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A Quintet of Trials: Part 3 RADIATE Beyond TNF Antagonists. P Emery University of Leeds, Leeds, UK. Currently available biologics target the cytokines TNF-  and IL-1, or T cells or B cells

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slide2
Currently available biologics target the cytokines TNF- and IL-1, or T cells or B cells

However, approximately 30–40% of RA patients do not achieve adequate disease control with currently available TNF-blocking therapy1

Due to lack of alternative treatment options, for many years switching from one TNF antagonist to another has become an established phenomenon, although there is only one formal randomised trial

Background

1. Voll RE & Kalden JR. Ann N Y Acad Sci 2005; 1051:799–810.

slide3

RADIATE: Study design

Randomisation

Patients with moderate to severe RA who had an inadequate clinical response (95%) or who were intolerant to 1 TNF antagonist and who were receiving a stable dose of MTX

Placebo + MTX (n=160)*

TCZ 4 mg/kg + MTX (n=163)

N=499

TCZ 8 mg/kg + MTX (n=175)

Week

0

4

8

12

16

20

24

IV infusion

Patients who did not achieve a 20% improvement from baseline in both SJC and TJC at Week 16 were offered rescue therapy (TCZ 8 mg/kg + MTX)Early withdrawals and patients on rescue therapy were considered non-responders for ACR and EULAR analyses

* One patient withdrawn before study treatment due to latex allergySJC=swollen joint countTJC=tender joint count

Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

slide4

Baseline demographics were balanced over all three arms

Data shown as mean except where indicated

Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

slide6

Baseline disease characteristics were similar for all three study arms

Data shown as meanSJC=swollen joint count; TJC=tender joint count HAQ–DI=health assessment questionnaire – disability indexESR=erythrocyte sedimentation rate

Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

radiate patient disposition
RADIATE: Patient disposition

Enrolled N=499

Placebo + MTXn=160

TCZ 4 mg/kg + MTXn=163

TCZ 8 mg/kg + MTXn=175

30 withdrew

24 withdrew

23 withdrew

Rescue therapyn=66

Rescue therapyn=20

Rescue therapy n=31

3 withdrew

1 withdrew

0 withdrew

Completed 24 weeksn=138

Completed 24 weeksn=152

Completed 24 weeksn=127

Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

slide8

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

TCZ significantly improved signs and symptoms compared with MTX alone at Week 24

p<0.0001

p<0.0001

p=0.0002

60

50.0%

50

p<0.0001

40

30.4%

28.8%

Patients (%)

30

20

16.8%

12.4%

10.1%

10

5.0%

3.8%

1.3%

0

ACR20

ACR50

ACR70

ACR70

Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

slide9

Rapid ACR responses with TCZ compared with MTX alone

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

70

ACR70

ACR50

ACR20

60

***

50

40

Patients (%)

***

***

30

20

***

**

10

0

2

12

24

2

12

24

2

12

24

Time (weeks)

** p<0.001 vs. placebo*** p<0.0001 vs. placebo

Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

slide10

Significant improvements in DAS28 at Week 24

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

0.0

–0.5

–1.0

–0.95

–1.5

Mean change in DAS28

–2.0

–2.04

–2.5

–3.0

p<0.0001

–3.16

–3.5

p<0.0001

ANOVA results (ITT)

Roche. Data on file.

slide11

Continued improvements in DAS28 with TCZ compared with MTX over time

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

8

7

6

Mean DAS28

5

4

3

0

4

8

12

16

20

24

Time (weeks)

Roche. Data on file.

slide12

More patients were in DAS28 remission (DAS28 <2.6) with TCZ at Week 24

p=0.0001

40

p=0.05

30.1%

30

Patients (%)

20

10

7.6%

1.6%

0

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

Placebo + MTX (n=158)

Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

slide13

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

TCZ improved symptoms at Week 24 irrespective of the number of prior anti-TNFs

IR tothree TNFantagonists

IR totwo TNFantagonists

IR to oneTNF antagonist

60

53.8%

50.0%

48.9%

50

40

34.6%

28.3%

Patients with ACR20 response (%)

30

22.2%

20

10.5%

10.9%

10

5.6%

0

n=

76

91

93

64

60

52

18

18

26

IR=inadequate response

Emery P, et al. Ann Rheum Dis 2008; 67:15161523.

slide14

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

TCZ improved DAS28 remission rates (DAS28 <2.6) at Week 24 irrespective of the number of prior anti-TNFs

IR tothree TNFantagonists

IR totwo TNFantagonists

IR to oneTNF antagonist

40

35

31.4%

30.9%

30

25.0%

25

Patients (%)

20

15

10

8.6%

8.3%

5

2.9%

0%

0%

0%

0

n=

76

91

93

64

60

52

18

18

26

IR=inadequate response

Roche. Data on file.

slide15

Rapid and durable normalisation of CRP levels with TCZ 8 mg/kg

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

3.0

2.5

2.0

Median CRP level (mg/dl)

1.5

1.0

0.5

ULN

0

0

4

8

12

16

20

24

Time (weeks)

ULN=upper limit of normal CRP=C-reactive protein

Roche. Data on file.

slide16

TCZ induced significant improvements in haemoglobin levels compared with MTX

p<0.0001

1.4

1.19

1.2

p=0.001

1.0

0.8

Mean change from baseline in haemoglobin at Week 24 (g/dl)

0.6

0.45

0.4

0.2

Placebo + MTX (n=158)

0

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

–0.29

Roche. Data on file.

effect of biologics on haemoglobin levels
Effect of biologics on haemoglobin levels

2.0

TCZ

Infliximab

Adalimumab

1.5

1.06

Mean change from baseline in haemoglobin (g/dl)

1.0

0.79

0.60

0.5

0.40

0.40

0.10

N=24

0

N=25

DMARD failures1(N=1,406)

DMARD failures2

Active RA3(N=832)

DMARD

failures4(N=209)

Active RA5(N=318)

The population, duration of treatment and dose varied between studies

1. Roche. Data on file. 2. Elliot MJ, et al. Lancet 1994; 344:1105–1110. 3. Doyle MK, et al. Ann Rheum Dis 2007; 66 (suppl. II):168. 4. Weinblatt ME, et al. Arthritis Rheum 2003; 48:35–45. 5. Furst DE, et al. J Rheumatol 2003; 30:2563–2571.

anaemia of chronic inflammation is commonly observed in ra
Anaemia of chronic inflammation is commonlyobserved in RA

Hepcidin inhibits:

Release of iron from macrophages (reticuloendothelial block)

Absorption of dietary iron (iron deficiency)

Inflammation

Macrophage iron release

IL-6

Hepcidin

Macrophage

Hepatocytes

Intestinal iron absorption

Adapted from: Andrews NC. J Clin Invest 2004; 113:1251–1253. Nemeth E, et al.J Clin Invest2004; 113:1271–1276.

slide19

Patients receiving TCZ reported a significant improvement in physical function

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

Time (weeks)

0.1

4

8

12

16

20

24

0.0

–0.1

Mean change in HAQ–DI

MCID=0.221

–0.2

–0.3

–0.4

–0.5

Roche. Data on file.

1. Wells G, et al. J Rheumatol 1993; 20:557–560.

MCID=minimal clinically important difference

slide20

FACIT-Fatigue scores were significantly increased, with greatest improvements in the TCZ group

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

12

*

10

8

Mean change from baseline in FACIT-Fatigue score

6

MCID=5.0

4

2

0

0

4

8

12

24

16

20

Time (weeks)

* p<0.05 vs. placebo

Mean baseline FACIT-Fatigue score 22.7−23.4

Roche. Data on file.

slide21

TCZ induced rapid improvements in SF-36 scores

Placebo + MTX (n=158)

TCZ 4 mg/kg + MTX (n=161)

TCZ 8 mg/kg + MTX (n=170)

PCS

MCS

10

6

8

MCID=2.5–5.01,2

4

6

Mean change from baseline in SF-36 PCS score

Mean change from baseline in SF-36 MCS score

4

2

MCID=2.5–5.01,2

2

0

0

12

4

0

8

16

24

20

0

4

8

16

20

24

12

Time (weeks)

Time (weeks)

Roche. Data on file.

1. Lubeck DP. Pharmacoeconomics 2004; 22 (suppl. 1):27–38. 2. Kosinski M, et al. Arthritis Rheum 2000; 43:1478–1487.

PCS=physical component summary scoreMCS=mental component summary score

slide22

TCZ was well tolerated compared with MTX treatment

Pooled Phase III safety data will be presented in subsequent sessionsAE=adverse event

Roche. Data on file.

slide23
ACTEMRA provides rapid and significant improvement in the signs and symptoms of RA in TNF-IR patients

ACR20/50/70 responses indicate superiority of ACTEMRA + MTX over placebo + MTX in TNF-IR patients

ACTEMRA 8 mg/kg + MTX achieves DAS28 remission in 30% of cases, a significantly higher proportion of TNF-IR patients compared with placebo + MTX

ACTEMRA is efficacious irrespective of the number of prior TNF antagonists, although the level of efficacy tends to be lower after failure with three prior TNF antagonists

RADIATE Beyond TNF Antagonists: Summary

TNF-IR patients=patients with an inadequate response to TNF antagonists

slide24
ACTEMRA in combination with MTX has demonstrated significant improvements across a range of outcomes in TNF-IR patients

ACTEMRA was well tolerated and did not increase the risk of infections

ACTEMRA represents a significant advance in the treatment of RA patients with an inadequate response to TNF antagonists

RADIATE Beyond TNF Antagonists: Conclusions

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