Caroline Keane

Efficacy and safety of tocilizumab in patients with polyarticular-course juvenile idiopathic arthritis: results from a phase 3, randomised, double-blind withdrawal trial

Objective To evaluate the interleukin-6 receptor inhibitor tocilizumab for the treatment of patients with polyarticular-course juvenile idiopathic arthritis (pcJIA). Methods This three-part, randomised, placebo-controlled, double-blind withdrawal study (NCT00988221) included patients who had active pcJIA for ≥6 months and inadequate responses to methotrexate. During part 1, patients received open-label tocilizumab every 4 weeks (8 or 10 mg/kg for body weight (BW) <30 kg; 8 mg/kg for BW ≥30 kg). At week 16, patients with ≥JIA-American College of Rheumatology (ACR) 30 improvement entered the 24-week, double-blind part 2 after randomisation 1:1 to placebo or tocilizumab (stratified by methotrexate and steroid background therapy) for evaluation of the primary end point: JIA flare, compared with week 16. Patients flaring or completing part 2 received open-label tocilizumab. Results In part 1, 188 patients received tocilizumab (<30 kg: 10 mg/kg (n=35) or 8 mg/kg (n=34); ≥30 kg: n=119). In part 2, 163 patients received tocilizumab (n=82) or placebo (n=81). JIA flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (difference in means adjusted for stratification: −0.21; 95% CI −0.35 to −0.08; p=0.0024). At the end of part 2, 64.6% and 45.1% of patients receiving tocilizumab had JIA-ACR70 and JIA-ACR90 responses, respectively. Rates/100 patient-years (PY) of adverse events (AEs) and serious AEs (SAEs) were 480 and 12.5, respectively; infections were the most common SAE (4.9/100 PY). Conclusions Tocilizumab treatment results in significant improvement, maintained over time, of pcJIA signs and symptoms and has a safety profile consistent with that for adults with rheumatoid arthritis. Trial registration number: NCT00988221.

A11: Assessment of Radiographic Progression in Patients With Polyarticular‐Course Juvenile Idiopathic Arthritis Treated With Tocilizumab: 2‐Year Data From CHERISH

The phase 3 CHERISH trial demonstrated the efficacy of tocilizumab (TCZ), an interleukin‐6 receptor inhibitor, in patients with polyarticular‐course juvenile idiopathic arthritis (pcJIA). This analysis investigated the progression of radiographic joint damage in patients with pcJIA treated with TCZ for up to 104 weeks in CHERISH.

PReS-FINAL-2180: Efficacy and safety of tocilizumab (TCZ) in patients with polyarticular-course juvenile idiopathic arthritis (pcJIA): 2-year data from CHERISH.

Efficacy and safety of TCZ, an IL-6 receptor inhibitor, were previously demonstrated at wk 40 of CHERISH, a phase 3 trial in patients (pts) with pcJIA [1].

A171: Tocilizumab Dosing in Juvenile Idiopathic Arthritis: Optimizing for Different Juvenile Idiopathic Arthritis Type and Patient Body Weight

Tocilizumab (TCZ), an interleukin‐6 receptor (IL‐6R) inhibitor, is effective in systemic and polyarticular juvenile idiopathic arthritis (sJIA, pJIA). Body weight (BW)‐adjusted intravenous dosing regimens (TCZ 8 mg/kg Q2W for sJIA and Q4W for pJIA) were assessed in Japanese phase 3 trials. In Japanese patients (pts), BW adjustment led to lower TCZ exposure with lower BW; thus, higher doses were proposed for pts with BW <30 kg in the global TENDER (sJIA) and CHERISH (pJIA) trials. Herein, we describe the pharmacokinetics (PK), pharmacodynamics (PD), and exposure‐efficacy/‐safety relationships of adjusted BW‐based TCZ therapy in sJIA/pJIA pts.

PReS-FINAL-2159: Tocilizumab (TCZ) dosing in juvenile idiopathic arthritis (JIA): optimising for different JIA type and body weight patients

TCZ, an IL-6R inhibitor, is effective in systemic and polyarticular juvenile idiopathic arthritis (sjia, pjia). BW-adjusted, intravenous dosing regimens (TCZ8 mg/kg Q2W for sjia and Q4W for pjia) were assessed in Japanese phase 3 trials. As shown in Results, BW adjustment led to lower TCZ exposure with lower BW; thus, higher doses were proposed for patients (pts) with BW<30 kg in the global TENDER (sjia) and CHERISH (pjia) trials.

PReS-FINAL-2070: Efficacy of biologic treatments in juvenile idiopathic arthritis with a polyarticular course: an indirect comparison

JIA ACR30 (62%), JIA ACR50 (59%), JIA ACR70 (54%) and JIA ACR90 (35%) response than ADA monotherapy (53%, 49%, 44% and 26%, respectively). On MTX background therapy and a JIA ACR30 placebo response of 53%, ADA had a higher expected probability of response at JIA ACR30 (76%), JIA ACR50 (75%), JIA ACR70 (66%) and JIA ACR90 (49%) than TCZ (72%, 70%, 61% and 44%, respectively). In neither monotherapy nor combination therapy did differences between TCZ and ADA reach statistical significance. Differences in the study populations, including previous use of biologics, were explored with sensitivity analysis. Conclusion Based on JIA ACR response rates from this analysis, the expected efficacy of ADA vs TCZ appears comparable in pcJIA. These data should be interpreted in the context of differences in the duration of the withdrawal phase, which was shorter in the TCZ study (CHERISH) than in the ADA trial and might have resulted in a smaller difference in the number of flares observed between placebo and TCZ. Differences in previous exposure to biologics might also have affected the results.

SAT0470 Efficacy of Biologic Treatments in Juvenile Idiopathic Arthritis with a Polyarticular Course: An Indirect Comparison

Background To date there are no head-to-head trials comparing the efficacy of biologic treatments for polyarticular-course JIA (pcJIA). Objectives To use statistical methods to estimate the relative efficacy of biologic treatments, alone and in combination with methotrexate (MTX), in the management of pcJIA by means of indirect comparison of randomised controlled trials (RCTs). Methods Based on a literature review, we identified RCTs of abatacept,1adalimumab2(ADA), etanercept,3infliximab4and tocilizumab5 (TCZ; CHERISH) in pcJIA. Comparative effectiveness was estimated on the reported American College of Rheumatology response rates (JIA ACR30/50/70/90) measured at the end of the randomised, double-blind phase by means of a Bayesian indirect comparison using a fixed-effects ordered probit model. Probabilities of achieving different levels of JIA ACR response were calculated for biologic treatments and placebo using all observed comparisons. Results The 5 RCTs identified showed differences in reporting JIA ACR responses with regard to methods of non-responder imputation during the blinded, controlled phase, allowing only for the comparison of ADA and TCZ. In the base-case analysis (Figure), for a JIA ACR30 placebo response of 31%, TCZ monotherapy had a higher predicted probability of achieving JIA ACR30 (62%), JIA ACR50 (59%), JIA ACR70 (54%) and JIA ACR90 (35%) vs ADA monotherapy, with 53%, 49%, 44% and 26%, respectively. On MTX background therapy and a JIA ACR30 placebo response of 53%, ADA had a higher expected probability of response at JIA ACR30 (76%), JIA ACR50 (75%), JIA ACR70 (66%) and JIA ACR90 (49%) vs TCZ, with 72%, 70%, 61% and 44%, respectively. In neither monotherapy nor combination therapy did differences between TCZ and ADA reach statistical significance. Differences in the study populations, including previous use of biologics, were explored with sensitivity analysis. Image/graph Conclusions Based on JIA ACR response rates from this analysis, the expected efficacy of ADA vs TCZ appears comparable in pcJIA. These data should be interpreted in the context of differences in the duration of the withdrawal phase, which was shorter in the TCZ study (CHERISH) than in the ADA trial and might have resulted in a smaller difference in the number of flares observed between placebo and TCZ. Differences in previous exposure to biologics might also have affected the results. References Lancet2008;372:383; N Engl J Med 2008;359:810; N Engl J Med 2000;342:763; Arthritis Rheum 2007;56:3096; Unpublished data from CHERISH Disclosure of Interest L. Sawyer Consultant for: F. Hoffmann-La Roche, A. Diamantopoulos Consultant for: F. Hoffmann-La Roche, H. Brunner Shareholder of: PRCSG, Grant/research support from: National Institutes of Health, Lupus Foundation, Cincinnati Center for Clinical and Transplantation Research, Consultant for: Roche, Novartis, GSK, MedImmune, Pfizer, BMS, F. De Benedetti Grant/research support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, SOBI, N. Ruperto Grant/research support from: Abbott, AstraZeneca, BMS Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: (to institution) Abbott, AstraZeneca, BMS Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, MedImmune, Pfizer, Roche, F. Dejonckheere Employee of: Roche, C. Keane Employee of: Roche