10/28/2013. Disclosures. Objectives. Background. Study Design. Key Inclusion Criteria

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1 Randomization (1:1:1:1) /28/13 Tocilizumab in Combination Therapy and Monotherapy Versus Methotrexate in Methotrexate-Naive Patients With Early Rheumatoid Arthritis: Clinical and Radiographic Outcomes from a Randomized, Placebo-Controlled Trial Gerd R. Burmester, 1 William Rigby, 2 Ronald F. van Vollenhoven, 3 Jonathan Kay, 4 Andrea Rubbert-Roth, Ariella Kelman, 6 Sophie Dimonaco, 7 Nina Mitchell 7 1 Charité-Universitätsmedizin Berlin, Free University and Humboldt University of Berlin, Berlin, Germany; 2 Dartmouth-Hitchcock Medical Center and Dartmouth Medical School, Lebanon, New Hampshire; 3 Karolinska Institute, Stockholm, Sweden; 4 UMass Memorial Medical Center and University of Massachusetts Medical School, Worcester, Massachusetts; University of Cologne, Cologne, Germany; 6 Genentech, Inc., South San Francisco, California; 7 Roche, Welwyn Garden City, United Kingdom Disclosures Gerd R. Burmester: Roche, 1-3 Abbott, 1-3 BMS, 1-3 Medimmune, 2 MSD, 2,3 Pfizer, 1-3 UCB 1-3 William Rigby: Roche 2 Ronald F. van Vollenhoven: Roche, 1,2 Abbott, 1,2 BMS, 1,2 GSK, 1,2 MSD, 1,2 Pfizer, 1,2 UCB 1,2 Jonathan Kay: Roche, 1,2 Abbott, 1 Amgen, 2 Ardea Biosciences, 1 Baxter Healthcare, 2 BMS, 2 Celgene, 2 Eli Lilly & Co., 1 Fidia Farmacutici, 1 Fourteen22, 2 Genentech, 2 Horizon Pharma, 2 Hospira, 2 Janssen Biotech, 2 Medac Pharma, 2 Molecular Partners A.G., 2 PanGenetics, B.V., 2 Pfizer, 2 Sanofi-Aventis, 1 Savient Pharma, 2 SpA, 1 UCB 2 Andrea Rubbert-Roth: Roche, 1-3 Chugai, 1,2 MSD, 2,3 Pfizer, 1,2 UCB 2,3 Ariella Kelman: Genentech/Roche 4 Sophie Dimonaco: Roche 4 Nina Mitchell: Roche 4 The FUNCTION trial was sponsored by Roche 1 Grant/research support; 2 Consultant; 3 Speakers bureau; 4 Employment. Background Long-term clinical and radiographic benefits can be achieved for patients with RA with early, efficacious treatment 1- Recommendations support intensive treatment of patients with severe early RA who exhibit features of poor prognosis 6,7 Tocilizumab (TCZ) has demonstrated efficacy and safety for the treatment of RA in phase 3 randomized controlled trials 8-13 This is the first study to evaluate both clinical and radiographic efficacy of TCZ in combination with methotrexate () and as monotherapy in patients with early RA Objectives Primary To assess the efficacy of TCZ + and TCZ monotherapy versus monotherapy in patients with early RA as measured by DAS28 remission (DAS28 ESR <2.6) at week 24 Secondary To assess the following secondary endpoints Prevention of structural joint damage (evaluated by van der Heijde modified Total Sharp Score [VdH mtss]) and improvement in physical function (evaluated by Health Assessment Questionnaire Disability Index [HAQ-DI]) Safety of TCZ in patients with early RA 1. Lard LR et al. Am J Med. 1;111: Emery P et al. Arthritis Rheum. ;62: Genovese MC et al. J Rheumatol. ;32: Boers M et al. Lancet. 1997;3: St Clair EW et al. Arthritis Rheum. 4;: Saag KG et al. Arthritis Rheum. 8;9: Smolen JS et al. Ann Rheum Dis. ;69: Emery P et al. Ann Rheum Dis. 8;67: Jones G et al. Ann Rheum Dis. ;69: Smolen JS et al. Lancet. 8;371: Genovese MC et al. Arthritis Rheum. 8;8: Kremer JM et al. Arthritis Rheum. 11;63: Yazici Y et al. Ann Rheum Dis. 12;71:198-. A hierarchy of statistical testing was implemented to control the type 1 error rate for multiplicity Study Design Screening (3 weeks) Treated (N = 117) Year 1 Blinded Treatment Year 2 Blinded Treatment Placebo + a () TCZ 8 mg/kg + a () TCZ 8 mg/kg + Placebo () TCZ 4 mg/kg + a (TCZ4 + ) Baseline Week 24 Week 2 b Week 4 Primary Primary endpoint: DAS28 Datacut remission at week 24 TCZ/placebo intravenous infusion every 4 weeks Radiographs at weeks, 24, 2, 4 Key Inclusion Criteria Adults with RA 2 years duration DAS28 >3.2 naive ESR 28 mm/h or CRP 1 mg/dl RF or anti-ccp positive or 1 joint erosion Oral corticosteroids permitted ( mg/d prednisone or equivalent) a dose: 7.- mg weekly (week -3: 7. mg/week; week 4-7: 1 mg/week; week 8 onward: mg/week). b Rescue: and TCZ4 + were increased to if DAS at week 2. 1

2 Patients, Patients With CDAI 2.8, Patients With DAS28 ESR <2.6, /28/13 Patient Disposition Patient Demographics (ITT Population) 38 (13) 21 (87) 2 (9) 226 (78) N = 1 34 (12) Randomized N = 1162 a 27 (88) 26 (89) 2 (88) () 32 (11) 24 (8) TCZ4 + 3 (12) 24 (8) 227 (78) 236 (81) 231 (8) Completed week 24 Completed week 2 TCZ4 + N = 287 N = 288 Female, Caucasian, Age, years, mean (SD) 49.6 (13.1) 49. (13.7) 49.9 (13.2) 1.2 (13.8) RA duration, years, mean [median].4 [.2]. [.3]. [.2].4 [.2] DMARD naive, Corticosteroid use, a 1162 patients randomized of 1846 patients screened. Five patients received no treatment (, n = 2;, n = 1; TCZ4 +, n = 2). ITT population, N = 117. Safety population, N = 113. Baseline Disease Characteristics (ITT Population) N = 287 TCZ4 + N = 288 RF +, Anti-CCP antibody +, DAS (.99) 6.7 (1.11) 6.7 (.99) 6.7 (1.) CRP, mg/dl 2.3 (2.7) 2.6 (3.) 2. (3.2) 2.6 (3.1) ESR, mm/h.4 (26.8) 2.8 (.2) 1.3 (28.4).7 (.6) SJC (66 joints) 16.2 (.4) 17.6 (12.4) 16. (.1) 16.1 (.2) TJC (68 joints) 27.4 (16.) 28.7 (16.7) 28.7 (16.3) 28.1 (1.6) HAQ-DI 1.48 (.66) 1. (.62) 1.8 (.67) 1.62 (.66) VdH mtss.66 (14.8) 6.17 (11.8) 6.8 (16.) 7.72 (17.16) JSN 2.34 (7.4) 2.67 (6.49) 3. (8.6) 3.6 (9.6) Erosion score 3.32 (7.64) 3.49 (.72) 3.8 (8.) 4.13 (8.1) Data are mean (SD) unless otherwise indicated. Primary Endpoint: DAS28 ESR Remission (ITT Population) * 4 * (N = 287) () () TCZ4 + (N = 288) * p <.1 (vs ); p <.1 (vs ) but tested after the hierarchical chain was broken. Significance was determined using logistic regression analysis, including treatment, region, and serologic status as covariates in the model. LOCF used for missing joint counts. No imputation used for ESR and Patient s Global Assessment of Disease Activity VAS. Non-responder imputation was used for missing data. If ESR=, then ESR=1 was substituted into the DAS28 calculation to enable a non-missing DAS28. * 49 Week 24 Week Secondary Endpoints: Proportion of Patients With ACR//7 Response at Weeks 24 and 2 (ITT Population) * ACR ACR ACR7 ACR ACR ACR7 Week 24 Week 2 p <.1 (vs ); *p <. (vs ); p <. (vs ) but tested after the hierarchical chain was broken. Significance was determined using logistic regression analysis, including treatment, region, and serologic status as covariates in the model. LOCF used for missing joint counts. No imputation used for missing HAQ-DI score and VAS assessments. If CRP was missing, ESR was substituted. Non-responder imputation was used for missing data. 7 * (N = 287) () () TCZ4 + (N = 288) Exploratory Endpoints: Proportion of Patients With CDAI Remission at Weeks 24 and 2 (ITT Population) Week 24 Week 2 (N = 287) () () TCZ4 + (N = 288) p <.1 (vs ); p <. (vs ). Analyses were exploratory; hence, p-values were unadjusted. CMH analysis stratified by region and serologic status was used to calculate p-values for CDAI remission. Data collected after withdrawal was set to missing. LOCF used for missing data. CDAI defined as the sum of TJC (28), SJC (28), Patient s Global Assessment of Disease Activity, and Physician s Global Assessment of Disease Activity. CDAI scores >22 were considered indicative of high disease activity,.1 22 indicative of moderate disease activity, 2.8 indicative of low disease activity, and <2.8 were considered remission

3 Patients With ACR/EULAR Remission, Change From Baseline in HAQ-DI (mean ± SE) Mean Change From Baseline in VdH mtss /28/13 Exploratory Endpoints: Proportion of Patients With ACR/EULAR Boolean and Index Remission at Weeks 24 and 2 (ITT Population) Week 24 Week 2 Week 24 Week 2 Boolean p <. (vs ). Analyses were exploratory; hence, p-values were unadjusted. No imputation used for missing data. Boolean remission defined as TJC (68), SJC (66), Patient s Global Assessment of Disease Activity, and CRP all 1 at the same visit. Index remission defined as SDAI 3.3 where SDAI is the sum of TJC (28), SJC (28), Patient s Global Assessment of Disease Activity, Physician s Assessment of Disease Activity, and CRP Index (N = 287) () () TCZ4 + (N = 288) Secondary Endpoint: Structural Joint Damage Change From Baseline in VdH mtss at Week 2 (ITT Population) Relative Reduction a 77 Relative Reduction a 93 Relative Reduction a Week 2 (N = 267) (N = 273) (N = 27) p <.1 (vs ); p <. (vs ) but tested after the hierarchical chain was broken. a Percentage reduction refers to the difference in change from baseline in VdH mtss relative to that seen on. Van Elteren's test was used to calculate p-values. Analysis was stratified by region and serologic status. Data collected after withdrawal were set to missing. Missing data were imputed using linear extrapolation TCZ4 + (N = 267) Secondary Endpoints: Physical Function Change From Baseline in HAQ- DI (ITT Population) Time, weeks (n PBO = 246 (N=287) [week 24]; 214 [week 2]) TCZ8 8 + (n(n=) = 2 [week 24]; 228 [week 2]) -.2 TCZ8 8 Mono (n(n=2) = 26 [week 24]; 2 [week 2]) TCZ4 4 + (n(n=288) = 2 [week 24]; 227 [week 2]) -.4 Safety: AEs (Safety Population) TCZ4 + AEs Patients with 1 AE, 23 (83.3) 26 (88.3) 2 (8.6) 26 (88.6) * * SAEs Patients with 1 SAE, 24 (8.) 31 (.7) 2 (8.6) (.) Deaths, 2 (.7) 2 (.7) 1 (.3) 4 (1.4) *Comparison of vs, p <.; Comparison of TCZ4 + vs, p <. analysed below the hierarchy break. No imputation used for missing data. The stratification factors, region and serologic status, were included in the model as well as the baseline value. p-values determined using analysis of variance. Multiple occurrences of the same AE in a patient were counted only once. Percentages are based on N. AEs of Special Interest Patients with 1 AE TCZ4 + Infections (all) a 136 (48.2) 137 (47.2) 138 (47.3) 1 (3.6) Serious infections a 6 (2.1) (3.4) 8 (2.7) 11 (3.8) Malignancies (SAEs) 3 (1.1) 1 (.3) 2 (.7) 4 (1.4) Gastrointestinal perforations 1 (.4) Myocardial infarctions (SAEs) 1 (.3) 1 (.3) 3 (1.) Stroke (ischemic/ hemorrhagic) (SAEs) Anaphylaxis/hypersensitivity (SAEs) 2 (.7) 2 (.7) 1 (.3) 1 (.3) Hepatic events (SAEs) b Bleeding events (SAEs) 1 (.4) 2 (.7) 1 (.3) 2 (.7) Demyelination a No opportunistic infections identified; 1 case of primary pulmonary TB (SAE) in the group (case originated from Europe; patient had exposure to a patient with active TB). b As identified by hepatic failure, fibrosis, and cirrhosis and other liver damage-related conditions SMQ. Shift in Liver Transaminase Levels From Normal at Baseline to Over 2 Weeks (Safety Population) >ULN- 3 ULN ALT ULN = U/L; AST ULN = 4 U/L. a Elevations occurred on 2 consecutive study visits. TCZ4 + ALT 4 (36.9) 141 (48.6) 4 (3.6) 113 (39.1) AST 84 (.8) 131 (4.2) 84 (28.8) 79 (27.3) >3 ULN- ULN ALT 11 (3.9) 28 (9.7) (3.4) 19 (6.6) AST 2 (.7) (3.4) 2 (.7) (1.7) > ULN ALT 2 (.7) 9 (3.1) 4 (1.4) 6 (2.1) AST (1.7) 2 (.7) 1 (.3) Consecutive elevation >3 ULN a ALT 1 (.4) 1 (.2) 1 (.3) 7 (2.4) AST 2 (.7) 2 (.7) 3

4 /28/13 Conclusions Efficacy TCZ therapy was effective in combination with and as monotherapy in -naive patients with early, active RA All TCZ treatment groups achieved greater inhibition of structural joint damage than Optimal results were achieved for patients treated with TCZ 8 mg/kg +, which showed superior results to for the primary and key secondary endpoints Acknowledgments We thank the investigators and patients who participated in the FUNCTION study Safety Overall, the safety profile observed in this population of -naive, early RA patients was consistent with the known safety profile of TCZ Deaths Age/Sex Treatment Event (onset study day) Treatment Related? 41/F Hypoglycemic coma (day 41) No 7/M Worsening lung neoplasia (day 49) No 1/F TCZ4 + Cerebral hemorrhage (day 61) No 83/F TCZ4 + Pneumonia (day 96) No 6/M Tension pneumothorax (day 2) No 83/M TCZ4 + Pulmonary infection (day 11) Yes 64/M Type A influenza viral pneumonia (day 17) No 6/F Septicemia (day 3) No 82/M TCZ4 + Atherosclerotic CVD (day 349) No Withdrawals Reason for Withdrawal N = 1 N () TCZ4 + Safety 18 (6) 49 (17) 32 (11) () AE a Death Non-safety 4 (16) 1 () 24 (8) () Insufficient therapeutic response Violation of selection criteria at entry 3 2 Other protocol violation 2 1 Refused treatment/did not cooperate/ consent Failure to return Other Total 63 (22) 64 (22) 6 (19) 9 () Shift in Bilirubin Levels From Normal at Baseline to Highest Post-Baseline Value Over 2 Weeks (Safety Population) TCZ4 + >ULN- 3 ULN 8 (2.8) 4 (13.8) 26 (8.9) 18 (6.2) >3 ULN- ULN 1 (.3) 1 (.3) > ULN 1 (.3) a Including intercurrent illness. ULN = 17 µmol/l. 4

5 Mean Value, mmol/l /28/13 Neutrophils by CTCAE Grade (Safety Population) TCZ4 + Grade -1 (<LLN-1. 9 /L) Grade -2 (< /L) Grade -3 (< /L) Grade -4 (<. 9 /L).3 Mean Change in Lipid Parameters During Study (Safety Population) () () () TCZ4 + () 6 Total Cholesterol 4 3 LDL-Cholesterol 2 HDL-Cholesterol Time, weeks The pattern of changes is consistent with previous TCZ study results