Syuto     (Kyusyu Univ)
                                                Center & Sch)
X-Ray assessment                    N. Miyasaka (Tokyo Medical          K. Saito     (Univ of Occupational &
                                                                                     Environmental Health)
Désirée van der Heijde                          & Dental Univ)
           (Univ Hosp Maastricht)   M. Hirakata (Keio Univ)             H. Miyahara (Kyushu Medical Center)
                                    N. Kamatani (Tokyo Women’s          M. Kondo     (Kondo clinic of
                                                                                     Rheumatol &
Medical Advisor                     S. Ozaki
                                                Medical Univ)
                                                (St. Marianna Univ)                  Orthopaedics)
N. Nishimoto (Osaka Univ)           S. Tohma    (Sagamihara National    T. Matsuda (Kagoshima Red Cross
                                                Hosp)                                Hosp)
Supervisor                          N. Ishiguro (Nagoya Univ Sch of     Y. Ueki      (Sasebo Central Hosp)
T. Kishimoto (Osaka Univ)                       Medicine)

				
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