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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. 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

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

Fab

Fc

Tocilizumab: Humanised anti-IL-6R antibody

CHIMERIC

HUMANISED

CDR

Antigenicity

in human

Anti-IL-6R antibody

TCZ

Murine protein

Human protein


Il 6 signals through membrane bound and soluble receptors

IL-6

IL-6

IL-6 signals through membrane-bound and soluble receptors

sIL-6R

mIL-6R

gp130

gp130

Membrane signalling

Trans-signalling


Tocilizumab binds mil 6r and sil 6r to inhibit il 6r signalling

IL-6

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

sIL-6R

mIL-6R

gp130

gp130

Membrane signalling

Trans-signalling


The satori study
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

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.


Major inclusion criteria
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
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Withdrawn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Withdrawn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


Patient demographic and baseline disease characteristics
Patient demographic and baseline disease characteristics

Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59.


Significant clinical responses with tocilizumab monotherapy

***

***

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


Consistent improvements in disease activity with tocilizumab monotherapy

***

***

***

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


Tocilizumab was very well tolerated
Tocilizumab was very well tolerated

*Upper respiratory tract infection

Nishimoto N, et al.Ann Rheum Dis 2006; 65(Suppl II):59.


Modest laboratory elevations
Modest laboratory elevations

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


Modest lipid elevations with tocilizumab but no change in the atherogenic index

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.


No significant differences between alt levels with tocilizumab versus placebo
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


The samurai study
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

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.


Major inclusion exclusion criteria
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

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


Patient demographic and baseline disease characteristics1
Patient demographic and baseline disease characteristics


Rapid and significant clinical response to tocilizumab monotherapy

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.


Rapid and sustained improvements in das28
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


Tss indicates considerable difference in favour of tocilizumab
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.


Radiographic outcomes show consistent and significant improvement
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


Tocilizumab monotherapy does not significantly increase the incidence of adverse events
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
Low incidence of serious infection with tocilizumab incidence of adverse events

Nishimoto N, et al. Ann Rheum Dis 2007; 66:1162–1167.


Adverse events were largely of mild or moderate severity
Adverse events were largely of mild or moderate severity incidence of adverse events

  • 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
Conclusions incidence of adverse events

  • 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
Collaborators incidence of adverse events

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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