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1 Screening & Randomization 11/7/ Disclosures: This study was funded by Roche Efficacy and Safety of Tocilizumab in Patients With Systemic Juvenile Idiopathic Arthritis: 2-Year Data From a Phase III Clinical Trial F. De Benedetti, H Brunner, N. Ruperto, A Kenwright, C. Devlin, I. Calvo, R. Cuttica, A. Ravelli, R Schneider, D. Eleftheriou, C. Wouters, R. Xavier, L. Zemel, E. Baildam, R. Burgos-Vargas, P. Dolezalova, S. M. Garay, R. Joos, A. Grom, N. Wulffraat, Z. Zuber, F. Zulian,. A. Martini, D. Lovell The authors disclose the following financial relationships: F. De Benedetti (All funds go to the children Hospital): Abbott, 1 BMS, 1,2 Pfizer, 1,2 SOBI, 1 Novimmune, 1 Roche, 1,2 Novartis 1 H. Brunner (all funds go to Cincinnati Children s Hospital): Amgen, 2 Bristol-Meyers Squibb, 1 Abbott, 1 Pfizer, 2 Roche, 2 Novartis, 2 UBC 2 N. Ruperto (all funds go to Gaslini Children s Hospital): BMS, 1,4 Abbott, 1 Novartis, 1 Roche, 1,4 Centocor, 1 ACRAF, 1 Pfizer, 1 Xoma 1 A. Kenwright: Roche,4 C. Devlin: Roche,4 I. Calvo: None R. Cuttica: None A. Ravelli: None R. Schneider: Roche, 2 Innomar Strategies 2 D. Eleftheriou: None C Wouters: GSK 1 R. Xavier: Roche, 1,2,4 Pfizer, 1,2,4 Janssen 2,4 L. Zemel: None E. Baildam: None R. Burgos-Vargas: Abbot, 2, BMS, 2, MSD, 2, Pfizer, 2, Roche 1,2, P. Dolezalova: None S. M. Garay: None R. Joos: None A. Grom: Novartis 2 N. Wulffraat: None Z. Zuber: None F. Zulian: None A. Martini (all funds go to Gaslini Children s Hospital): BMS, 1,4 Abbott, 1 Novartis, 1,2 Roche, 1,2 Centocor, 1 ACRAF, 1 Pfizer, 1 Xoma 1 D. Lovell (all funds go to Cincinnati Children s Hospital): Astra-Zeneca, 2 Wyeth, 2 Amgen, 2 BMS, 1 Abbott, 1 Pfizer, 2 Regneron, 2 Roche, 2 Novartis, 2 UBC, 2 Xoma 2 1 Research grants; 2 Consulting fees; Employee; 4 Speakers bureau; Stocks, stock options, or bond holdings. Evidence-Based Medicine (EBM) TENDER: 12-Week Randomized, Double-Blind, Placebo- Controlled, Parallel-Group, 2-Arm Study (Part I) with Single- Arm, Open-label Extension (Parts II and III) Years in Total 4 Woo P, Wilkinson N, Prieur AM, et al. Open-label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther. 2;7:R1281-R1288. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 28;71: De Benedetti F, Brunner H, Ruperto N, et al. Efficacy and safety of tocilizumab (TCZ) in patients (pts) with systemic juvenile idiopathic arthritis (sjia): TENDER 2-week data. Presented at EULAR 211. Ann Rheum Dis 211;7(Suppl):67 Study Design Double-Blind Period (Part I) 7 pts 7 pts TCZ 8 or 12 mg/kg a x 6 Placebo x Week Day Escape with rescue therapy Open-Label Period (Parts II - III) TCZ 8 or 12 mg/kg a every 2 weeks for 92 weeks (subsequent -year extension added) a 8 mg/kg if body weight kg; 12 mg/kg if body weight < kg. TENDER: Key Inclusion Criteria TENDER: Demographic and Baseline Characteristics 6 Diagnosis of sjia according to ILAR criteria Age 2 17 years Persistent disease activity for 6 months, with an inadequate response to corticosteroids and NSAIDs due to toxicity or lack of efficacy active joints OR 2 active joints with fever >8 C Maximum dose of oral corticosteroids:. mg/kg/day (prednisone equivalent) Stable dose of oral corticosteroids, MTX, and/or NSAIDs No other DMARDs or biologic allowed N = 112 Age (y), mean (SD) 9.7 (4.6) Disease duration (y), mean (SD).2 (4.1) Previous DMARDs use, n (%) 82 (7) Previous TNF inhibitor use, n (%) 81 (72) Previous IL-1 inhibitor use, n (%) 4 (48) Physician VAS, mean (SD) 64.9 (22.) Parent/patient VAS, mean (SD) 8.7 (24.4) Number of active joints, mean (SD) 19.8 (1.7) Number of joints with LOM, mean (SD) 19.8 (1.6) ESR (mm/h) mean (SD) 7.6 (4.2) CHAQ-DI, mean (SD) 1.7 (.9) CRP (mg/l), mean (SD) (49.24) Fever (last 7 days), n (%) 48 (4) Background oral corticosteroid dose, (mg/kg/day PDN eq), mean (SD). (.2) Re-baselined at the first dose of TCZ. 1

2 Double-blind Baseline to Week 12 Open-label Mean (SE) CHAQ-DI 11/7/211 TENDER: Efficacy in Double-Blind Phase JIA ACR + Absence of Fever at Week 12 JIA ACR /7/9 Responses at Week 12 7 TENDER Patient Disposition Placebo n=7 Screened N=126 Enrolled N=112 Tocilizumab n= % (9% CI: )*, Placebo (n=7) n=9 n= Placebo TCZ TCZ (n=7) JIA JIA JIA (n=7) (n=7) ACR ACR7 ACR9 *Weighted difference. p<.1 Cochran-Mantel-Haenszel analysis adjusted for randomization stratification factors applied at baseline TCZ (n=7) Completed Escaped Completed Escaped a Withdrew 17 (46%) 2 (4%) 72 (96%) 2 (%) Fever AE 1 (27%) JIA ACR Refused Tx Flare 9 (24%) Other c 1 (%) AE Enrolled in Open-Label Extension Phase N=11 Death Withdrew 18 Response Ongoing N=92 Other b a 1 patient in the TCZ group received escape therapy on study day 1; the investigator initially suspected MAS, which was later determined to be liver function test elevations. b patients refused treatment, and 1 patient did not return. c Patient was initially suspected to have MAS, which was later determined to be an sjia flare. TENDER: Analyses of 14-Week Data Baseline Patients randomized to TCZ day 1 Patients randomized to placebo were re-baselined at the first TCZ dose Endpoints Durability and magnitude of TCZ efficacy response Effect of TCZ to reduce or eliminate oral corticosteroids Safety of TCZ in chronic administration Analysis population 61 patients received at least 14 weeks of TCZ treatment Patients who withdrew because of insufficient therapeutic response before week 14 were included and considered nonresponders (n=) for JIA ACR responses Patients who withdrew for nonefficacy-related reasons were excluded (n=1 [9 safety and 6 other]) for JIA ACR responses 9 JIA ACR Responses Over Time JIA ACR JIA ACR JIA ACR JIA ACR9 n = Percentage is based on number of patients who reached time point + patients who withdrew because of insufficient therapeutic response and are assumed to have been nonresponders. 1 No Active Joints and Inactive Disease Over Time No Active Joints Inactive Disease Physical Function Over Time No Joints with limitation CHAQ-DI score b of movement a. 2. CHAQ-DI >.7 Baseline: 82.1% 2. Week 14: 4.7% a Patients who withdrew because of insufficient therapeutic response are assumed to be nonresponders. b Patients who withdrew are excluded. 12 2

3 Mean (SE) Dose 11/7/211 Mean Oral Corticosteroid Dose Over Time 1 Cumulative Safety % discontinued CS by week 14 Mean dose decreased to.4 mg/kg/day Patients who withdrew have been excluded at postwithdrawal visits.. Prior Safety Update a Week 14 b Exposure to TCZ, y Rate of SAEs/1PY (n) 24.8 (9) 2. (47) Rate of infections/1py (n).6 (4) (7) Rate of serious infection AEs/1PY (n) 11.4 (18) 1.9 (22) SAEs related (remotely, possibly, probably) to TCZ/1 PY (n) 8. (1) 7.4 (1) Macrophage activation syndrome/1py (n) 1.9 () 1. () AEs leading to withdrawal/1py (n).8 (6) c. (6) c Deaths/1PY (n).6 (1) 1. () Pneumothorax 1 1 Sepsis (possibly related) 1 Road Traffic Accident 1 a Includes all safety data in the database up to and including August 1, 21. b Includes all safety data in the database up to the week 14 infusion (based on date of randomization) for each pt. The last date for this was May 1, 211. c Includes 2 withdrawals because of transaminase increases that were protocol mandated. 16 Deaths after discontinuation from TENDER Pat # Country 11* Netherlands 1611 Italy Event name Death of unknown cause Age at death 1 y mo. Atrioventricular 17 y block (in 9 mo. hyperkalaemia) 164 Italy Cardiac arrest 18 y 7 mo. Date of Death (duration from last TCZ dose) July-1 (6 mo.) Dec-11-1 (1 y 1 mo.) Duration of TCZ tx Date of last TCZ dose wks Jan-21-1 Reason for withdrawal from TENDER therapeutic response AE - Pulmonary 4 wks Nov-18-9 venoocclusive disease Apr-1-11 (1 y 2 mo.) 48 wks Feb-1-1 therapeutic response Most Common* Serious Adverse Events Event, n (%) N = 112 Varicella 4 (.6) Gastroenteritis 4 (.6) Macrophage activation syndrome (2.7) Pneumonia (2.7) Dehydration 2 (1.8) Herpes zoster 2 (1.8) * Patient 11 entered another biologic study April 21. *Preferred terms with incidence > 1 patient 18 TENDER: Clinical Laboratory Evaluations Grade a No. (%) Neutrophils (-<1, cells/mm ) 26 (2.2) 4 (< cells/mm ) 2 (1.8) b Platelets (2,-<, cells/mm ) 1 (.9) c 4 (<2, cells/mm ) ALT (>-2 x ULN) 9 (8.) 4 (>2 x ULN) 1 (.9) c Conclusions TENDER 2-year results demonstrated sustained efficacy and no change in the safety profile during long-term TCZ treatment Responses occurred early and were maintained over time 6% of patients who received 14 weeks of TCZ were able to discontinue oral corticosteroids 7% in inactive disease status by week 14 a Common Toxicity Criteria Vers. Grades. b Both single occurrences, returned to normal no associated infection. c Platelet decrease and ALT increase occurred during MAS.

4 11/7/ Argentina Cuttica Espada Garay Australia Allen Chaitow Murray Belgium Joos Wouters Brazil Silva Xavier Canada Roth Schneider Czech Republic Dolezalova Germany Horneff Huppertz Minden Greece Mantzourani Siammopoulou Vougiouka Italy Cortis Gerloni Martini Zulian Mexico Burgos Maldonado Netherlands Norway Poland Slovakia Wulffraat Flato Zuber Rovensky Spain Calvo Garcia Consuegra UK Baildam Woo USA Investigators 4 centers from 17 countries Brown Chalom Jerath Kimura Lovell Myones O'Neill Onel Spalding Zemel Back-up Infections N = 112 Infections and infestations/1 PY (7) Serious infection AEs/1 PY (n) 1.9 (22) Infections (remotely, possibly, probably) related to study treatment 8 Gastroenteritis 1 Otitis media 1 Pharyngotonsillitis 1 Septic arthritis 1 Streptococcal sepsis 1 Tonsillitis 1 Upper respiratory infection 1 Varicella 1 TENDER: Oral Corticosteroid Tapering Allowed if ESR <2 mm/hr and In double-blind phase at weeks 6 and 8 (not at week 1) If absence of fever and JIA ACR7 In open-label extension phase (not at weeks 24,, 76, and 12) If absence of fever and JIA ACR Not permitted more frequently than every 2 weeks Maximum tapering allowed: 2% of current (last visit) dose in double-blind phase and at investigator s discretion in open-label JIA ACR Responses Over Time JIA ACR and absence of fever JIA ACR 2 JIA ACR JIA ACR7 JIA ACR n = Percentage is based on number of patients who reached time point + patients who withdrew because 2 No Active Joints and No Joints With Limitation Of Movement Over Time No Active Joints No Joints with limitation of movement n =

5 Mean (SE) Number of Active Joints 11/7/211 Physician Global Assessment VAS 1 mm 1 2 Patient/Parent Global Assessment VAS 1 mm n = n = Active Joint Count Over Time n = Percentage is based on number of patients who reached time point + patients who withdrew are excluded.