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A Quintet of Trials: Parts 1 & 2 TOWARD a New Future and a New OPTION in RA. K Pavelka Institute of Rheumatology and Clinic of Rheumatology, Charles University, Prague, Czech Republic. The OPTION and TOWARD studies. 1. Smolen JS, et al. Lancet 2008; 371 :987 997.

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A quintet of trials parts 1 2 toward a new future and a new option in ra

A Quintet of Trials: Parts 1 & 2TOWARD a New Future and a New OPTION in RA

K PavelkaInstitute of Rheumatology and Clinic of Rheumatology, Charles University, Prague, Czech Republic


The option and toward studies
The OPTION and TOWARD studies

1. Smolen JS, et al. Lancet 2008; 371:987997.

2. Genovese MC, et al. Arthritis Rheum 2008; 58:29682980.


The option and toward studies1
The OPTION and TOWARD studies

International, randomised, double-blind, placebo-controlled, Phase III clinical trials in patients with moderate to severe RA of ≥6 months’ duration who had an inadequate response to prior DMARD therapy

Patients unsuccessfully treated with an anti-TNF agent were excluded

OPTION

TCZ + MTX vs. placebo + MTX

TOWARD

TCZ + traditional DMARDs vs. placebo + traditional DMARDs

1. Smolen JS, et al. Lancet 2008; 371:987997.

2. Genovese MC, et al. Arthritis Rheum 2008; 58:29682980.


Baseline disease characteristics were well balanced between treatment groups itt
Baseline disease characteristics were well balanced between treatment groups (ITT)

Data shown as mean; pooled analysis of OPTION and TOWARD

SJC=swollen joint countTJC=tender joint count HAQ=health assessment questionnaireCRP=C-reactive proteinESR=erythrocyte sedimentation rate

Roche. Data on file.Genovese M et al. EULAR Congress 11-14 June 2008 Poster THU0185.


Option and toward study designs
OPTION and TOWARD: Study designs

Screening

Treatment period

TCZ 8 mg/kg + MTX (n=205)

Randomisation (n=623)

OPTION

TCZ 4 mg/kg + MTX (n=214)

R

1:1:1

Placebo + MTX (n=204)

TCZ 8 mg/kg + DMARDs (n=803)

TOWARD

Randomisation (n=1,220)*

2:1

R

Placebo + DMARDs (n=413)

Infusions

Week

0

2

4

6

8

10

12

14

16

18

20

22

24

Rescue therapy

*Two patients randomised to placebo + DMARDs and two patients randomised to TCZ 8 mg/kg + DMARDs were not dosed

1. Smolen JS, et al. Lancet 2008; 371:987997. 2. Genovese MC, et al. Arthritis Rheum 2008; 58:29682980.


Pooled analysis
Pooled analysis

The primary endpoint was the proportion of patients achieving ACR20 at Week 24

Patients from both studies who received TCZ 8 mg/kg or placebo (plus DMARDs/MTX) were included in the pooled analysis (ITT population)

All subsequent data slides show data from the pooled analysis of OPTION and TOWARD

6


Option patient disposition
OPTION: Patient disposition

EnrolledN=623

Placebo + MTXn=204

TCZ 4 mg/kg + MTXn=214

TCZ 8 mg/kg + MTX n=205

12 withdrew

25 withdrew

13 withdrew

Rescue therapyn=68

Rescue therapy n=31

Rescue therapy n=19

3 withdrew

3 withdrew

1 withdrew

Completed 24 weeks191 (93%)

Completed 24 weeks189 (93%)

Completed 24 weeks186 (87%)

Smolen JS, et al. Lancet 2008; 371:987997.


Toward patient disposition
TOWARD: Patient disposition

EnrolledN=1,220

Placebo + DMARDsn=415

TCZ 8 mg/kg + DMARDsn=805

2 received no study medication

2 received no study medication

53 withdrew

43 withdrew

Rescue therapy n=19

Rescue therapyn=45

Completed 24 weeksn=370 (89%)

Completed 24 weeksn=751 (93%)

Genovese MC, et al. Arthritis Rheum 2008; 58:29682980.


Baseline demographics were well balanced between treatment groups itt
Baseline demographics were well balanced between treatment groups (ITT)

Data shown as mean except where indicated

Genovese M et al. EULAR Congress 11-14 June 2008 Poster THU0185.


Concomitant dmards at baseline itt toward study
Concomitant DMARDs at baseline (ITT) (TOWARD study*) groups (ITT)

* All patients were receiving MTX only at baseline in the OPTION study

Smolen J et al.EULAR Congress 11-14 June 2008; Abstract: FRI0172.


A significant improvement in acr criteria was seen with tcz treatment
A significant improvement in ACR criteria was groups (ITT)seen with TCZ treatment

TCZ 8 mg/kg + DMARDs (n=1,008)

Placebo + DMARDs (n=617)

p<0.0001

p<0.0001

p<0.0001

70

60.3%

60

50

38.9%

40

Patients (%)

30

25.1%

20.8%

20

9.6%

10

2.6%

0

ACR20

ACR50

ACR70

Data shown for ACR responses at Week 24

Genovese M, et al. EULAR Congress 11-14 June 2008; Abstract THU0185.


The acr response to tcz was rapid and sustained
The ACR response to TCZ was rapid and sustained groups (ITT)

Placebo + DMARDs (n=617)

TCZ 8 mg/kg + DMARDs (n=1,008)

ACR20

ACR20

70

60

50

40

Patients (%)

30

20

10

0

0

4

8

12

16

20

24

Time (weeks)

Beaulieu A, et al. EULAR Congress 11-14 June 2008; Abstract THU0184.


The acr response to tcz was rapid and sustained1
The ACR response to TCZ was rapid and sustained groups (ITT)

Placebo + DMARDs (n=617)

TCZ 8 mg/kg + DMARDs (n=1,008)

ACR20

ACR20

ACR50

ACR50

70

60

50

40

Patients (%)

30

20

10

0

0

4

8

12

16

20

24

Time (weeks)

Beaulieu A, et al. EULAR Congress 11-14 June 2008; Abstract THU0184.


The acr response to tcz was rapid and sustained2
The ACR response to TCZ was rapid and sustained groups (ITT)

Placebo + DMARDs (n=617)

TCZ 8 mg/kg + DMARDs (n=1,008)

ACR20

ACR20

ACR50

ACR50

ACR70

ACR70

70

60

50

40

Patients (%)

30

20

10

0

0

4

8

12

16

20

24

Time (weeks)

Beaulieu A, et al. EULAR Congress 11-14 June 2008; Abstract THU0184.


Das28 scores improved rapidly with tcz treatment
DAS28 scores improved rapidly with TCZ treatment groups (ITT)

TCZ 8 mg/kg + DMARDs (n=1,008)

Placebo + DMARDs (n=617)

7

6

∆ = –1.25

5

Mean DAS28

4

∆ = –3.18

3

4

8

12

16

20

24

0

Time (weeks)

Roche. Data on file.


Significantly more patients were in das28 remission das28 2 6 at week 24 with tcz
Significantly more patients were in DAS28 remission (DAS28 <2.6) at Week 24 with TCZ

p<0.0001

35

29.7%

30

25

20

Patients (%)

15

10

5

2.7%

0

Placebo + DMARDs (n=617)

TCZ 8 mg/kg + DMARDs (n=1,008)

Smolen J et al.EULAR Congress 11-14 June, 2008; Abstract: FRI0172.


More patients had a clinical response by eular response criteria at week 24 with tcz
More patients had a clinical response by EULAR response criteria at Week 24 with TCZ

Patients with a good/moderate response

79.7%

80

70

60

50

40

36.6%

Patients (%)

30

20

10

0

Placebo + DMARDs (n=617)

TCZ 8 mg/kg + DMARDs (n=1,008)

Smolen J et al.EULAR Congress 11-14 June, 2008; Abstract: FRI0172.


Eular response was rapid and sustained with tcz
EULAR response was rapid and sustained with TCZ criteria at Week 24 with TCZ

TCZ 8 mg/kg + DMARDs (n=1,008)

Placebo + DMARDs (n=617)

Patients with a good/moderate response

90

80

79.7%

70

60

Patients (%)

50

40

36.6%

30

20

10

0

0

4

8

12

16

20

24

Time (weeks)

Roche. Data on file.


Tcz induced rapid and sustained normalisation of crp levels
TCZ induced rapid and sustained normalisation criteria at Week 24 with TCZof CRP levels

TCZ 8 mg/kg + DMARDs (n=1,008)

Placebo + DMARDs (n=617)

3.0

2.5

2.0

∆ = –0.387

Mean CRP levels (mg/dl)

1.5

1.0

ULN

∆ = –2.337

0.5

0.0

0

4

8

12

16

20

24

Time (weeks)

ULN=upper limit of normal

Genovese M, et al. EULAR Congress 11-14 June 2008; Abstract THU0185.


Tcz has the potential to reverse chronic anaemia
TCZ has the potential to reverse chronic anaemia criteria at Week 24 with TCZ

TCZ treatment increased levels of haemoglobin compared with DMARD therapy alone

Greatest improvement in patients with baseline haemoglobin level <LLN

Placebo + DMARDs (n=132*)

TCZ 8 mg/kg + DMARDs (n=208*)

16

15

14

Haemoglobin level (g/dl)

13

∆ = 1.6029

12

11

0

4

8

12

16

20

24

Time (weeks)

* Patients with haemoglobin <LLN at baselineLLN=lower limit of normal

Smolen J et al.EULAR Congress 11-14 June, 2008; Abstract: THU0168.


Facit fatigue scores at week 24 were significantly improved with tcz
FACIT-Fatigue scores at Week 24 were significantly improved with TCZ

p<0.0001

10.0

8.04

7.5

Mean change from baseline in FACIT-Fatigue score

MCID=5.0

5.0

3.69

2.5

0

Placebo + DMARDs (n=617)

TCZ 8 mg/kg + DMARDs (n=1,008)

MCID=minimal clinically important difference

Roche. Data on file.


Disability was significantly improved at week 24 for tcz treated patients
Disability was significantly improved at Week 24 for TCZ-treated patients

p<0.0001

80

67.9%

60

49.9%

Patients with an improvement in

HAQ-DI score ≥0.25 at Week 24 (%)

40

20

0

Placebo + DMARDs (n=617)

TCZ 8 mg/kg + DMARDs (n=1,008)

HAQ–DI=health assessment questionnaire–disability index

Smolen J et al.EULAR Congress 11-14 June 2008; Abstract AB0353.


Improvements were seen in sf 36 summary scores at week 24 with tcz
Improvements were seen in SF-36 summary scores at Week 24 with TCZ

TCZ 8 mg/kg + DMARDs (n=1,008)

Placebo + DMARDs (n=617)

12

p<0.0001

p<0.0001

10

9.2

8

6.4

Change from baseline in SF-36 scores at Week 24

6

4.7

4

MCID=2.5–5.01–3

3.0

2

0

Physical component score

Mental component score

Alten R et al.EULAR Congress 11-14 June, 2008; Abstract: AB0345.1. Lubeck DP, Pharmacoeconomics 2004;22:27–38.2. Samsa G, et al. Pharmacoeconomics 1999;15:141–55. 3. Kosinski M, et al. Arthritis Rheum 2000;43(7):1478–1487.

MCID=Minimal clinically important difference


The toxicity profile of tcz dmards vs placebo dmards was comparable
The toxicity profile of TCZ + DMARDs vs. with TCZplacebo + DMARDs was comparable

Pooled safety data will be presented in subsequent sessions

AE=adverse event

Smolen J et al.EULAR Congress 11-14 June 2008; Abstract FRI0163.


Serious infections were uncommon
Serious infections were uncommon with TCZ

Pooled safety data will be presented in subsequent sessions

Smolen J et al.EULAR Congress 11-14 June 2008; Abstract FRI0163.


Toward a new future and a new option in ra summary
TOWARD a New Future and a New OPTION in RA: with TCZ Summary

ACTEMRA 8 mg/kg + DMARDs compared with placebo + DMARDs resulted in:

Higher proportion of patients achieving ACR20, ACR50, ACR70 and good/moderate EULAR responses

Higher mean reduction in DAS28

Higher DAS28 remission rates

Rapid reduction in clinical and laboratory variables of inflammation with normalisation of CRP and haemoglobin levels

ACTEMRA 8 mg/kg + DMARDs was well tolerated in patients who had an inadequate response to prior DMARD therapy


Toward a new future and a new option in ra conclusions
TOWARD a new future and a new OPTION in RA: with TCZ Conclusions

ACTEMRA:

Significantly decreased disease activity and this improvement was sustained over 24 weeks

Improved fatigue and reduced inflammation, as demonstrated by rapid and sustained normalisation of CRP levels

Normalised haemoglobin levels in RA patients with chronic anaemia

Led to rapid, sustained and clinically relevant improvement in patient quality of life, as demonstrated by improvements in HAQ-DI and SF-36 scores


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