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IL-6 Inhibition in RA An Emerging Role for Tocilizumab HIGHLIGHTS FROM EULAR 2008 PRESENTATIONS

IL-6 Inhibition in RA An Emerging Role for Tocilizumab HIGHLIGHTS FROM EULAR 2008 PRESENTATIONS. Three-year extension of the Samurai study: Radiographic findings. Nishimoto et al. EULAR 2008, abstract FRI0153.

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IL-6 Inhibition in RA An Emerging Role for Tocilizumab HIGHLIGHTS FROM EULAR 2008 PRESENTATIONS

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  1. IL-6 Inhibition in RA An Emerging Role for Tocilizumab HIGHLIGHTS FROMEULAR 2008 PRESENTATIONS

  2. Three-year extension of the Samurai study: Radiographic findings Nishimoto et al. EULAR 2008, abstract FRI0153 • The Samurai study was a randomized trial designed to evaluate the effect of tocilizumab (TCZ) on radiographic progression at one year vs. conventional DMARDs in patients with early RA • At the end of the one-year randomized study • 128 patients continued to receive TCZ 8 mg/kg • 113 patients on conventional DMARDs also received TCZ • The 3-year radiographic analysis was based on 212 patients who had radiographic data from baseline, 1 and 3-year visits

  3. Nishimoto et al. EULAR 2008, abstract FRI0153

  4. Patient Disposition Nishimoto et al. EULAR 2008, abstract FRI0153

  5. Nishimoto et al. EULAR 2008, abstract FRI0153

  6. Nishimoto et al. EULAR 2008, abstract FRI0153

  7. Three-year extension of the Samurai study: Radiographic findings • In the TCZ group, 37.5% of patients at 1 year, and 38.3% at 3 years, had no radiographic progression (TSS change equal to or <0.5) • In the DMARDs/TCZ group, 20.7% at 1 year, and 18.5% at 3 years, had no radiographic progression • The yearly progression rate during the 2nd and 3rd year was significantly suppressed in both groups compared with that seen during the randomized trial in the first year • The mean radiographic score changes over 3 years were all significantly lower in the TCZ group than in the DMARDs/TCZ group • Switch from DMARDs to TCZ significantly suppressed radiographic progression but efficacy was less than that in the TCZ group Nishimoto et al. EULAR 2008, abstract FRI0153

  8. Nishimoto et al. EULAR 2008, abstract FRI0153

  9. Three-year extension of the Samurai study: Radiographic findings • TCZ significantly suppressed radiographic progression in this 3-year long-term study • The mean erosion score did not increase at all in the second and third year of TCZ treatment • Early as opposed to late introduction of TCZ was more effective in preventing joint damage Nishimoto et al. EULAR 2008, abstract FRI0153

  10. Three-year extension of the Samurai study: Radiographic findings Nishimoto et al. EULAR 2008, abstract FRI0153

  11. SAMURAI study: Conclusions • TCZ significantly suppressed radiographic progression in this 3-year long-term study • The mean erosion score did not increase at all in the second and third year of TCZ treatment • Early as opposed to late introduction of TCZ was more effective in preventing joint damage Nishimoto et al. EULAR 2008, abstract FRI0153

  12. Rapid Improvement in Signs and Symptoms of RA with Tocilizumab: Pooled Analysis of OPTION & TOWARD Trials Pooled analysis (ITT population) from 1625 patients Treatment regimens OPTION • TCZ 8 mg/kg every 4 weeks + MTX 10 to 25 mg/week • or PBO + MTX 10-25 mg/week TOWARD • TCZ 8 mg/kg every 4 weeks + stable DMARD therapy • or PBO + stable DMARD therapy Beaulieu et al. EULAR 2008, abstract THU0184

  13. Pooled Analysis of OPTION & TOWARD: Results Mean ACR Response differences for TCZ vs. PBO Beaulieu et al. EULAR 2008, abstract THU0184

  14. Pooled Analysis of OPTION & TOWARD: Results Mean treatment response differences for TCZ vs. PBO Beaulieu et al. EULAR 2008, abstract THU0184

  15. Summary • TCZ 8 mg/kg + DMARD therapy produced early, sustained and clinically significant improvements in signs and symptoms of RA compared with controls • Improvement was accompanied by early, rapid and sustained reductions in CRP, suggesting an early and significant effect on inflammation • Rapid increases in hemoglobin suggest that the beneficial effects of TCZ therapy may extend beyond those associated with the joints Beaulieu et al. EULAR 2008, abstract THU0184

  16. Changes in liver enzymes & Bilirubin:Pooled analysis of OPTION & TOWARD • It is crucial to know whether the addition of tocilizumab (TCZ) to DMARD therapy, especially MTX, increases hepatic toxicity over that seen with DMARDs alone • ALT, AST and bilirubin values were pooled from 2, phase III RCT of TCZ, given with stable DMARD therapy, in patients with inadequate response to DMARDs • ALT, AST and bilirubin were monitored throughout the 24-week study Beaulieu et al. EULAR 2008, abstract FRI0173

  17. Results • More patients in the TCZ + DMARD arm had an increase in liver enzymes than in controls during study treatment • Most patients had increases of >1-3 upper limit of normal (ULN) in both treatment groups, with fewer shifts to 3x ULN • A greater proportion of TCZ + DMARD patients with liver enzyme elevations had ≥2 consecutive ALT or AST elevations than controls • Most patients in both treatment groups had normalization of liver enzymes after a single elevation of AST or ALT, with no dose interruption Beaulieu et al. EULAR 2008, abstract FRI0173

  18. Results • Most liver enzymes had returned to baseline by last study observation in patients withdrawn from study because of liver enzyme elevations • One patient in the PBO + DMARD arm discontinued therapy because of an ALT increase >5x ULN • Shifts in total bilirubin to <3x ULN occurred in 9% of TCZ + DMARD vs. <1% for PBO + DMARD Beaulieu et al. EULAR 2008, abstract FRI0173

  19. Results • No patients in the TCZ + DMARD group experienced a simultaneous increase in ALT and AST to 3x ULN or greater and an increase in total bilirubin ≥ 2x ULN • No clinical signs of hepatic injury were observed in patients with increases in ALT, AST and total bilirubin Beaulieu et al. EULAR 2008, abstract FRI0173

  20. Efficacy Data Based on ACR Criteria:Pooled analysis of OPTION & TOWARD Trials This pooled ITT analysis included 1625 patients: • 1008 treated with TCZ + DMARD • 617 treated with PBO + DMARD Efficacy according to ACR20, ACR50 and ACR70 responses Adjusted mean changes from baseline in core ACR response criteria were also evaluated at each visit Genovese et al. EULAR 2008, abstract THU0185

  21. ACR Response Rates at Week 24 34% 29% 18% Genovese et al. EULAR 2008, abstract THU0185

  22. Pooled analysis of OPTION & TOWARD:Efficacy Mean treatment differences at week 24 (All in favor of TCZ + DMARD) Genovese et al. EULAR 2008, abstract THU0185

  23. Summary • TCZ + DMARD produced clinically significant reductions in signs and symptoms of RA vs. DMARD alone in patients with an inadequate response to previous DMARD therapy • There were significant improvements from baseline in all core ACR response criteria and this effect improved throughout the 24-week study • Pooled data support the use of TCZ for DMARD- unresponsive patients with moderate to severe RA Genovese et al. EULAR 2008, abstract THU0185

  24. A PK/PD analysis of the relationship between tocilizumab concentration and efficacy • This analysis described the relationship between TCZ concentrations and efficacy, as assessed by DAS28 over 24 weeks using a population PK/PD model • The PK/PD model was used to simulate DAS 28 time profiles in patients treated with TCZ 8 mg/kg or 4 mg/kg for 24 weeks • 12,618 DAS28 observations from 1703 patients were used for model development • OPTION (4153 observations from 572 patients) • TOWARD (8465 observations from 1131 patients For external validation, 2350 observations from 443 patients in the RADIATE Trial were used. Levi et al. EULAR 2008, abstract THU0174

  25. A PK/PD analysis of the relationship between tocilizumab concentration and efficacy • Relationships between cumulative TCZ exposure for serum concentration-time profiles and DAS28 time course were assessed and stratified into low, medium and high exposure categories. • An exposure-response relationship was observed between TCZ treatment and DAS28 reduction, with clear differences between the lowest and medium TCZ exposure categories Levi et al. EULAR 2008, abstract THU0174

  26. A PK/PD analysis of the relationship between tocilizumab concentration and efficacy • The maximal effect of TCZ was estimated at 72.5%, corresponding to a maximum 5-point DAS reduction for a typical initial baseline DAS28 of 6.8, with low inter-patient variability • The effect of DMARD background therapy represented only a small fraction of the total effect on DAS28 observed for the two TCZ doses (estimated 0.8 point DAS reduction from baseline) Levi et al. EULAR 2008, abstract THU0174

  27. Effect of tocilizumab (TCZ) exposure on mean DAS28 response Levi et al. EULAR 2008, abstract THU0174

  28. Proportion of patients achieving DAS28 remission and good EULAR response according to tocilizumab dosage: Simulation results Levi et al. EULAR 2008, abstract THU0174

  29. Conclusions • TCZ serum concentration levels were predictive of reduction in DAS28 • Serum concentrations corresponding to TCZ 8 mg/kg were more effective in reducing disease activity than those corresponding to 4 mg/kg Levi et al. EULAR 2008, abstract THU0174

  30. Improvement in hemoglobin and FACIT-fatigue score: Pooled analysis of OPTION & TOWARD • A common type of anemia in RA is anemia of chronic inflammation • IL-6 is a key mediator of this anemia, stimulating production of acute phase proteins including hepcidin, a hormone that blocks iron transport • Inhibition of hepcidin production by tocilizumab (TCZ), an IL-6 inhibitor, should improve iron transport from the gut Smolen et al. EULAR 2008, abstract THU0168

  31. Improvement in Hb and FACIT-fatigue score: Pooled analysis of OPTION & TOWARD • A total of 1008 TCZ + DMARD patients and 617 controls were included in this ITT pooled analysis • In patients with Hb below the lower limit of normal (LLN) at baseline, TCZ + DMARD rapidly increased Hb levels and they remained stable and within the normal range across time • In patients with Hb above the LLN at baseline, TCZ + DMARD slightly increased Hb at treatment onset and they remained stable within the normal range across time • In patients with very low baseline Hb (8.5-10 g/dL) mean change in Hb at week 24 was significantly greater with TCZ + DMARD at 2.55 g/dL vs 0.34 g/dL for controls Smolen et al. EULAR 2008, abstract THU0168

  32. Improvement in Hb and FACIT-fatigue score: Pooled analysis of OPTION & TOWARD Smolen et al. EULAR 2008, abstract THU0168

  33. Changes from baseline in FACIT fatigue scoreaccording to improvements in Hb from baseline to Week 24 of <1.0 g/dL and ≥1.0 g/dL Smolen et al. EULAR 2008, abstract THU0168

  34. Hb levels over time (g/dL) Smolen et al. EULAR 2008, abstract THU0168

  35. Changes from baseline in DAS28 score according to improvements in Hb from baseline toWeek 24 of <1.0 g/dL and ≥1.0 g/dL Smolen et al. EULAR 2008, abstract THU0168

  36. Improvement in Hb and FACIT-fatigue Score: Pooled Analysis of OPTION & TOWARD • Mean change in FACIT-fatigue scores at week 24 were significantly greater in TCZ + DMARD patients than controls, especially in patients who experienced at 1.0 g/dL or greater increase in Hb over BSE • TCZ + DMARD patients with a 1.0 g/dL or greater increase in Hb at week 24 had significantly greater improvements in FACIT-fatigue scores than those with <1.0 g/dL increase in Hb • Control patients with a 1.0 g/dL or greater increase in Hb at week 24 experienced greater FACIT-fatigue improvements compared with those with < 1.0 g/dL increase but the difference was not significant. Smolen et al. EULAR 2008, abstract THU0168

  37. Improvement in Hb and FACIT-fatigue Score: Pooled Analysis of OPTION & TOWARD • In both treatment groups, patients who achieved a greater improvement in DAS28 score tended to experience a greater improvement in Hb • This observation suggests that a reduction in disease activity may be associated with improved Hb levels • Normalization of Hb in anemic RA patients may be a suitable marker of disease activity • Fatigue improves along with improving Hb levels and reduced disease activity Smolen et al. EULAR 2008, abstract THU0168

  38. Pooled analysis of OPTION & TOWARD: Baseline neutrophil counts and serious infections • The immunomodulatory effects of biologic therapies may increase the risk of serious infections • IL-6 also plays a pivotal role in regulating the immune system • This analysis examined baseline characteristics and neutrophil counts in patients who developed serious infections in OPTION & TOWARD Smolen et al. EULAR 2008, abstract THU0169

  39. Pooled analysis of OPTION & TOWARD: Baseline neutrophil counts and serious infections • Serious infections were defined as those leading to death or hospitalization or requiring iv antibiotics • Neutrophil counts were determined at baseline, and then every 2 weeks until week 16 then every 4 weeks until week 32 • A total of 1008 patients on TCZ + DMARD and 618 PBO + DMARD controls were included in this analysis Smolen et al. EULAR 2008, abstract THU0169

  40. Pooled analysis of OPTION & TOWARD: Baseline neutrophil counts and serious infections Smolen et al. EULAR 2008, abstract THU0169

  41. Pooled analysis of OPTION & TOWARD: Baseline neutrophil counts and serious infections Smolen et al. EULAR 2008, abstract THU0169

  42. Pooled analysis of OPTION & TOWARD: Baseline neutrophil counts and serious infections • The proportion of patients with diabetes at BSE was higher among those who developed a serious infection • Patients receiving corticosteroids were also over-represented among those who developed serious infections • There was no indication that a low neutrophil count increased the risk of serious infections Smolen et al. EULAR 2008, abstract THU0169

  43. Reduction in inflammatory biomarkers with increasing exposure to tocilizumab: Pooled data • Data were pooled from 4 RCTs evaluating tocilizumab (TCZ) ± DMARD therapy • A total of 2243 patients were included in the graphic analysis: • 833 controls • 201 in low TCZ exposure • 539 in medium TCZ exposure • 670 in high TCZ exposure • The purpose of this analysis was to investigate treatment effect on main biomarkers of inflammation Levi et al. EULAR 2008, abstract THU0177

  44. Reduction in inflammatory biomarkers with increasing exposure to tocilizumab: Pooled data Levi et al. EULAR 2008, abstract THU0177

  45. Reduction in inflammatory biomarkers with increasing exposure to tocilizumab: Pooled data • Across all 4 studies, increased exposure to TCZ was associated with a decrease in CRP, ESR and SAA levels • High TCZ exposure was associated with a pronounced reduction in CRP levels by week 2 • The effect of TCZ on CRP persisted throughout the 24-week trials Levi et al. EULAR 2008, abstract THU0177

  46. Reduction in inflammatory biomarkers with increasing exposure to tocilizumab: Pooled data • Upper limit of normal levels of CRP, ESR and SAA were more likely to be sustained between consecutive infusions with increasing TCZ exposure • TCZ 8 mg/kg led to more persistent reductions in inflammatory biomarkers compared with 4 mg/kg • TCZ’s consistent effect on CRP from week 2 likely reflects not only a decrease in inflammation but also inhibition of hepatic IL-6R signaling and consequent decrease in CRP synthesis Levi et al. EULAR 2008, abstract THU0177

  47. IL-6 Inhibition with tocilizumab:Summary of findings • Radiographic • Tocilizumab significantly suppressed radiographic progression for 3 years of follow-up and the mean erosion score remained stable • Early introduction of TCZ protects joints more effectively than late introduction

  48. IL-6 Inhibition with tocilizumab:Summary of findings Safety Profile • More pts on TCZ/DMARD arm had liver enzyme increases, however, in most AST and ALT levels normalized during continued therapy, with few patients having dose interruptions • No drug-induced hepatic injury observed • Patients with diabetes as well as those receiving corticosteroid were over-represented among those who are at risk for serious infection • There was no indication that a low neutrophil count increases the risk of serious infections

  49. IL-6 Inhibition with tocilizumab:Summary of findings • Efficacy • Tocilizumab produced significant improvements in all core ACR response criteria • In patients with an inadequate response to previous DMARD therapy, the TCZ/DMARD combination produced clinically significant reductions in signs and symptoms of RA vs. DMARD alone • More patients achieved DAS28 and DAS28 < 2.6 with TCZ + DMARD than DMARD alone • Pooled data support the use of the TCZ/DMARD combination for DMARD-unresponsive patients with moderate to severe RA

  50. IL-6 Inhibition with tocilizumab:Summary of findings PK/PD profile • TCZ serum concentration levels were predictive of reduction in DAS28 • Serum concentrations corresponding to TCZ 8 mg/kg were more effective in reducing disease activity than at 4 mg/kg • Across all 4 studies, increased exposure to TCZ was associated with a decrease in CRP, ESR and SAA levels • High TCZ exposure was associated with a pronounced reduction in CRP levels by week 2 • Upper limit of normal levels of CRP, ESR and SAA were more likely to be sustained between consecutive infusions with increasing TCZ exposure

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