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A Quintet of Trials: Part 3 RADIATE Beyond TNF Antagonists

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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A Quintet of Trials: Part 3 RADIATE Beyond TNF Antagonists

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  1. A Quintet of Trials: Part 3RADIATE Beyond TNF Antagonists P EmeryUniversity of Leeds, Leeds, UK

  2. 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.

  3. 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withdrawals and patients on rescue therapy were considered non-responders for ACR and EULAR analyses * One patient withdrawn before study treatment due to latex allergySJC=swollen joint countTJC=tender joint count Emery P, et al.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.

  4. 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.

  5. Exposure to prior TNF antagonists Roche. Data on file.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  21. 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

  22. 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.

  23. 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

  24. 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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