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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

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
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.

the option study
The OPTION study
  • TOcilizumab
  • Pivotal
  • Trial in methotrexate
  • Inadequate
  • RespONders
study population
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
main objectives
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
study design 1
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
study design 2
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

key inclusion criteria
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
enrolment randomisation and study completion
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

significant clinical benefit with tocilizumab treatment

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.

rapid and sustained response with tocilizumab acr20
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.

rapid onset and sustained action with tocilizumab das28
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.

rapid and sustained improvement in haq score with tocilizumab
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.

rapid and sustained improvement in sf 36 physical component with tocilizumab

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.

facit fatigue score improvement with tocilizumab

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.

tocilizumab induces rapid normalisation of crp levels

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.

safety
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
tocilizumab plus mtx provides rapid and significant improvement in disease activity
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
summary
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
acknowledgements
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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