Janssen Research & Development Briefing Document Arthritis Advisory

Janssen Research & Development

Briefing Document

Arthritis Advisory Committee

PLIVENSIA™ (sirukumab)

Status: Approved Date: 28 June 2017 Prepared by: Janssen Research & Development, LLC EDMS number: EDMS-ERI-141203773

ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE

1 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

TABLE OF CONTENTS

TABLE OF CONTENTS ...... 2

LIST OF IN-TEXT TABLES...... 4

LIST OF IN-TEXT FIGURES ...... 5

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...... 7

1. EXECUTIVE SUMMARY ...... 9

2. INTRODUCTION & BACKGROUND ...... 16 2.1. Rheumatoid Arthritis: Unmet Medical Need and Current Treatment Paradigm...... 16 2.1.1. IL-6 pathway and IL-6 Receptor Inhibitory Agents in RA ...... 17 2.2. Sirukumab ...... 19 2.2.1. Inhibition of IL-6 by Sirukumab in RA ...... 19 2.2.2. Placement within the RA Treatment Paradigm ...... 19 2.3. Formulation Development...... 19 2.3.1. Pharmaceutical Form...... 20 2.3.2. Device Information...... 20 2.4. Proposed Indication and Dosing ...... 21 2.5. Regulatory History...... 21

3. OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM ...... 23

4. SUMMARY OF CINICAL PHARMACOLOGY ...... 26 4.1. Pharmacokinetics...... 26 4.2. Drug-Drug Interactions...... 26 4.3. Immunogenicity...... 27 4.4. Biomarkers ...... 27

5. SUMMARY OF CLINICAL EFFICACY ...... 29 5.1. Efficacy Endpoints...... 29 5.2. Phase 2 Study...... 29 5.2.1. Phase 2 Study Design ...... 29 5.2.2. Phase 2 Efficacy Results: Signs and Symptoms...... 31 5.2.3. Phase 2 Exposure-Response Analysis ...... 33 5.2.4. Dose Rationale for Phase 3 Studies...... 35 5.3. Phase 3 Studies ...... 36 5.3.1. Statistical Analyses...... 37 5.4. Phase 3 Studies - Combination Therapy ...... 41 5.4.1. Study ARA3002 (DMARD-IR)...... 41 5.4.2. ARA3003 (Anti-TNFα-IR)...... 56 5.5. Efficacy by Baseline Demographic and Disease Characteristics ...... 68 5.5.1. Study ARA3002 ...... 68 5.5.2. Study ARA3003 ...... 70 5.6. Phase 3 Studies – Monotherapy...... 72 5.6.1. Sirukumab Received as Monotherapy in ARA3002 and ARA3003...... 72 5.6.2. Study ARA3005 (Monotherapy)...... 74 5.7. Efficacy Exposure-Response Analyses ...... 81 5.7.1. Efficacy by Sirukumab Trough Concentration Quartiles...... 81 5.7.2. Efficacy Exposure-Response Modeling Analysis ...... 83 5.8. Efficacy Conclusions ...... 84

6. SUMMARY OF CLINICAL SAFETY ...... 86

2 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

6.1. General Approach to Evaluating and Managing Safety in the Sirukumab Development Program ...... 86 6.2. Comorbidities and Concomitant Medications of Study Population ...... 86 6.3. Safety Database (Exposure)...... 87 6.4. Overview of Safety Analysis ...... 88 6.4.1. Studies ARA3002 and ARA3003...... 88 6.4.2. Study ARA3005 ...... 90 6.4.3. 120-day Safety Update ...... 90 6.5. Adverse Events ...... 90 6.5.1. Studies 3002 and 3003...... 90 6.5.2. Study 3005...... 92 6.6. Serious Adverse Events...... 93 6.6.1. Deaths...... 95 6.7. Adverse Events of Special Interest ...... 100 6.7.1. Infections ...... 103 6.7.2. Gastrointestinal Perforations ...... 106 6.7.3. MACE...... 107 6.7.4. Malignancies...... 110 6.7.5. Aminotransferase Abnormalities...... 112 6.7.6. Neutrophil and Platelet Counts...... 113 6.7.7. Lipids...... 114 6.7.8. Injection-site Reactions...... 117 6.7.9. Hypersensitivity Reactions...... 118 6.8. Safety in Subpopulations ...... 119 6.9. Exposure-Response Analysis for Safety...... 119 6.10. 120-day Safety Update ...... 119 6.11. Sirukumab Safety with Indirect Reference to Other Drugs Used for Rheumatoid Arthritis ...... 120 6.12. Safety Conclusions ...... 121

7. DOSE RECOMMENDATION...... 124

8. BENEFIT-RISK ASSESSMENT ...... 125 8.1. Overall Assessment ...... 125 8.2. Postmarketing Safety Surveillance Plan...... 127 8.3. Benefit-risk Conclusions...... 128

9. CONCLUSIONS...... 129

REFERENCES...... 130

APPENDICES...... 134

3 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

LIST OF IN-TEXT TABLES Table 1: Overview of Phase 2 and Phase 3 Studies of Sirukumab in Patients with Active Rheumatoid Arthritis ...... 25 Table 2: Overview of Key Efficacy Endpoints (Studies ARA3002 and ARA3003) ...... 38 Table 3: Summary of Patient Disposition in Study ARA3002 (DMARD-IR) ...... 43 Table 4: Baseline Demographics and Disease Characteristics...... 44 Table 5: Primary and Major Secondary Endpoint in ARA3002...... 46 Table 6: Inhibition of Progression of Structural Damage; vdH-S Score at Weeks 24 and 52 ...... 49 Table 7: Erosion and Joint Space Narrowing Score at Weeks 24 and 52...... 50 Table 8: HAQ-DI-related Endpoints (Study ARA3002)...... 52 Table 9: SF-36-related Endpoints (Study ARA3002)...... 54 Table 10: FACIT-F-related Endpoints (Study ARA3002)...... 56 Table 11: Summary of Patient Disposition at Week 24 (Study ARA3003) ...... 58 Table 12: Summary of Patient Disposition at Week 52 (Study ARA3003) ...... 58 Table 13: Baseline Demographics and Disease Characteristics (Study ARA3003)...... 59 Table 14: Primary and Major Secondary Endpoint (Study ARA3003)...... 60 Table 15: HAQ-DI-related Endpoints (Study ARA3003)...... 62 Table 16: SF-36-related Endpoints (Study ARA3003)...... 63 Table 17: FACIT-F-related Endpoints (Study 3003) ...... 65 Table 18: Improvement in Clinical Outcomes; Randomized Patients with Prior Use of Anti-TNFα Biologics Only and Patients With Prior Use of Other Biologic DMARDs (Study ARA3003) ...... 66 Table 19: Improvement in Signs and Symptoms and Physical Function; Randomized Patients With No Use of DMARDs at Baseline (Studies ARA3002, ARA3003) ...... 73 Table 20: Summary of Patient Disposition at Week 24 (Study ARA3005) ...... 76 Table 21: Baseline Demographics and Disease Characteristics (Study ARA3005)...... 77 Table 22: Summary of Primary and Key Secondary Endpoints; Full Analysis Set (Study ARA3005) ...... 78 Table 23: Medical History and Concomitant Medications: All Patients in ARA3002 and ARA3003...... 87 Table 24: Number of Patients by Duration of Exposure Category; Sirukumab Controlled Analysis Set (Study CNTO136ISS)...... 87 Table 25: Treatment-emergent AEs in the DMARD-IR and TNFα-Failure Studies...... 91 Table 26: Adverse Reactions Occurring in at Least 2% or More of Patients on Sirukumab 50 mg and at Least 1% Greater than Placebo...... 92 Table 27: Summary of Safety in Study ARA3005 (SCS Cut-off)...... 93 Table 28: Number of patients with 1 or more treatment-emergent SAEs by MedDRA SOC through 18 weeks of exposure...... 94 Table 29: AEs of Interest: Incidence per 100 Patient-Years in the DMARD-IR and TNFα-Failure Studies ...... 101 Table 30: Incidence of Infection in Patients with and without ANC

4 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

LIST OF IN-TEXT FIGURES Figure 1: Classic and Trans IL-6 Signal Transduction...... 18 Figure 2: Dose-response in Changes of Pharmacodynamic Biomarkers Following 12-week Treatment with Sirukumab (Study C1377T04 Part B) ...... 28 Figure 3: Study Design - Study C1377T04 – Part A ...... 30 Figure 4: Study Design - Study C1377T04 – Part B ...... 30 Figure 5: Proportion of Patients who Achieved ACR 20/ACR 50 Responses by Visit (Study C1377T04 Part B) ...... 32 Figure 6: Mean (SE) Changes from Baseline in DAS28 (CRP) (left panel) or Clinical Disease Activity Index (CDAI) (right panel) over time (Study C1377T04 Part B)...... 33 Figure 7: Proportion of Patients Who Achieved ACR 20 Response and ACR 50 Response at Week 24 by Trough Serum Sirukumab Concentration (quartiles) at Week 24; PK Analysis Set (Study C1377T04 Part B)...... 34 Figure 8: The Probability of Achieving a Target Value of ≥20% or ≥30% Difference in ACR 20 Response Relative to Placebo at Week 24 by Different Dose Regimens ...... 35 Figure 9: Study Design - ARA3002 (DMARD-IR) ...... 42 Figure 10: Line Plot of the Proportion of Patients Who Achieved an ACR 20 Response by Visit Through Week 52; (Placebo Controlled Period) (Study ARA3002)...... 47 Figure 11: Change from Baseline in CDAI Score by Visit through Week 52; Full Analysis Set (Placebo Controlled Period) (Study ARA3002) ...... 48 Figure 12: Probability Plot of Change from Baseline in vdH-S at Week 52; Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment (Study ARA3002) ...... 51 Figure 13: Change From Baseline in HAQ-DI Score by Visit Through Week 52; Full Analysis Set (Placebo Controlled Period) (Study ARA3002) ...... 53 Figure 14: Change in SF-36 Individual Domain Scores at Week 24 (Study ARA3002) ...... 55 Figure 15: Study Design - ARA3003 (Anti-TNFα-IR) ...... 57 Figure 16: Line Plot of the Proportion of Patients Who Achieved an ACR20 Response by Visit Through Week 24; Placebo Controlled Period) (Study ARA3003)...... 61 Figure 17: Change in SF-36 Individual Domain Scores at Week 24 (Study ARA3003) ...... 64 Figure 18: ACR 20 Response at Week 16 by number of prior Anti-TNFs and Biologic Therapies (ARA3003) ...... 67 Figure 19: ACR 20 Response at Week 16 by Prior Use of Tocilizumab (Study ARA3003) ...... 68 Figure 20: Odds Ratios (Sirukumab 50 mg, Placebo; Sirukumab 100 mg, Placebo) for Comparing the Proportion of Patients Who Achieved ACR 20 Response at Week 16; Full Analysis Set (Placebo Controlled Period) (Study ARA3002)...... 69 Figure 21: Odds Ratios (Sirukumab 50 mg, Placebo; Sirukumab 100 mg, Placebo) for Comparing the Proportion of Patients Who Achieved ACR 20 Response at Week 16; Full Analysis Set (Placebo Controlled Period) (Study ARA3003)...... 71 Figure 22: Study Design - ARA3005...... 75 Figure 23: Change from Baseline in DAS28 (ESR) by Visit through Week 24; Full Analysis Set (Study ARA3005) ...... 80 Figure 24: Proportion of Patients Who Achieved ACR 20 or ACR 50 Responses at Week 16 by Trough Serum Concentration Quartiles at Week 16 (Studies ARA3002 and ARA3003) ...... 82 Figure 25: Observed versus Predicted Week 16 ACR20/ACR50/ACR70 Responses Using Steady-State Trough Concentration as Exposure Metric (Pooled Data)...... 83 Figure 26: Rate of Serious Adverse Events per 100 PY* ...... 95 Figure 27: Rate of Deaths per 100 PY* ...... 96 Figure 28: Analysis of Death Over Time (SCS Cut-off) ...... 99 Figure 29: Mortality rates from the sirukumab RCT program and published rates from comparator RCT programs ...... 100 Figure 30: Rate of Serious Infections per 100 PY* ...... 104 Figure 31: Rate of Gastric Perforations per 100 PY*...... 106 Figure 32: Rate of MACE per 100 PY* ...... 108 Figure 33: Indirect comparison of the incidence of MI and stroke on sirukumab and tocilizumab ...... 109

5 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 34: Rate of Malignancies per 100 PY*...... 110 Figure 35: Mean LDL and HDL changes over time with sirukumab ...... 115 Figure 36: Baseline, Pre- and Post-Lipid Lowering Agent (LLA) LDL Cholesterol for Patients Starting LLAs Post-Baseline (N=205) Sirukumab Combined (50mg q4w and 100mg q2w) ...... 116 Figure 37: Change from baseline in total cholesterol in patients with or without MACE on sirukumab 50 mg (red) and 100 mg (blue)...... 117 Figure 38: Rates of mortality and events of interest in the Sirukumab Phase 3 program with a summary of data from RCTs/ RA development programs...... 121 Figure 39: Risk Differences for Key Benefits and Key AEI: Studies ARA3002 and ARA3003...... 126

6 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ACR American College of Rheumatology ADR Adverse drug reactions AE Adverse event AEI Adverse events of interest ALT Alanine aminotransferase Anti-CCP Anti-cyclic citrullinated peptide ARDS Acute Respiratory Distress Syndrome AST Aspartate aminotransferase AUC Area under the curve CDAI Clinical Disease Activity Index CL/F Apparent clearance of drug after extravascular administration CRP C-reactive protein DAS28 Disease Activity Index Score 28 DMARD Disease-modifying anti-rheumatic drug DMARD-IR DMARD-inadequate responder EE Early escape EQ-5D EuroQol EQ-5D Descriptive System E-R Exposure-response ES Erosion score ESR Erythrocyte sedimentation rate EULAR European League Against Rheumatism FACIT-Fatigue Functional Assessment of Chronic Illness Therapy-Fatigue FVP Final Vialed Product GI Gastrointestinal HAQ-DI Health Assessment Questionnaire-Disability Index HDL High-density lipoprotein HCP Health Care Professional IgG1k Immunoglobulin G1 k IL Interleukin JAK Janus kinase inhibitor JSN Joint space narrowing LDL Low-density lipoprotein LE Late escape mAb Monoclonal antibody MACE Major adverse cardiovascular events MCR Major clinical response MCS Mental Component Score MI Myocardial infarction MTX Methotrexate NSAID Nonsteroidal anti-inflammatory drug PCS Physical Component Score PD Pharmacodynamics PFS Prefilled syringe PFS-AI PFS with SmartJect® Autoinjector PFS-U PFS with UltraSafe Passive®Delivery System PK Pharmacokinetics PMR Polymyalgia rheumatica q2w every 2 weeks q4w every 4 weeks QOL Health-related quality of life RA Rheumatoid arthritis SAE Serious adverse event SCS Summary of clinical safety SDAI Simplified Disease Activity Index SF-36 36-item Short Form health survey

7 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

SINF Serious infections SOC System Organ Class T1/2 Terminal half-life TB Tuberculosis TNFα Tumor necrosis factor alpha TNFα-IR TNFα- inadequate responder ULN Upper limit of normal vdH-S Van der Heijde-modified Sharp

8 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

1. EXECUTIVE SUMMARY This document provides background information on the clinical development program of sirukumab for the treatment of rheumatoid arthritis (RA) and outlines the benefit-risk profile supporting its use in this patient population.

Sirukumab (PLIVENSA™) is a human anti-IL-6 immunoglobulin G1 kappa (IgG1) monoclonal antibody (mAb) that binds specifically with high affinity to the cytokine IL-6, preventing IL-6-mediated signalling. Inhibition of the IL-6 pathway in RA has been clinically validated by tocilizumab (ACTEMRA), a treatment targeting the IL-6 pathway by binding the IL-6 receptor (IL-6R). Recently, another IL-6R antagonist, sarilumab (KEVZARA), was approved by the Food and Drug Administration (FDA). Sirukumab would be the first inhibitor of IL-6 to be approved by the FDA for the treatment of RA.

The proposed indication for sirukumab is as follows:

PLIVENSIA, an interleukin-6 (IL-6) inhibitor, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or are intolerant to one or more disease modifying anti-rheumatic drugs (DMARDs). PLIVENSIA may be used as monotherapy or in combination with nonbiologic DMARDs, including methotrexate (MTX).

Disease and Unmet Medical Need Rheumatoid arthritis is a common, chronic, life-long, autoimmune disease affecting approximately 1.3 million people in the US. Although it primarily affects joints and is a leading cause of disability when left untreated, RA also has extra-articular manifestations with systemic effects including cardiovascular morbidity, fatigue, and depression. A variety of treatment options including nonsteroidal anti-inflammatory drugs (NSAID), non-biologic disease modifying antirheumatic drugs (DMARD), or biologic DMARDs are available. It is well recognized that proinflammatory cytokines, including tumor necrosis factor alpha (TNFα), interleukin-1 (IL-1), and interleukin-6 (IL-6), play significant roles in the pathogenesis of the disease, contributing to both joint inflammation and comorbidities. In the last 2 decades, new treatments targeting these pathways have provided additional treatment options for patients.

However, RA patients are still not adequately managed and often are left with few remaining therapeutic options due to loss of response to available agents, and poor compliance due to inconvenient dosing. Many patients still fail to achieve control of their disease and sustained disease remission is uncommon. Due to the duration and chronic nature of RA, patients can expect to require treatment for up to 40 years over their lifetime. Individual patient factors and comorbidities influence treatment selection and use; however, how patients will respond to a given therapy remains unpredictable. Patients commonly discontinue medication due to inadequate response, loss of response, adverse reactions, or other issues such as poor compliance resulting from frequent or inconvenient dosing.52,59 Patients try multiple drugs within a class or will cycle to new therapies in a different class. The relatively high likelihood that a patient will

9 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document stop responding to any particular therapy means that many patients will exhaust available treatment options during the course of their disease. Thus, there still remains a considerable unmet need in this chronic disease that requires lifelong therapy. In addition to the currently approved biologic therapies, new safe, effective and convenient therapies are required to improve the signs and symptoms of the disease, slow down joint structural damage, and address the systemic manifestations of RA to improve the overall quality of life for patients.

Sirukumab Clinical Development Program A large global clinical development program evaluated a diverse patient population representative of current clinical practice, including difficult-to-treat patients who continue to have active disease in spite of previous use of biologics.

This program was designed to meet the needs of patients and to comply with global regulatory authorities.

 A Phase 2 study, C1377T04, was designed as a placebo-controlled, proof-of-concept and dose-finding study in MTX-IR patients with active RA.  Two global pivotal Phase 3 studies were designed to evaluate sirukumab 50 mg q4w and 100 mg q2w given subcutaneously in combination with background DMARDs:  ARA3002: the first pivotal study (2-year duration) with a one year placebo-control arm in patients who were inadequate responders to single or combination disease modifying antirheumatic drug (DMARD) therapy that included methotrexate (MTX) or sulfasalazine (SSZ). Patients could also have received a biologic DMARD prior to study entry. This study included x-ray evaluation of joint damage.  ARA3003: the second pivotal study (1-year duration) with a 6-month placebo-control arm in patients who were inadequate responders to treatment with 1 or more anti-tumor necrosis factor alpha (TNFα) agents or intolerant to 2 or more anti-TNFα agents. Patients were also allowed to have previous exposure to other biologics including anti- IL-6 agents. All eligible patients from ARA3002 and ARA3003 could continue treatment in the ARA3004 long-term extension (LTE) study for a maximum of up to 5 years.

 Efficacy of sirukumab monotherapy was investigated by:  a subgroup analysis of patients treated with sirukumab without concomitant DMARDs in studies ARA3002 and ARA3003, and a 1-year active comparator study, ARA3005, in biologic-naïve patients with active RA who were intolerant to MTX.

Summary of Major Efficacy Findings In the 2 pivotal Phase 3 placebo-controlled studies, ARA3002 (DMARD-IR study) and ARA3003 (anti-TNFα-IR study), benefits were demonstrated across a difficult-to-treat patient population representing the full spectrum of moderately to severely active adult RA, ie, patients

10 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document naive to biologic treatment who had responded inadequately to conventional DMARDs through to those who have failed to respond to multiple biologics.

The benefits of treatment were observed as early as Week 2 with efficacy maintained through Week 52. Relative to placebo, sirukumab was effective in combination with DMARDs in the treatment of active RA, demonstrating consistent and clinically meaningful:

 Inhibition of structural damage Robust and significant inhibition of progression of structural damage as measured by change in Van der Heijde-modified Sharp (vdH-S) at Week 52 and seen as early as Week 24 in ARA3002

 Improvement in physical function Statistically significant and clinically meaningful improvements in HAQ-DI

 Improvement in patient reported outcomes Clinically meaningful improvements in SF-36 physical and mental scores, in all 8 individual domains of the SF-36 as well as clinical relevant improvements in FACIT-fatigue

Subpopulation data from studies ARA3002 and ARA3003 in patients treated with sirukumab without concomitant DMARDs, and data from the monotherapy study ARA3005 in biologic-naïve patients with active RA established the efficacy of sirukumab as monotherapy. Whilst in the monotherapy subgroup a small incremental benefit of 100 mg q2w over 50 mg q4w was observed, it is not considered sufficient to justify recommending sirukumab 100 mg q2w.

Overall, both dose regimens of sirukumab 50 mg every 4 weeks (q4w) and 100 mg every 2 weeks (q2w) were efficacious for the treatment of RA in combination with DMARDs and in monotherapy.

The 50 mg q4w dose regimen is recommended as the optimal dose schedule as if offers near maximum efficacy with 4-fold less exposure.

Summary of Major Safety Findings The safety of sirukumab in the RA population was evaluated in a total of 3428 patients participating in 7 studies, representing 4548 patient-years of follow-up in sirukumab treated patients with a median duration of treatment of 1.33 years.

11 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Important identified risks for sirukumab are serious infections, GI perforation, injection-site and hypersensitivity reactions, and certain laboratory abnormalities:

 Serious infections occurred with higher incidence in sirukumab-treated patients than in placebo-treated patients.  GI perforations, mostly in the lower GI tract, occurred in small numbers, but in more sirukumab-treated patients than placebo- or adalimumab-treated patients.  Injection-site reactions were generally mild to moderate in severity. Serious hypersensitivity reactions were uncommon, and none were anaphylactic reactions as defined by Sampson criteria.62  Laboratory abnormalities were commonly observed in sirukumab-treated patients, including decreases in neutrophils, leukocytes, and platelets, and increases in aminotransferases, unconjugated bilirubin, and lipids, including cholesterol and triglycerides.  Decreases in neutrophils, leukocytes, and platelets were consistent with the anti- inflammatory effects of blocking IL-6, and most did not require dose interruption or treatment discontinuation.  Increases in aminotransferases and unconjugated bilirubin were, in general, asymptomatic and did not require dose interruption or treatment discontinuation.  Increases in lipids were not associated with substantial changes in atherogenic indices, and responded to treatment with lipid lowering agents. Important potential risks for sirukumab were similar to those observed with other biologics used to treat moderate to severely active RA and include cardiovascular events and malignancy. Major adverse cardiovascular events (MACE) and malignancies were observed in clinical studies of sirukumab, and rates of these events were consistent with expected rates in patients with RA.

12 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

During the placebo-controlled periods of the clinical studies, 1 death was reported in each treatment group. With longer-term follow-up in the controlled and uncontrolled portions of clinical studies after escape and group cross-overs were permitted, combined mortality rates were consistent with the rates observed in clinical studies of other drugs developed for rheumatoid arthritis. The causes of death varied and were consistent with the rates and causes of death seen in an RA population treated with biologics. No dose relationship was observed.

Multiple additional analyses evaluating covariates associated with mortality identified factors such as higher average inflammatory burden, baseline characteristics of older age, male gender, corticosteroid use, hypertension, smoking, previous MI, but not sirukumab treatment itself.

Overall, the safety profile of each of the dosing regimens of sirukumab studied in Phase 3 was comparable with the safety profile of biologic agents currently used in the treatment of RA. The identified adverse events for sirukumab are common to other agents used in the treatment of RA, and rheumatologists are accustomed to monitoring and treating these side effects. The clinical studies of sirukumab demonstrated that these AEs can be managed through careful evaluation by the treating physician, and follow-up guidance that has been included into the proposed product labeling. Additionally, the Sponsor is committed to continued evaluation of the benefits and risks of sirukumab by way of:

 Safety data from the 5-year study ARA3004, the long-term extension (LTE) of studies ARA3002 and ARA3003 with an estimated 8500 patient-years of follow-up,  A proposed observational study evaluating the risk of uncommon events such as serious infections (including TB and opportunistic infections), MACE, malignancy, and all-cause mortality, established registries in the US and EU, and  Pregnancy outcomes study using an established US pregnancy registry.

13 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Assessment of key efficacy and safety data indicated that sirukumab 50 mg q4w has a positive benefit-risk profile.

Risk Differences for Key Benefits and Key AEI: Studies ARA3002 and ARA3003

NOTE: Pooled efficacy and safety data are from Phase 3 Studies ARA3002 and ARA3003 50 mg q4w.

1. Only includes patients randomized to sirukumab 50 mg q4w and does not include patients initially randomized to placebo who EE/LE/CO to sirukumab 50 mg q4w. 2. MACE is defined as CV death, MI, and stroke

Conclusions The sirukumab clinical program was designed to study the broad range of patients encountered in current clinical practice in whom the drug would most likely be used, including patients who had previously been treated with multiple prior biologic agents.

14 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document can make a meaningful difference in their lives by not only improving the signs and symptoms of RA but also the systemic manifestations of RA that are important to patient such as physical and mental function and fatigue. Appropriate warnings and precautions for use and advice on the management of patients treated with sirukumab have been included in the proposed labelling. Long-term monitoring and evaluation of adverse events of interest will be performed as described.

Since both doses were efficacious in this broad range of patients, the four-fold lower dose was considered optimal to minimize exposure and the potential for AEs. The recommended dosage for adult patients with RA is 50 mg q4w, given as a subcutaneous (SC) injection. Sirukumab will be available in 2 different presentations, either a prefilled syringe (PFS) or an autoinjector (AI). Sirukumab represents an important addition to the treatment options for patients with RA and can make a meaningful difference in their lives by not only improving the signs and symptoms of RA but also the systemic manifestations of RA that are important to patients such as physical and mental function and fatigue.

15 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

2. INTRODUCTION & BACKGROUND

2.1. Rheumatoid Arthritis: Unmet Medical Need and Current Treatment Paradigm Rheumatoid arthritis is one of the most common autoimmune diseases and one of the most common forms of arthritis. It affects approximately 1% of the world population19 and approximately 1.3 million people in the United States.12 Rheumatoid arthritis is a leading cause of disability that not only impacts the joints, but also has extra-articular manifestations with systemic effects and social repercussions, such as fatigue and depression.

Treatment for RA focuses on lowering the inflammation that mediates disease, relieving pain, preventing joint damage, and improving the overall quality of life. Current RA guidelines recommend that clinicians establish a set of treatment outcome goals in conjunction with the patient to achieve and maintain a low level of disease activity or remission (a “Treat to Target” approach)51 Treatment should be aimed at remission, although achieving low disease activity (LDA) may be acceptable for patients with long-standing, established disease who cannot attain remission. The choice of treatment is selected and adjusted according to the stage of a patient’s disease and individual patient factors and comorbidities such as cardiovascular disease, pulmonary disease, risk of carcinoma, and decreased life expectancy which all can influence treatment selection and use. In addition, since the genetic and other biomarkers that would predict an individual patient’s response to a specific therapy are not currently known, it is important to note that an individual patient's response to a particular treatment may vary. However, despite the availability of a variety of treatments, many patients fail to achieve their treatment goals, and sustained disease remission is uncommon.2,56

Initial RA treatment has relied upon NSAIDs and DMARDs such as MTX. Nonsteroidal anti-inflammatory drugs are given for their immediate analgesic and anti-inflammatory effect, but in general do not influence the disease process itself, whilst DMARDs can improve signs and symptoms of the disease and also slow down joint structural damage. In addition, corticosteroids may be given to modify the underlying inflammatory process. Although DMARDs such as MTX do provide benefit, MTX failure and discontinuation is common in the first 5 years (as high as 50%)37 and is associated with a higher likelihood of discontinuation of subsequent treatments.

Although the etiology of RA is thought to be heterogeneous, it is recognized that proinflammatory cytokines, specifically tumor necrosis factor alpha (TNFα), interleukin-1 (IL-1) and interleukin-6 (IL-6), play a critical role in the pathogenesis of the disease by contributing to both joint inflammation and systemic comorbidities.5 This has led to the development of drugs specifically targeting these cytokines, launching an era of biologic drugs that have altered the therapeutic approach and outcome of RA. Consequently, the American College of Rheumatology (ACR) drafted pharmacologic treatment guidelines to incorporate use of these agents.6,49 For example, patients whose disease activity remains moderate or high despite the use of MTX often have an anti-TNFα agent or other biologic DMARD added to their treatment regimen. However, even with the addition of a TNFα antagonist to their treatment regimen, only 20-50% of these patients have their disease managed effectively (ie, treatment target goals achieved) after 6

16 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document months.58 Discontinuation rates for anti-TNFα therapy range between 24%-81%.52 Failure to respond to one anti-TNFα therapy results in more recalcitrant patients who have lower response rates to subsequent anti-TNFα biologics.19,24

Due to inadequate response or loss of response and adverse effects, patients frequently discontinue and/or switch between several agents both within a drug class (eg, between different anti-TNFα agents) or to a completely new drug class (eg, to an anti-IL-6R antagonist).49 This is supported by data that indicate that switching to an agent with a different mechanism of action is more effective than switching within a drug class.19,20,24 A variety of agents with different mechanisms of action are needed as options for prescribers and patients, particularly those with moderately to severely active RA who inadequately respond to or are intolerant to the currently available DMARDs or biologics such as anti-TNFα agents.

In addition, many of the current treatments fail to address the unmet needs of the patient which are often of a more subjective nature such as impaired physical and mental function, fatigue, and pain.59 For example, depression is an under recognized, common comorbidity of RA15 with a high frequency of onset upon initial diagnosis24,64 with a high prevalence (15-39%) among RA patients25,30 that is a robust, independent, reversible determinant of disability over time.26,64 Inflammatory cytokines, in particular IL-6, have been strongly linked to depression.2,17,27,29

2.1.1. IL-6 pathway and IL-6 Receptor Inhibitory Agents in RA IL-6 is a soluble, glycosylated protein expressed by a variety of immune (T-cells, B-cells, macrophages, and microglia) and non-immune cell types (fibroblasts, endothelial cells, adipocytes, myocytes, and neurons). IL-6 facilitates diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute-phase protein synthesis, and stimulation of hematopoiesis. IL-6 signals via a receptor complex comprising its specific receptor, the IL 6 receptor alpha (IL-6Rα) and gp130, the signal transducing subunit. The IL-6Rα exists in 2 forms; a membrane-bound form and a soluble form.34 Once a monomer of IL-6 binds a monomer of either form of the IL-6Rα (termed “classic” signaling when using the membrane bound form and “trans” signaling when using the soluble form), the IL-6-IL-6Rα complex is engaged by a gp130 homodimer. Activation of IL-6 signal transduction is initiated and mediated by gp-130-associated Janus activated kinases (JAKs) and phosphorylation of signal transducer and activator of transcription 3 (STAT-3), resulting in subsequent intracellular signaling (Figure 1).30,45,57

17 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 1: Classic and Trans IL-6 Signal Transduction

A substantial body of evidence has demonstrated a key role for IL-6 in RA.22,64 Serum IL-6 levels have been shown to correlate with disease activity and structural damage progression.4,23 Increased concentrations of IL-6 in the joints may stimulate leukocyte recruitment to the joint, promote osteoclast maturation and activation, suppress chondrocytes, and stimulate synovial proliferation, contributing to inflammation and joint damage.

Monoclonal antibodies (mAbs) that target the IL-6 pathway by blocking the IL-6R (eg, tocilizumab and sarilumab) have been clinically validated and are currently approved for treatment of adult patients with moderately to severely active RA who have had an inadequate response or intolerance to one or more DMARDs23,13; however, agents that directly inhibit the circulating extracellular IL-6 cytokine are not yet approved for the treatment of RA. Siltuximab (SYLVANT®) a mouse-human chimeric mAb (murine variable region with human constant region) that binds IL-6, is approved for the treatment of multicentric Castleman’s disease.

18 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

2.2. Sirukumab

2.2.1. Inhibition of IL-6 by Sirukumab in RA Sirukumab (also known as CNTO 136) is an immunoglobulin G1 kappa (IgG1) mAb that was derived from siltuximab by a process of a humanization and affinity-maturation resulting in a mAb that binds with high affinity (0.175 pM) and specificity to the cytokine IL-6 preventing IL-6-mediated signaling.

Sirukumab inhibits the direct pro-inflammatory effects of IL-6 in the joints, which can lead to joint pain, inflammation, and joint destruction. The direct effects of IL-6 neutralization by sirukumab are reflected in near normalization of acute phase reactants, especially serum C-reactive protein (CRP) and Serum Amyloid A (SAA). Similarly, increased levels of other proteins which are linked to joint destruction such as matrix metalloproteinase 3 (MMP-3) are nearly normalized.

In addition, by inhibiting IL-6-mediated inflammation outside of the joint, sirukumab can have an impact on other IL-6 induced systemic pathologies. For example, sirukumab has been shown to improve the anemia of chronic inflammation in RA by decreasing hepcidin, a hepatic acute phase reactant which regulates iron accessibility.33 Furthermore, it is hypothetically possible that sirukumab may have an impact on the effects of IL-6 in the CNS such as depression which is a major comorbidity for patients with RA.17

2.2.2. Placement within the RA Treatment Paradigm Current ACR guidelines (2015) highlight the importance of discussion about individualized treatment decision-making between patients and their clinicians. Access to a variety of treatment options remains critical for patients with moderately to severely active RA who inadequately respond or are intolerant to currently available DMARDs or biologics such as anti-TNFα agents. Sirukumab has demonstrated robust and consistent efficacy and safety in 3 different patient populations that reflect more difficult to treat patients in current clinical practice: DMARD intolerant or inadequate responder (DMARD-IR), anti-TNFα intolerant or inadequate responder (anti-TNFα-IR) and MTX intolerant or inadequate responder (monotherapy). Of note, sirukumab not only demonstrated efficacy on signs and symptoms and radiographic endpoints, but also showed benefit in quality of life endpoints which remains an area of high unmet medical need.

Sirukumab represents an additional option for clinicians and patients, including those who have failed other biologics, offering an alternative treatment approach to suppressing IL-6 mediated inflammation, a well-validated pathway relevant to RA. Sirukumab is available in 2 different presentations suitable for self-administration with a convenient every 4 week dosing schedule.

2.3. Formulation Development Sirukumab drug substance is manufactured by Janssen Sciences Ireland UC (formerly Janssen Biologics) in Cork, Ireland using a NS0 cell line and continuous perfusion cell culture followed by purification. The drug substance is subsequently formulated to 50 and 100 mg/mL and filled in 1 mL syringes, then assembled into a device in a Johnson & Johnson facility, Cilag AG in 19 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Schaffhausen, Switzerland. The formulated solution contains 50 or 100 mg sirukumab active drug substance, sorbitol, glacial acetic acid, sodium acetate trihydrate, and polysorbate 20 and water for injection. All excipients comply with USP/NF, Ph. Eur, and JP/JPE compendia specifications. No preservatives or excipients of human or animal origin are present. Recommended storage conditions are 2ºC to 8ºC with protection from light for a proposed period of up to 24 months.

2.3.1. Pharmaceutical Form

Three different drug product presentations of sirukumab were used in clinical studies as indicated in Table 1, Section 3. The intended commercial presentations are the pre-filled syringe and the autoinjector described below:

1. Sirukumab Final Vialed Product (FVP) is a single-use, sterile, ready-to-use liquid-filled vial product for intravenous (IV) or subcutaneous (SC) administration. Each 1 mL of the solution contains 100 mg sirukumab active drug substance, sorbitol, acetate buffer, and polysorbate 20, at a pH of 5.0. No preservatives are present.

2. Sirukumab prefilled syringe-UltraSafe (PFS-U) is a single-use, sterile, ready-to-use liquid- filled 1-mL-long syringe product supplied with a passive safety needle guard (UltraSafe Passive Delivery System, Safety Syringes, Inc.) for SC administration. Each 1 mL of the solution contains 100 mg or 50 mg sirukumab active drug substance, sorbitol, acetate buffer, and polysorbate 20, at a pH of 5.0. No preservatives are present.

3. Sirukumab prefilled syringe-SmartJect Autoinjector (PFS-AI) is a single-use, sterile, ready-to-use liquid-filled 1-mL-long syringe product supplied with a spring-powered, disposable device for SC administration of liquid biologic drug products (SmartJect Autoinjector) that is permanently assembled on the syringe. Each 1 mL of the solution contains 100 mg or 50 mg sirukumab active drug substance, sorbitol, acetate buffer, and polysorbate 20, at a pH of 5.0. No preservatives are present.

2.3.2. Device Information Two product presentations have been developed for sirukumab to facilitate safe and effective SC administration by intended users, and to enable clinicians to select the presentation best suited to the needs of the individual patient:

 A PFS assembled with an automatically activated UltraSafe needle guard (PFS-U)  A PFS assembled with the SmartJect autoinjector (PFS-AI)

The design of both devices was driven by extensive patient and care giver involvement and reflects current state-of-the-art technology.

The PFS-U with the UltraSafe needle guard permits conventional needle insertion and injection, typically preferred by Health Care Professionals (HCPs) administering drug to patients. After the dose is fully injected, a guard automatically releases and extends and locks over the needle permitting safe disposal into a sharps container.

20 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

The SmartJect autoinjector was specifically designed for self-administration by patients with RA and features an oversized grip and actuation button. After pressing the device against the injection site, the user pushes the actuation button and waits approximately 3-5 seconds as the needle is automatically inserted, the dose is delivered, and the needle retracts. Visual and audible indicators signal that the injection is complete.

Both delivery devices were evaluated in the pivotal Phase 3 RA studies with sirukumab, and both devices have been used with other Janssen drugs and have an 8-year history of safe and effective clinical and commercial use. The PFS-U and PFS-AI designs are supported by multiple Human Factors Studies and clinical studies. PK data from healthy patients and RA patients demonstrated the comparability of SC delivery by the 2 delivery devices, and they can be used interchangeably.

The PFS-U and PFS-AI are described in greater detail in Appendix 1.

2.4. Proposed Indication and Dosing The proposed indication for sirukumab is as follows:

 PLIVENSIA, an interleukin-6 (IL-6) inhibitor, is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or are intolerant to one or more disease modifying anti-rheumatic drugs (DMARDs). PLIVENSIA may be used as monotherapy or in combination with nonbiologic DMARDs, including methotrexate (MTX).

The recommended dosage for adult patients with RA is 50 mg every 4 weeks given as a SC injection. The use of sirukumab with other biological DMARDs or targeted small molecules is not recommended. Sirukumab would be available as a solution for injection for SC administration in 2 presentations:

 SmartJect® autoinjector/prefilled pen, containing 1 mL solution with 50 mg sirukumab  Prefilled syringe, containing 1 mL solution with 50 mg sirukumab

2.5. Regulatory History Since the start of the clinical development program for sirukumab for the treatment of RA in 2008, the Sponsor has had regular interactions with the FDA regarding its development.

In March 2008, a pre-IND meeting to discuss the development of sirukumab for the treatment of adult patients with moderately to severe RA was held. The IND for sirukumab in RA was submitted to the Agency in June 2008.

In April 2011, the End-of-Phase 2 meeting was held to discuss the pivotal Phase 3 studies including overall design and study efficacy evaluations, dose selection, statistical analysis methods, and safety evaluations, as well as to obtain advice on the plans for use of the to-be-marketed product presentation in clinical studies.

21 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

In July 2013, the Agency provided information regarding the type of data required to support a claim for use of sirukumab as a monotherapy. The agreement was established on the size of the safety database needed to support registration.

At the pre-BLA meeting on 18 May 2016, the Agency provided input regarding the overall content and format of the BLA submission. In addition, the Agency agreed with the proposed approach in response to their request for additional sensitivity analyses to address missing data, and the Statistical Analysis Plans (SAPs) for the individual clinical trials and the Integrated Summary of Safety (ISS).

The sirukumab Biologics License Application (BLA) in RA was submitted to the FDA in September 2016. A 120-Day Safety Update was submitted in January 2017.

In addition, Janssen obtained input in parallel from other health authorities in the EU and Japan to support global registration of sirukumab.

22 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

3. OVERVIEW OF CLINICAL DEVELOPMENT PROGRAM The global development program for sirukumab in RA was designed to fully evaluate the efficacy as well as the safety of sirukumab in adults with moderately to severely active RA, representing a diverse patient population with RA akin to current clinical practice, including DMARD intolerant or inadequate responder or TNFα intolerant or inadequate responder, and MTX intolerant or inadequate responder patients. A complete overview of the sirukumab clinical development program (Phases 2 and 3) to support the marketing license application of sirukumab in RA is provided in Table 1.

The sirukumab clinical development program in RA was designed to meet the needs of health authorities globally.

During the conduct of the studies, multiple steps were implemented to ensure proper operational study oversight focusing on identification and resolution of operational and quality issues to ensure data integrity, protocol compliance, and safety of the study participants.

All clinical studies were conducted in compliance with internal SOPs, ICH, FDA, GCP and regulatory guidelines. Investigator site and data audits were performed during study conduct to evaluate compliance with aforementioned internal SOPs, ICH, FDA, GCP and regulatory guidelines and ensure the accuracy and reliability of the clinical study data.

A total of five Phase 1 studies were conducted with sirukumab, including a first-in-human study of IV administration; a multiple ascending-dose study of IV administration in stable lupus patients; a study in healthy Japanese and Caucasian patients with SC administration; an absolute SC bioavailability and PK comparability study; and a drug interaction study in patients with RA.

The Phase 2 study C1377T04 was designed as a sequential proof of concept and dose finding study to establish the efficacy of subcutaneous sirukumab in patients with active RA despite MTX therapy and to examine the efficacy and safety of multiple doses of sirukumab administered SC to determine the doses to be studied in the Phase 3 program.

The ARA3002 and ARA3003 pivotal Phase 3 studies (Sections 5.4.1 and 5.4.2, respectively) were 2 placebo-controlled, mutually confirmatory studies that provided independent substantiation of the efficacy and safety of sirukumab in the treatment of moderate to severe RA. Both studies were similarly designed with the same primary and major secondary clinical endpoints (Table 1). Study ARA3002 also had a radiographic endpoint.

To ensure the design of the program addressed patients with the greatest unmet needs, these studies included:

 Patients who had responded inadequately to previous therapy with one or more conventional nonbiologic DMARDs who required biologic therapy (study ARA3002)  Patients with an inadequate response or who were intolerant to anti-TNFα agents and needed a drug with another mode of action (study ARA3003)

23 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Sirukumab monotherapy was evaluated in proportion of patients intolerant to MTX as part of studies ARA3002 and ARA3003 (12% overall). Additionally, a further study ARA3005 was conducted to assess the efficacy and safety of sirukumab monotherapy compared with adalimumab monotherapy in biologic-naïve s patients with active RA who were intolerant to MTX, who were considered inappropriate for treatment with MTX, or who were inadequate responders to MTX [Section 5.6.2]). Another small study ARA3001 was conducted to assess the safety and efficacy of sirukumab monotherapy specifically in Japanese patients who were inadequate responders to MTX or SSZ.

To better understand the impact of long-term use of sirukumab, patients who completed participation in ARA3002 or ARA3003 studies were eligible for inclusion in the ARA3004 5-year long-term extension (LTE) study.

The overall safety database for the Phase 3 development program included approximately 3000 patients treated with sirukumab for up to 3.4 years, with approximately 2000 patients treated with sirukumab for at least 1 year to allow a robust evaluation of the safety of sirukumab in RA (Section 6).

Collectively, the development program provided a robust data set to allow for the evaluation of the efficacy and safety of sirukumab in several key RA patient populations with unmet medical needs (Section 8). A detailed presentation of the safety and efficacy data from the program is provided in the next sections.

24 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 1: Overview of Phase 2 and Phase 3 Studies of Sirukumab in Patients with Active Rheumatoid Arthritis

Drug Patients Population / Number of Study Phase Study Design Key Objective(s) Presentation Patients Enrolled C1377T04 2 Vial Patients with active RA despite Phase 2, 2-part, multicenter, randomized, double- MTX therapy blind, parallel-group, placebo controlled, proof-of- n=187 concept and dose finding study designed to evaluate Proof-of-concept (part A, n=36; part B, n=151) the efficacy and safety of multiple doses of sirukumab Dose finding administered subcutaneously in patients with active RA despite MTX therapy ARA3002 3 PFS-U Patients with active RA despite Phase 3 multicenter, randomized, double-blind, DMARD therapy parallel-group, placebo-controlled, study to evaluate Pivotal DMARD-IR n=1670 the efficacy and safety of sirukumab administered SC in patients with active RA despite DMARD therapy ARA3003 3 PFS-U Patients with active RA despite anti- Phase 3 multicenter, randomized, double-blind, TNFα therapy parallel-group, placebo-controlled, study to evaluate Pivotal Anti-TNFα- n=878 the efficacy and safety of sirukumab administered SC IR in patients with active RA despite anti-TNFα therapy ARA3004 3 PFS-AI Patients who participated in Study Multicenter, parallel-group study of long-term safety ARA3002 or Study ARA3003 and and efficacy of sirukumab for RA in patients Long-term extension consented to enroll in the LTE completing treatment in Studies ARA3002 and n=1820 (as of 16 August 2016) ARA3003 ARA3005 3 PFS-U Biologic naïve patients with active Phase 3 study to evaluate the efficacy and safety of RA who are intolerant to MTX, who sirukumab monotherapy compared with adalimumab are considered monotherapy inappropriate for treatment with Monotherapy MTX, or who are inadequate responders to MTX n=559 ARA3001 3 PFS-U Active RA patients unresponsive to Phase 3 multicenter, randomized, double-blind, MTX or sulfasalazine parallel-group study to evaluate efficacy and safety of Safety (Japan only) n=122 sirukumab administered SC in Japanese patients with active RA unresponsive to methotrexate or Monotherapy sulfasalazine

25 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

4. SUMMARY OF CINICAL PHARMACOLOGY

4.1. Pharmacokinetics The PK characteristics of sirukumab are consistent with typical human IgG monoclonal antibodies that target soluble ligands. Following SC administration as a single dose in healthy patients or as repeat doses in patients with RA, the area under the concentration-time curve (AUC) and maximal serum concentration (Cmax) increased in a dose-proportional manner over a dose range of 25 to 100 mg.

Following SC administration, the time to reach maximum serum concentrations (Tmax) ranged from 3 to 5 days. A single SC administration of 50 mg or 100 mg to healthy patients produced a mean ± standard deviation Cmax of 4.50 ± 1.48 µg/mL and 9.34 ± 3.10 µg/mL, respectively. The mean absolute bioavailability following a single SC dose of sirukumab was approximately 90%. Following repeat SC administrations of sirukumab in patients with RA, trough serum sirukumab concentrations reached steady state by Week 12 with median steady-state trough concentrations in different Phase 3 studies ranging from 1.40 to 1.75 µg/mL and 8.30 to 10.13 µg/mL, respectively, for 50 mg q4w and 100 mg q2w.

The mean volume of distribution ranged from 121.3 to 247.7 mL/kg in healthy patients. As a human IgG1κ monoclonal antibody, sirukumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. The mean systemic clearance appeared to be dose independent and ranged from 3.8 to 6.1 mL/day/kg following a single IV administration of sirukumab 0.3 to 10.0 mg/kg. The mean terminal half-life ranged from 15 to 19 days in both healthy patients and RA patients.

Age, sex, race, immunogenicity, baseline disease characteristics and concomitant use of MTX and other DMARDs, NSAIDs, or corticosteroids had no significant impact on the PK of sirukumab. Diabetic comorbidity and body weight were identified to influence the apparent clearance (CL/F) of sirukumab. Diabetic comorbidity increased sirukumab CL/F by approximately 13%, a small effect that does not warrant dose adjustment. On the other hand, body weight had a more influential effect on sirukumab CL/F. Compared with a patient with a standard body weight of 70 kg, a patient weighing 100 kg is expected to have approximately 32% higher CL/F, which prompted further analysis to evaluate the relative benefit of weight- based dosing adjustment. Further efficacy subgroup analysis in Phase 3 studies showed that sirukumab was efficacious across different weight groups, with comparable efficacy between sirukumab 50 mg q4w and 100 mg q2w dose regimens in patient with increasing body weight. Therefore, body weight-based dose adjustment is not warranted (Section 5.5).

4.2. Drug-Drug Interactions The propensity for direct drug-drug interactions between sirukumab and substrates, inhibitors or inducers of cytochrome P450 enzymes (CYP) and/or drug transporters is low since sirukumab is catabolized by proteolysis at the reticuloendothelial system, which is different from the metabolic pathways via CYPs and transporters for small-molecule drugs. However, CYP enzyme

26 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document activities can be suppressed in patients with inflammation. A reduction of inflammation following treatment with sirukumab may normalize CYP enzyme activities.

The effect of sirukumab treatment on CYP enzyme activities (CYP2C9, CYP2C19, CYP3A4, and CYP1A2) was evaluated in subjects with active RA. One week following a single SC administration of 300 mg sirukumab, AUCinf for midazolam, omeprazole, and S-warfarin were reduced by approximately 30%, 45%, and 18%, respectively, while caffeine AUCinf was increased by approximately 20%. Similar results were observed at 3 and 6 weeks after sirukumab SC administration, which indicated that the effect of sirukumab on CYP substrates was sustained for at least 6 weeks. The effect of sirukumab on the CYP enzymes may be clinically relevant for CYP substrates with narrow therapeutic indices, where the dose is individually adjusted. Therefore, upon initiation or discontinuation of sirukumab, in patients being treated with these types of medicinal products, therapeutic monitoring of effect (eg, warfarin) or drug concentration (eg, cyclosporine, theophylline) should be performed and the individual dose of the drug adjusted as needed. Caution should be exercised when sirukumab is coadministered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (eg, oral contraceptives).

4.3. Immunogenicity The incidence of antibodies to sirukumab through Week 52 was low (2.6% overall, 3.9% for 50 mg q4w, and 1.4% for 100 mg q2w) in the placebo-controlled Phase 3 studies (ARA3002 and ARA3003). Of the patients who were positive for antibodies to sirukumab through Week 52, 13.2% of these patients were positive for neutralizing antibodies (NAbs) to sirukumab, equating to an overall incidence of NAbs of 0.3% in all sirukumab-treated patients in these 2 studies. The incidence of antibodies to sirukumab was similar in patients regardless of DMARD use; however, concomitant use of MTX seemed to slightly decrease the incidence of antibodies to sirukumab (2.4% vs 3.8% in patients with and without MTX, respectively).

In the monotherapy study ARA3005, the incidence of antibodies to sirukumab through Week 24 was low (3.2% overall, 1.8% for 50 mg q4w, and 4.7% for 100 mg q2w). Of the patients who were positive for antibodies to sirukumab, 9.1% of these patients was positive for NAbs to sirukumab, equating to an overall incidence of NAbs of 0.3% in all sirukumab treated-patients in this study. The immunogenicity results from the Phase 3 Japanese monotherapy study (ARA3001) were consistent with the results observed in study ARA3005.

The presence of antibodies to sirukumab did not have an apparent impact on sirukumab CL/F, clinical efficacy and safety (injection site reactions or hypersensitivity).

4.4. Biomarkers Acute phase and inflammation-related biomarkers are known to be linked to RA disease severity (including radiographic progression) and the IL-6 inflammatory pathway.23 The suppression of these inflammatory biomarkers has been shown to correlate to clinical efficacy in the Phase 3 studies.

27 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

In the Phase 2 study, the biological effect of sirukumab on a series of acute phase and inflammatory biomarkers was evaluated following treatment with 4 different dose regimens of sirukumab (25 mg q4w, 50 mg q4w, 100 mg q4w and 100 mg q2w). Full biological impact of sirukumab treatment was achieved with sirukumab 50 mg q4w and higher dose regimens, but not with 25 mg q4w. The pharmacodynamic effects with sirukumab 25 mg q4w on acute phase (CRP and SAA) and inflammation-related disease (MMP-3) biomarkers were modestly lower than the maximal impact observed with 50 mg q4w and higher treatment regimens (Figure 2). The most pronounced difference was seen with the suppression of MMP-3. Sirukumab 25 mg q4w resulted in only 24% decrease in MMP-3 levels, compared with an 18% decrease observed with placebo, whereas sirukumab 50 mg q4w, 100 mg q4w and 100 mg q2w decreased MMP-3 levels by 53%, 60% and 50%, respectively, after 12-weeks treatment. These data suggested that sirukumab 50mg q4w or higher would be required to be fully effective in suppressing the IL-6-mediated inflammation pathway.

In the Phase 3 studies, rapid decreases in CRP and SAA levels were observed as early as Week 2. Sustained suppression of CRP and SAA in sirukumab-treated patients was observed. Consistent with the effect on acute phase reactants, treatment with sirukumab was associated with reductions in platelet count and neutrophil count; however, both generally remained within the normal range. Increases in hemoglobin levels were also observed and were associated with decreased levels of hepcidin which may lead to increased iron availability.

Figure 2: Dose-response in Changes of Pharmacodynamic Biomarkers Following 12-week Treatment with Sirukumab (Study C1377T04 Part B)

Percent change from baseline to week in serum levels of the indicated protein, displayed as the geometric mean ± standard error for the indicated treatment group. * p<0.05 vs. sirukumab 25 mg q4w. P-values indicated for trends of p<0.10 for sirukumab treatment group vs. sirukumab 25 mg q4w.

28 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

5. SUMMARY OF CLINICAL EFFICACY This section provides a summary of the Phase 2 and 3 data demonstrating the efficacy of sirukumab in patients with moderately to severely active RA. Data are provided from (1) a Phase 2 proof-of-concept and dose-finding study, C1377T04, which informed the choice of dosing regimens for the Phase 3 studies, (2) two global placebo-controlled Phase 3 studies (ARA3002 and ARA3003) demonstrating the efficacy of treatment with sirukumab in improving signs and symptoms, improving physical function and patient-reported health-related quality of life as well as inhibiting progression of structural damage (ARA3002 only) where most patients received background synthetic-DMARDs and 3) an active-controlled Phase 3 study (ARA3005) demonstrating the efficacy of sirukumab given as monotherapy.

5.1. Efficacy Endpoints The efficacy of sirukumab in Phase 2 and 3 was evaluated using validated measures as per FDA (February 1999) and EMA guidance (December 2003) for industry on clinical development programs for products for the treatment of RA. A summary of these efficacy measures is provided in Appendix 8.

5.2. Phase 2 Study

5.2.1. Phase 2 Study Design Study C1377T04 was a 2-part, international, multicenter, randomized, double-blind, parallel- group, placebo-controlled, study designed as a proof of concept study (Part A) and a dose- finding study (Part B) to evaluate the efficacy and safety of multiple doses of sirukumab administered SC in patients with active RA despite MTX therapy. All patients were to remain on a stable dose of MTX through Week 24 unless the dose needed to be adjusted for signs/symptoms of MTX toxicity. Active disease was defined as at least 6 tender joints out of 68 and 6 swollen joints out of 66 despite MTX therapy at a dose of ≥15 mg/week (≥8 mg/week at Japanese sites) for at least 4 months prior to screening. In addition, patients had to have been anti-cyclic citrullinated peptide antibody (anti-CCP) positive or rheumatoid factor (RF) positive at screening and a screening C-reactive protein (CRP) ≥1.0 mg/dL. As RA is a chronic disease, the totality of the data including onset of effect, and benefit risk through 12 weeks and 24 weeks were evaluated. A total of 187 patients were randomized in this study.

In Part A (the proof-of-concept portion), 36 patients were randomly assigned in a 1:1 ratio to receive sirukumab 100 mg SC q2w or placebo SC through Week 10. At Week 12, patients randomized to sirukumab were to receive placebo and patients randomized to placebo were to receive sirukumab 100 mg SC injections q2w through Week 22 (Figure 3). The major efficacy endpoints for Part A were the change from baseline in Disease Activity Index Score 28 (DAS) using CRP (DAS28 [CRP]) at Week 12 and ACR 50 response at Week 12.

29 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 3: Study Design - Study C1377T04 – Part A

In Part B (the dose-finding portion), 151 patients were randomly assigned in a 1:1:1:1:1 ratio to receive SC placebo, sirukumab 100 mg q2w, sirukumab 100 mg q4w, sirukumab 50 mg q4w, or sirukumab 25 mg q4w for a 24-week blinded dosing period. At Week 12, patients randomized to the placebo group were to receive sirukumab 100 mg SC injections q2w through Week 24 (Figure 4). The primary endpoint in Part B was ACR 50 response at Week 12.

Figure 4: Study Design - Study C1377T04 – Part B

30 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

The Phase 2 dose regimens were selected based on the clinical PK, PD (high-sensitivity CRP [hs-CRP]) and safety data from the first-in-man study C0136T01 as well as preclinical toxicology data. In study C0136T01, a single IV administration of 0.3 to 10.0 mg/kg sirukumab was well tolerated. Based on the relationship between sirukumab concentration and hs-CRP observed in C0136T01, SC administration of sirukumab at 100 mg q2w was predicted to produce trough serum concentrations that would effectively suppress CRP levels. The inclusion of 3 lower dose regimens (25 mg q4w, 50 mg q4w and 100 mg q4w) in the Phase 2 study was aimed to estimate a minimally efficacious dose for the treatment of RA through the evaluation of an 8- fold dose range. The 6-month toxicology study with once-weekly IV sirukumab doses in cynomolgus monkeys demonstrated that the no observed effect level for IV sirukumab was 50 mg/kg weekly, which supported adequate safety margins for the 4 dose regimens evaluated in the Phase 2 study.

5.2.2. Phase 2 Efficacy Results: Signs and Symptoms Part A of the study established proof-of-concept with sirukumab 100 mg q2w by achieving a statistically significant difference from placebo in improvement from baseline in DAS28 (CRP) and a nominally significant difference in the proportion of patients achieving an ACR 20 response at Week 12. In addition, a higher proportion of patients receiving sirukumab than placebo achieved ACR 50 response at Week 12.

Part B evaluated 4 sirukumab dosing regimens (25 mg q4w, 50 mg q4w, 100 mg q4w, and 100 mg q2w) and a placebo control arm (cross-over to 100 mg q2w at Week 12) for a 24-week blinded dosing period. A higher proportion of patients achieved the primary endpoint of ACR 50 response at Week 12 in Part B in each of the 4 sirukumab treatment groups compared with the placebo group; patients in the sirukumab 100 mg q2w and 50 mg q4w treatment groups achieved statistically significant (p <0.05) greater response compared with placebo (Figure 4).

Dichotomous Endpoints The time courses of proportion of patients who achieved ACR 20/ACR 50 responses by visit in Part B are graphically displayed in Figure 5. Similarly, the time courses of proportion of patients who achieved DAS28 (CRP) Good Responses (ie, DAS28 [CRP] improvement from baseline >1.2 and DAS28 (CRP) 3.2 at the visit) or DAS28 (CRP) ≤2.6 are presented in Appendix 2. All sirukumab treatment groups demonstrated efficacy compared with the placebo group at Week 12. No clear dose-response relationships were observed for ACR 20/ACR 50 response rates and DAS28 (CRP) ≤2.6 at Week 12. Nevertheless, a separation of the 2 higher dose regimens (100 mg q4w and 100 mg q2w) from the 2 lower dose regimens (25 mg q4w and 50 mg q4w) was still observed for the higher thresholds of response such as ACR 50, DAS28 (CRP) <2.6, particularly at later time points such as Week 24. These results showed that greater disease control can be achieved with longer duration of treatment. The dose-response trends observed at later time points were relevant to the decision regarding what doses to advance to Phase 3 since they are likely to reflect the benefit of chronic treatment with sirukumab.

31 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 5: Proportion of Patients who Achieved ACR 20/ACR 50 Responses by Visit (Study C1377T04 Part B)

Figures based on observed data

Continuous Endpoints The mean changes from baseline in DAS28 (CRP) or Clinical Disease Activity Index (CDAI) through Week 24 in Part B are presented in Figure 6. From the time course of mean changes from baseline in DAS28 (CRP) or CDAI, no clear dose-response relationships were seen for either DAS28 (CRP) or CDAI at early time points up to Week 12. In contrast, from Week 16 to Week 24, there was a clear separation among the 4 dose regimens for DAS28 (CRP) and a trend of dose-response was also evident for CDAI. Sirukumab 25 mg q4w had the least improvement from baseline in both DAS28 (CRP) and CDAI while sirukumab 100 mg q2w had the greatest improvement from the baseline for both DAS28 (CRP) and CDAI.

In line with the FDA's guidance60 for developing drug products for the treatment of RA, the results from the Phase 2 study of sirukumab also demonstrated that continuous endpoints such as DAS28 (CRP) and CDAI are more sensitive than dichotomous endpoints for assessing dose- response relationships in a dose-ranging study where the sample size for each dose group is relatively small.

32 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 6: Mean (SE) Changes from Baseline in DAS28 (CRP) (left panel) or Clinical Disease Activity Index (CDAI) (right panel) over time (Study C1377T04 Part B)

Figures based on observed data

5.2.3. Phase 2 Exposure-Response Analysis

5.2.3.1. Efficacy by Sirukumab Trough Concentration Quartiles Exposure-Response analysis can provide important information for dose selection. To evaluate the relationship between steady-state trough sirukumab concentration and clinical efficacy, the proportions of patients who achieved a certain clinical endpoint such as ACR 20, ACR 50 and DAS28 (CRP) ≤2.6 were compared among patients in the different quartiles of steady-state trough serum sirukumab concentrations at Week 12 and Week 24 using combined data from all 4 sirukumab dose groups.

At Week 12, no apparent E-R relationship was observed. However, an E-R relationship was observed at Week 24, with a greater proportion of patients achieving ACR 20/ACR 50 responses (Figure 7) and DAS28 (CRP) ≤2.6 (Appendix 3) at higher trough concentration quartiles. Compared with the E-R relationship with ACR 20, the higher threshold efficacy endpoints of ACR 50 and DAS28 (CRP) ≤2.6 showed clearer E-R relationships.

Treatment with sirukumab 25 mg q4w resulted in a median steady-state trough concentration of approximately 1.0 g/mL and was mainly represented in the lowest concentration quartiles. Therefore, the 25 mg q4w dose regimen was expected to result in lower efficacy compared with the 3 higher dose regimens. In contrast, treatment with sirukumab 50 mg q4w and 100 mg q2w resulted in a median steady-state trough concentration of approximately 1.6 g/mL and 11.4 g/mL, which mainly represented in the 2nd and 4th concentration quartile, respectively. These E-R results from this study, particularly in terms of higher threshold efficacy endpoints such as ACR50 and DAS28 (CRP) ≤2.6, supported the selection of sirukumab 50 mg q4w and 100 mg q2w for further evaluation in the Phase 3 studies.

33 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Exposure-response was more evident than dose response, which may be explained by the overlap in the sirukumab trough concentrations between dose regimens, and limited precision in efficacy measurements due to the modest sample size for each dose regimen. A relatively wider spread of exposure range when compared with dose range allows easier identification of a positive E-R trend. Thus, clinical efficacy is better predicted by drug exposure than dose alone.

Figure 7: Proportion of Patients Who Achieved ACR 20 Response and ACR 50 Response at Week 24 by Trough Serum Sirukumab Concentration (quartiles) at Week 24; PK Analysis Set (Study C1377T04 Part B)

This figure only includes patients treated with Sirukumab 25 mg q4w, 50 mg q4w, 100 mg q4w or 100 mg q2w from Week 0. ACR responses were based on the observed data. Patients with missing Sirukumab concentration, missing ACR 20 status, or missing ACR 50 status were excluded.

5.2.3.2. Exposure-Response Modeling Analysis In addition to serum trough level-efficacy analyses, a PK/ACR 20 E-R model was developed to support the dose selection for the Phase 3 studies. The PK/ACR 20 modeling analysis predicted that only the sirukumab 100 mg q2w dose regimen had an >80% probability of achieving a target value (PTV) of ≥30% difference and nearly 100% probability of achieving a target value of ≥ 20% difference in ACR 20 response relative to placebo at Week 24 (Figure 8). The lowest dose that was predicted to provide >80% probability of achieving a ≥20% difference in ACR 20 response compared with placebo was 50 mg q4w. The 25 mg q4w dose regimen was predicted to have approximately 70% probability of achieving a ≥20% difference compared with placebo.

These E-R analyses based on the Phase 2 data supported 50 mg q4w and 100 mg q2w to be evaluated in the Phase 3 studies and suggested that 25 mg q4w may provide sub-optimal clinical efficacy.

34 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 8: The Probability of Achieving a Target Value of ≥20% or ≥30% Difference in ACR 20 Response Relative to Placebo at Week 24 by Different Dose Regimens

5.2.4. Dose Rationale for Phase 3 Studies Based on a comprehensive analysis of all available information from the Phase 2 study including efficacy (ie, different endpoints at different time points), safety, PK, PD (ie, acute phase and inflammatory biomarkers) and E-R analysis, the justification for further evaluating the two dose regimens of sirukumab 50 mg q4w and 100 mg q2w in the Phase 3 RA studies is summarized below:

 ACR 20/ACR 50/ACR 70 response rates at Week 12, the time point for primary endpoint evaluation, did not show clear dose-response relationships. However, apparent dose- response trends were observed with both dichotomous and continuous efficacy endpoints at later time points.  When assessed by continuous efficacy endpoints including changes from baseline in both DAS28 (CRP) and CDAI, sirukumab 25 mg q4w showed the least improvement while sirukumab 100 mg q2w showed the greatest improvement. There was a clear separation of 25 mg q4w from 50 mg q4w and higher dose regimens for improvements in DAS28 (CRP) and CDAI at time points later than Week 16.

35 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

 Sirukumab 100 mg q2w group achieved the greatest clinical efficacy based on various endpoints compared with the 3 lower dose regimens. The 50 mg q4w regimen, which produces a 4-fold lower AUC and a 6-fold lower trough sirukumab concentration compared with 100 mg q2w, was selected to provide a lower drug exposure for assessing the benefit- risk profile of sirukumab.  An apparent E-R trend was observed for ACR 20/ACR 50 response rates and DAS28 (CRP) ≤2.6 at Week 24 by trough serum sirukumab concentration quartiles. The 100 mg q2w group was mainly represented in the highest concentration quartile with the highest response rates while the 25 mg q4w group was mainly represented in the lowest concentration quartile and was expected to result in lower efficacy compared with the 3 higher dose regimens.  The E-R modeling analysis suggested that sirukumab 50 mg q4w would be required to have a >80% probability of achieving a target of 20% difference in ACR 20 response rate relative to placebo, while sirukumab 100 mg q2w would have the potential for achieving ≥30% difference in ACR 20 response relative to placebo. In contrast, sirukumab 25 mg q4w was predicted to have <70% probability to achieve a 20% difference in ACR 20 response rate relative to placebo.  The 3 higher dose regimens (50 mg q4w, 100 mg q4w and 100 mg q2w) achieved full suppression of acute phase and inflammation-related biomarkers (CRP, SAA, and MMP-3) while the 25 mg q4w dose regimen demonstrated a lower level of suppression (Section 4.4).  No dose-related safety events were observed in the Phase 2 study with regard to overall treatment emergent adverse events or laboratory abnormalities. In conclusion, based on the totality of the Phase 2 data, it was expected that sirukumab 50 mg q4w would be a minimum dose regimen for achieving adequate efficacy (ie, ACR 20 response rate of 20% relative to placebo) while sirukumab 100 mg q2w would have the potential to achieve greater efficacy than sirukumab 50 mg q4w.

5.3. Phase 3 Studies Data presented are derived from two pivotal Phase 3 placebo-controlled studies, ARA3002 (DMARD-IR trial) and ARA3003 (TNFα-IR trial). Benefits were demonstrated across a number of difficult-to-treat patient populations representative of the full spectrum of patients moderately to severely active adult RA seen in current clinical practice, including patients naive to biologic treatment who had responded inadequately to conventional DMARDs through to those who have failed multiple biologics. The benefits of treatment were observed as early as Week 2 with the magnitude of response maintained through Week 52. Sirukumab in combination with DMARDs demonstrated consistent and clinically meaningful:

 Improvement in signs and symptoms Consistent, clinically and statistically significant improvements were demonstrated in ACR 20 as well as higher thresholds of efficacy, including ACR 50 response, major clinical response (MCR) and DAS28 (CRP)≤2.6. Within each study, ACR 20 response was consistent across a range of demographic and baseline disease subgroups.

36 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

 Inhibition of structural damage Robust, clinically and statistically significant inhibition of progression of structural damage as measured by change in vdH-S at Week 52 and seen as early as Week 24

 Improvement in physical function Statistically significant and clinically meaningful improvements in HAQ-DI

 Improvement in patient reported outcomes Consistent and clinically meaningful improvements in SF-36 physical and mental scores, in all 8 individual domains of the SF-36 as well as clinical relevant improvements in FACIT- fatigue

Subpopulation data from studies ARA3002 and ARA3003 in patients treated with sirukumab without concomitant DMARDs and data from the sirukumab monotherapy study ARA3005 in biologic-naïve patients with active RA establish the efficacy of sirukumab as monotherapy.

The Phase 3 clinical development program for sirukumab included more than 3200 adult RA patients encountered in clinical practice who may be candidates for biologic therapy. Both ARA3002 and ARA3003 each provide up to 1 year and ARA3005 provides up to 24 weeks of sirukumab treatment experience.

5.3.1. Statistical Analyses

5.3.1.1. Studies ARA3002 and ARA3003 A summary of the primary, major and other secondary endpoints evaluated for studies ARA3002 and ARA3003 is presented in Table 2.

37 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Treatment Failure (TF) Rules Treatment failure criteria were pre-specified. Through Week 52 for ARA3002 and Week 24 for ARA3003, a patient was deemed a TF if (1) treatment was initiated with DMARDs, systemic immunosuppressives, and/or biologics for RA (2) treatment was initiated or increased with oral corticosteroids for RA, or intravenous or intramuscular administration of corticosteroids for RA (3) study agent injection was discontinued due to any reason(s), (4) MTX increase above the baseline dose.

5.3.1.1.1. Analysis Methods for the Primary Endpoints

5.3.1.1.2. ACR 20 Response at Week 16 (ARA3002 and ARA3003) A Cochran-Mantel-Haenszel (CMH) test stratified by the use of MTX at baseline (0 mg/week, >  t  .5 mg/week, or ≥ 12.5 mg/week) was used to test treatment difference between a sirukumab group (50 mg q4w or 100 mg q2w) and the placebo group with respect to the proportion of patients who achieve an ACR 20 response at Week 16. The 95% confidence intervals (CIs) for the treatment differences were calculated based on the Wald statistics.

Pre-specified Imputation Rules: Patients who met TF criteria prior to Week 16 or had a missing ACR 20 response at Week 16 were considered non-responders. A summary of observed versus imputed data is provided in Appendix 9.

5.3.1.1.3. Change from Baseline in vdH-S Score at Week 52 (ARA3002) An analysis of variance (ANOVA) model was used to test the difference between a sirukumab group (50 mg q4w or 100 mg q2w) and the placebo group. In the model, the dependent variable is the van der Waerden normal score of change from baseline in vdH-S score at Week 52 and the independent variables are treatment group and use of MTX at baseline (0 mg/week, > 0 to < 12.5 mg/week, or ≥ 12.5 mg/week).

Pre-specified Imputation rules: For patients in the placebo group who met early escape (EE) criteria at Week 18, all scores after Week 18 (such as: scores at Weeks 24 and 52) were set to missing.

For patients in all treatment groups with missing vdH-S score at Week 52, the missing score at Week 52 was imputed by linear extrapolation, i.e., the predicted score using a linear regression model based on all observed scores prior to Week 52 (including baseline score) or set to baseline score if only baseline score is available.

Refer to Appendix 9 for analyses details on major secondary endpoints and a summary of observed versus imputed data for each primary endpoint.

39 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

5.3.1.1.4. Sensitivity Analyses For each of the primary endpoints an extensive number of sensitivity analyses were performed to explore the effect of missing data and to assess different assumptions on the impact of escape. Please refer to Appendix 9 for full details.

5.3.1.1.5. Subgroups To evaluate the consistency of sirukumab efficacy across subgroups of patients, pre-specified analyses were performed on the primary endpoint, ACR 20 at Week 16, in ARA3002 and ARA3003 by baseline demographics, disease characteristics and prior or concomitant treatment for RA. Refer to Appendix 13 for full details.

5.3.1.2. Study ARA3005 Data from all randomized patients who received at least 1 (partial or complete) dose of study agent, ie, full analysis set (FAS), were included and analyzed according to the randomized treatment groups.

ARA3005 was designed to demonstrate the superior efficacy of sirukumab monotherapy compared with adalimumab monotherapy. There were 2 primary endpoints:

 Change from baseline in DAS28 (ESR) at Week 24  Proportion of patients with an ACR 50 response at Week 24 A pre-specified hierarchy was used to control for multiple endpoints and doses (Appendix 9). Each of the hypotheses was tested at a 2-sided α-level of 0.05 provided that the significance was achieved for the preceding hypothesis in the specified order. If a given comparison was not significant at the 2-sided α-level of 0.05, the remaining treatment group comparisons were considered supportive analysis. Treatment failure criteria were pre-specified and details are provided in Appendix 9.

5.3.1.2.1. Analysis Method for the Primary Endpoints (ARA3005)

5.3.1.2.1.1. Change from Baseline in DAS28 (ESR) at Week 24 To compare the mean difference between sirukumab and adalimumab, an analysis of covariance (ANCOVA) model was used with change from baseline in DAS28 (ESR) at Week 24 as the dependent variable, and randomized treatment group, reason (efficacy or safety) for which patients failed MTX at baseline and baseline DAS28 (ESR) score as the independent variables. The model included data from all 3 randomized treatment groups. The treatment difference between sirukumab and adalimumab was estimated by difference in the least squares means (LSmeans) between these 2 groups. A 95% confidence interval (CI) and p-value for difference in the LSmeans between sirukumab and adalimumab was calculated based on contrast test statistics.

40 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Pre-specified Imputation rules For patients with non-missing DAS28 (ESR) score at baseline and missing DAS28 (ESR) score at Week 24, the missing DAS28 (ESR) value at Week 24 was replaced using the observed baseline DAS28 (ESR) score [that is, imputed as no change from baseline in DAS28 (ESR) score at Week 24]. For patients who met EE criteria, DAS28 (ESR) at Week 24 was replaced using LOCF from time of escape.

5.3.1.2.2. ACR 50 Response at Week 24 (ARA3005) A Cochran-Mantel-Haenszel (CMH) test stratified by reason (efficacy or safety) for which patients failed MTX at baseline was used to test treatment difference between sirukumab and adalimumab on proportion of patients who achieved an ACR 50 response at Week 24. A 95% CI for the treatment difference was calculated based on the Wald statistic.

Pre-specified Imputation rules Patients who met TF criteria prior to Week 24 or escape criteria at Week 16 were considered non-responders.

5.4. Phase 3 Studies - Combination Therapy

5.4.1. Study ARA3002 (DMARD-IR)

5.4.1.1. Design Study ARA3002 was designed as a key pivotal placebo-controlled study with clinical and radiographic endpoints assessing sirukumab in patients with moderately to severely active RA who had inadequate response to DMARDs, including MTX and SSZ. Background DMARDs were allowed but not required. Patients were not required to be biologic naïve however patients with a history of intolerance to at least 2 or inadequate response to at least 1 anti-TNF agent after 3 months of therapy were excluded. In addition, patients with a history of intolerance to or inadequate response to tocilizumab were excluded. Active disease was defined as at least 6 tender joints out of 68 and 6 swollen joints out of 66. In addition, patients must have had a screening CRP 8.00 mg/L and met 1 of the following 3 criteria prior to the first administration of study agent: (a) anti-CCP-positive at screening, (b) RF-positive at screening, or (c) documented history of radiographic evidence of erosive RA in hands or feet. Patients using nonbiologic DMARDs, must have been on a stable dose for at least 4 weeks prior to the first administration of study agent.

A total of 1670 patients were randomly assigned in a 1:1:1 ratio to receive treatment with placebo SC q2w, sirukumab 50 mg SC q4w, or sirukumab SC 100 mg q2w (Figure 9).

41 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 9: Study Design - ARA3002 (DMARD-IR)

The primary endpoints of the study were ACR 20 response at Week 16 and the change from baseline in vdH-S score at Week 52. To evaluate sirukumab’s treatment effect on radiographic progression, the study was designed with rescue treatment opportunities to reduce the risk to placebo patients of disease progression

At Week 18 (early escape) and Week 40 (late escape), patients in the placebo group who had <20% improvement from baseline in swollen and tender joint count were re-randomized to either sirukumab 50mg q4w or 100mg q2w in a blinded manner.

In addition, from Week 28, based on the investigators discretion, all randomized patients, who had <20% improvement from baseline in swollen and tender joint counts could adjust or initiate an additional DMARD (MTX, SSZ, hydroxycloroquine, chloroquine or bucillamine) or oral corticosteroids.

At Week 52, all remaining patients in the placebo group crossed over and were re-randomized in a 1:1 ratio to the 2 sirukumab groups to receive a sirukumab dose regimen from Week 52 through Week 104. Once all patients had crossed over, additional efficacy and safety assessments were continued for an additional 52 weeks to further characterize maintenance of benefit and longer-term safety. After study completion, patients had the option to enroll into a long-term extension study (ARA3004) for an additional 3 years (total follow up 5 years).

Efficacy data through week 52 is included in this submission.

42 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

5.4.1.2. Study Population A total of 1670 patients were enrolled at 185 sites globally. Most of the patients were enrolled in Eastern Europe (48.3%), followed by North America (16.3%), Asia-Pacific (16.0%), Latin America (13.4%), and South Africa (6.0%). Most of the patients completed 52 weeks of treatment either on their initial treatment or after having received escape therapy (Table 3). More patients in the sirukumab groups withdrew for adverse events than patients in the placebo group. Conversely, more patients in the placebo group met the criteria for escape therapy than in the sirukumab groups. Of the patients randomized to placebo, 273 (49.1%) remained on placebo through Week 52. Note that only about one-half (49%) of patients originally randomized to placebo were able to stay on placebo through Week 52. Of the patients randomized to sirukumab, 84-86% completed 52 weeks of treatment.

Table 3: Summary of Patient Disposition in Study ARA3002 (DMARD-IR) Sirukumab Placebo 50 mg q4w 100 mg q2w Patients randomized 556 557 557 Early escape 187 (34%) 81 (15%) 57 (10%) Late escape 24 (4%) 18 (3%) 21 (4%) Discontinued 97 (17%) 76 (14%) 87 (16%) Reason for discontinuation Adverse event 25 (4.5%) 40 (7.2%) 42 (7.5%) Lack of efficacy 23 (4.1%) 5 (0.9%) 14 (2.5%) Withdrawal of consent 19 (3.4%) 12 (2.2%) 16 (2.9%) Lost to follow-up 5 (0.9%) 4 (0.7%) 3 (0.5%) Physician decision 4 (0.7%) 1 (0.2%) 2 (0.4%) Pregnancy 1 (0.2%) 1 (0.2%) 0 Death 5 (0.9%) 2 (0.4%) 4 (0.7%) Other 15 (2.7%) 11 (2.0%) 6 (1.1%) Completed study through 52 459 (83%) 481 (86%) 470 (84%) weeks Completed study agent administrations through 52 273 (49.1%) 481 (86.4%) 470 (84.4%) weeks

Baseline disease characteristics were generally well balanced across the 3 treatment groups and were representative of a population of patients with moderately to severely RA with unfavorable prognostics factors (Table 4). In addition, the mean baseline total vdH-S score of approximately 42 indicated the presence of structural damage in this population.

Patients had to have been inadequate responders to single-agent or combination DMARD therapy that included MTX or SSZ as specified in the protocol: ~68.0% of patients had used 2 or more DMARDs Nearly all (98.5%) patients had a history of MTX use and over one third had prior exposure to biologic therapies. At baseline, 92.0% of patients were taking DMARDs.

43 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 4: Baseline Demographics and Disease Characteristics Sirukumab Placebo 50 mg q4w 100 mg q2w Analysis Set: Randomized Patients 556 557 557

Female 436 (78%) 447 (80%) 452 (81%) Age (years) Mean (SD) 52.9 (11.86) 52.9 (11.80) 53.0 (11.31) Median 54.0 54.0 54.0 Range (18, 82) (18, 82) (20, 81) Weight (kg) Mean (SD) 72.7 (17.4) 72.3 (18.6) 71.6 (17.1) Median 70.4 68.8 70.0 Range (37.5, 164.8) (37.5, 155.0) (39.7, 172.3) Disease Duration (years) Mean (SD) 8.3 (7.0) 8.7 (7.5) 8.8 (7.6) Median 6.4 7.0 7.0 Range (0.3, 38.0) (0.4, 43.6) (0.4, 50.0) CRP (mg/dL) Mean (SD) 2.5 (3.4) 2.4 (2.6) 2.4 (2.6) Median 1.7 1.6 1.6 Range (0.04, 47.80) (0.01, 25.20) (0.03, 20.60) Rheumatoid Factor Positive 444 (80%) 433 (78%) 468 (84%) Anti-CCP Positive 467 (84%) 476 (86%) 484 (87%) DAS28 (CRP) Mean (SD) 5.9 (0.9) 5.9 (0.9) 5.8 (0.9) Median 5.9 5.9 5.8 Range (2, 9) (3, 8) (2, 8) HAQ disability index (0-3) Mean (SD) 1.56 (0.65) 1.50 (0.62) 1.52 (0.66) Median 1.63 1.50 1.63 Range (0.00, 3.00) (0.00, 3.00) (0.00, 2.88) Baseline DMARDs 508 (91%) 517 (93%) 511 (92%) Baseline Corticosteroids 341 (61%) 331 (59%) 360 (65%) ≥ 2 prior DMARDs 373 (67%) 378 (68%) 384 (69%) Prior biologic use 196 (35%) 175 (31%) 212 (38%) Baseline vdH-S score Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment 550 553 551 Mean (SD) 41.94 (46.67) 41.82 (45.3) 42.51 (49.312) Median 25.25 22.50 25.50 Range (0.0; 260.2) (0.0; 225.5) (0.0; 334.8)

44 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

5.4.1.3. Results

5.4.1.3.1. Signs and Symptoms Sirukumab demonstrated statistically significant and clinically meaningful reductions in signs and symptoms of RA over placebo. For the first primary endpoint of ACR 20 response at Week 16, as well as all 4 major secondary endpoints were met, statistical significance was shown for both sirukumab doses (50 mg q4w and 100 mg q2w) compared with placebo based on pre-specified multiple testing procedures (Table 5). The onset of ACR response was rapid, with differences between sirukumab and placebo as early as Week 2 (the first scheduled assessment) for ACR 20 (Figure 10). ACR 20 response peaked within 12 weeks and was maintained through Week 52.

45 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 5: Primary and Major Secondary Endpoint in ARA3002 Sirukumab Placebo 50 mg q4w 100 mg q2w Primary Endpoints ACR 20 response at Week 16 556 557 557 Patients in response 147 (26.4%) 305 (54.8%) a 298 (53.5%) a Difference vs. placebo (95% CI)e 0.28 (0.23, 0.34) 0.27 (0.22, 0.33)

Patients evaluable for change from 550 553 551 baseline in vdH-S score at Week 52 Mean (SD) 3.69 (9.245) 0.50 (2.961) a 0.46 (3.258) a Mean Difference (95% CI)h -3.19 (-4.03, -2.41) -3.23 (-4.08, -2.44)

Major Secondary Endpoints Patients evaluable for change from 556 557 557 baseline in HAQ-DI d Score at Week 24 Mean (SD) -0.22 (0.53) -0.43 (0.58) a -0.46 (0.57) a LSMean Difference (95% CI) g -0.23 (-0.29, -0.17) -0.26 (-0.32, -0.20)

Patients evaluable for ACR 50 Response at 556 557 557 Week 24 Patients in response 69 (12.4%) 168 (30.2%) a 185 (33.2%) a Difference (95% CI) e 0.18 (0.13, 0.22) 0.21 (0.16, 0.26)

Patients evaluable for DAS28 (CRP) ≤2.6 556 557 557 at Week 24 Patients in response 31 (5.6%) 145 (26.0%) a 142 (25.5%) a Difference (95% CI)e 0.21 (0.16, 0.25) 0.20 (0.16, 0.24)

Patients evaluable for Major Clinical 556 557 557 Response by Week 52 Patients in response 10 (1.8%) 30 (5.4%) b 50 (9.0%) a Difference (95% CI)e 0.04 (0.01, 0.06) 0.07 (0.05, 0.10)

Other Secondary Endpoints Patients evaluable for ACR 70 Response at 556 557 557 Week 24 Patients in response 19 (3.4%) 83 (14.9%) c 91 (16.3%) c Difference (95% CI)e 0.12 (0.08, 0.15) 0.13 (0.10, 0.16)

Patients evaluable for change from 556 557 557 baseline in CDAI d at Week 24 Mean (SD) -10.68 (15.302) -18.45 (14.936) c -18.80 (14.075) c LSMean Difference (95% CI)f -7.77 (-9.50, -6.03) -8.11 (-9.85, -6.38) a p value <0.001 compared with placebo b p value 0.001 compared with placebo c nominal p value <0.001 compared with placebo d a negative change from baseline (i.e., a decrease) indicates improvement e the confidence intervals were based on Wald statistic. f the confidence intervals and p-values are based on ANCOVA g the confidence intervals were based on ANCOVA. h the confidence interval was based on the 2.5th and 97.5th percentiles of the mean differences from the bootstrap samples.

For ACR 20, ACR 50, ACR 70, MCR, DAS28 (CRP) ≤2.6: Patients with missing data, treatment failure, or early escape were treated as non- responders For change in HAQ and CDAI: Patients with missing data, or post early escape had values imputed by LOCF

46 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 7: Erosion and Joint Space Narrowing Score at Weeks 24 and 52 Sirukumab Placebo 50 mg q4w 100 mg q2w Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment 550 553 551

Patients evaluable for change from baseline in erosion score at Week 24 550 553 551 Mean (SD) 1.21 (3.348) 0.10 (1.306) a 0.08 (1.321) a Median 0.00 0.00 0.00 Range (-6.2; 42.5) (-6.0; 8.0) (-5.0; 14.5) IQ range (0.00; 1.32) (0.00; 0.50) (-0.50; 0.00) Mean Difference (95% CI)c -1.10 (-1.42, -0.82) -1.13 (-1.44, -0.844)

Patients evaluable for change from baseline in erosion score at Week 52 550 553 551 Mean (SD) 2.23 (5.903) 0.12 (1.809) a 0.08 (2.005) a Median 0.00 0.00 0.00 Range (-12.6; 54.1) (-9.2; 10.0) (-6.5; 23.4) IQ range (0.00; 2.50) (-0.43; 0.50) (-0.50; 0.50) Mean Difference (95% CI)c -2.11 (-2.64, -1.60) -2.14 (-2.68, -1.62)

Patients evaluable for change from baseline in erosion score at Week 52 550 553 551 Patients with change of ≤ 0 293 (53.3%) 377 (68.2%) a 401 (72.8%) a % Difference (95% CI)b 0.149 (0.092, 0.206) 0.195 (0.139, 0.251)

Patients evaluable for change from baseline in JSN score at Week 24 550 553 551 Mean (SD) 0.76 (2.540) 0.24 (1.404) a 0.21 (1.537) a Median 0.00 0.00 0.00 Range (-4.6; 32.5) (-3.8; 16.8) (-9.8; 23.5) IQ range (0.00; 0.64) (0.00; 0.00) (0.00; 0.00) Mean Difference (95% CI)c -0.51 (-0.76, -0.28) -0.54 (-0.79, -0.30)

Patients evaluable for change from baseline in JSN score at Week 52 550 553 551 Mean (SD) 1.46 (4.311) 0.38 (1.839) a 0.38 (2.184) a Median 0.00 0.00 0.00 Range (-9.5; 45.5) (-4.2; 17.2) (-20.3; 22.0) IQ range (0.00; 1.35) (0.00; 0.50) (0.00; 0.50) Mean Difference (95% CI)c -1.08 (-1.48, -0.71) -1.09 (-1.49, -0.70)

Patients evaluable for change from baseline in JSN score at Week 52 550 553 551 Patients with change of ≤ 0 335 (60.9%) 390 (70.5%) a 391 (71.0%) a % Difference (95% CI)b 0.096 (0.040, 0.152) 0.101 (0.045, 0.156) a nominal p value <0.001 compared with placebo b The confidence intervals were based on Wald statistic. c The 95% CI was based on the 2.5th and 97.5th percentiles of the mean differences from the bootstrap samples. JSN= joint space narrowing For patients in the placebo group who met EE criteria at Week 18, all the scores after Week 18 were set to missing. And then for patients in all treatment groups with missing vdH-S score at Week 24 or 52 (including those placebo EE patients with values were set to missing due to EE), the missing score at Week 24 or 52 was imputed by linear extrapolation, or if only baseline value was available, imputed by baseline score.

50 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

A probability plot of change from baseline in vdH-S at Week 52, showing the distribution of change for the population as a whole, shows clear separation between the sirukumab groups and the placebo group at week 52 but no separation between the sirukumab groups (Figure 12).

Figure 12: Probability Plot of Change from Baseline in vdH-S at Week 52; Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment (Study ARA3002)

For patients in the placebo group who met EE criteria at Week 18, all the scores after Week 18 were set to missing. And then for patients in all treatment groups with missing vdH-S score at Week 24 or 52 (including those placebo EE patients with values were set to missing due to EE), the missing score at Week 24 or 52 was imputed by linear extrapolation, or if only baseline value was available, imputed by baseline score SDC=smallest detectable change; EE=Early Escape

5.4.1.3.3. Physical Function The Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient-completed questionnaire specific for RA, which assesses the degree of difficulty a patient has experienced in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other activities. A decrease from baseline in HAQ-DI score indicates improvement; a change of <-0.22 is considered to be clinically meaningful.

51 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Significant improvements in physical function were demonstrated with sirukumab treatment compared with placebo (Table 8). At week 24, mean change from baseline in HAQ-DI score was statistically significantly different with sirukumab compared with placebo. Results for the mean change from baseline in HAQ-DI score at Week 24 were robust, with consistent findings across all planned sensitivity analyses (details provided in Appendix 9).

A higher proportion of patients treated with sirukumab compared with placebo achieved clinically relevant improvements in functional ability (a change of <-0.22 in HAQ-DI score, defined as a clinically meaningful change. Similar improvements were observed with sirukumab 50 mg q4w and 100 mg q2w groups. The improvements in HAQ-DI were maintained through Week 52 (Figure 13).

Table 8: HAQ-DI-related Endpoints (Study ARA3002) Sirukumab Placebo 50 mg q4w 100 mg q2w Patients evaluable for change from baseline in HAQ-DI c Score at Week 24 (major 556 557 557 secondary endpoint) Mean (SD) -0.22 (0.53) -0.43 (0.58) a -0.46 (0.57) a LSMean Difference (95% CI) d -0.23 (-0.29, -0.17) -0.26 (-0.32, -0.20)

Patients evaluable for HAQ-DI Response (Change of <-0.22 From Baseline) at 556 557 557 Week 24 Patients in response 261 (46.9%) 351 (63.0%) b 364 (65.4%) b Difference (95% CI)e 0.16 (0.10, 0.22) 0.18 (0.13, 0.24) a p value <0.001 compared with placebo b nominal p value <0.001 compared with placebo c a negative change from baseline (i.e., a decrease) indicates improvement d the confidence intervals were based on ANCOVA. e the confidence intervals were based on Wald statistic. Patients with missing data or post early escape had values imputed by LOCF

52 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 9: SF-36-related Endpoints (Study ARA3002) Sirukumab Placebo 50 mg q4w 100 mg q2w Physical component summary (PCS) at 556 557 557 baseline Mean (SD) 33.8 (6.9) 34.2 (7.2) 33.5 (6.8)

Patients evaluable for change from 556 557 557 baseline in PCS at Week 24 Mean (SD) 2.3 (6.3) 5.4 (7.3) a 5.9 (7.1) a LSMean Difference (95% CI)c 3.07 (2.26, 3.88) 3.559 (2.75, 4.37)

Patients evaluable for clinical ≥5 point improvement in PCS from baseline at 556 557 557 Week 24 Patients in response 171 (30.8%) 263 (47.2%) a 283 (50.8%) a Difference (95% CI)d 0.17 (0.11, 0.22) 0.20 (0.14, 0.26)

Mental component summary (MCS) at 556 557 557 baseline Mean (SD) 40.5 (11.1) 40.6 (10.6) 41.8 (10.9)

Patients evaluable for change from 556 557 557 baseline in MCS at Week 24 Mean (SD) 2.9 (9.2) 4.9 (9.7) a 4.2 (9.5) b LSMean Difference (95% CI)c 2.01 (0.90, 3.12) 1.32 (0.21, 2.43)

Patients evaluable for clinical ≥5 point improvement in MCS from baseline at 556 557 557 Week 24 Patients in response 200 (36.0%) 253 (45.4%) b 243 (43.6%) b Difference (95% CI)d 0.09 (0.04, 0.15) 0.08 (0.02, 0.13) a nominal p value <0.001 compared with placebo b nominal p value <0.05 compared with placebo c The confidence intervals are based on ANOVA. d The confidence intervals are based on Wald statistic. Patients with missing data or post early escape had values imputed by LOCF

Clinically meaningful improvements compared with placebo were also noted in all 8 individual domains of the SF-36 at Week 24 (Figure 14).

54 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 14: Change in SF-36 Individual Domain Scores at Week 24 (Study ARA3002)

anominal p value <0.05compared with placebo Patients with missing data or post early escape had values imputed by LOCF

5.4.1.3.5. Fatigue Fatigue is a major symptomatic manifestation of RA with studies indicating that’s its prevalence among RA patients is over 80%.65 The FACIT-fatigue, a questionnaire, assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. The total FACIT-F score ranges from 0 to 52, with a higher score indicating less fatigue. In rheumatology, a change of ≥4 points from baseline are considered clinically meaningful.

Treatment with sirukumab was effective in reducing fatigue. Clinically meaningful improvements from baseline (≥4-point increase) in FACIT-fatigue were observed for both sirukumab doses (mean change of 6.5 for both dose groups compared with placebo 3.3) at Week 24 (Table 10).

55 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 10: FACIT-F-related Endpoints (Study ARA3002) Sirukumab Placebo 50 mg q4w 100 mg q2w Patients evaluable for change from baseline in FACIT-Fatigue Score at 556 557 557 Week 24 Mean (SD) 3.3 (9.3) 6.5 (9.5) a 6.5 (9.4) a LSMean Difference (95% CI)b 3.20 (2.09, 4.30) 3.2 (2.10, 4.31)

Patients evaluable for ≥ 4 point improvement in FACIT-F from baseline 556 557 557 at week 24 Patients in response 244 (43.9%) 342 (61.4%) a 331 (59.4%) a Difference (95% CI)c 0.18 (0.18, 0.23) 0.16 (0.10, 0.21) a Nominal p value <0.001 compared with placebo b The confidence intervals are based on ANOVA. c The confidence intervals are based on Wald statistic. Patients with missing data or post early escape had values imputed by LOCF

5.4.2. ARA3003 (Anti-TNFα-IR)

5.4.2.1. Design Study ARA3003 was designed as the second pivotal placebo-controlled study assessing sirukumab in patients with moderately to severely active RA who were inadequate responders to treatment with 1 or more anti-TNFα agents or intolerant to 2 or more anti-TNFα agents. Patients could also have been treated with biologics other than TNFα antagonists providing there was adequate washout prior to first administration of study agent. Patients with a history of intolerance to tocilizumab or inadequate response were excluded. Active disease was defined as at least 4 tender joints out of 68 and 4 swollen joints out of 66. In addition, patients must have had a screening CRP ≥8.00 mg/L or erythrocyte sedimentation rate (ESR) ≥28mm/hr and met 1 of the following 3 criteria prior to the first administration of study agent: (a) anti-CCP-positive at screening, (b) RF-positive at screening, or (c) documented history of radiographic evidence of erosive RA in hands or feet. Patients using non-biologic DMARDs must have been on a stable dose for at least 4 weeks prior to the first administration of study agent.

A total of 878 patients were randomly assigned in a 1:1:1 ratio to receive placebo SC q2w, sirukumab 50 mg q4w, or sirukumab SC 100 mg q2w (Figure 15).

56 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 15: Study Design - ARA3003 (Anti-TNFα-IR)

The primary endpoint of the study was ACR 20 response at Week 16. At Week 18 (early escape, EE), patients in the placebo group who had <20% improvement from baseline in swollen and tender joint count were re-randomized to either sirukumab 50 mg q4w or 100 mg q2w in a blinded manner. Patients in the placebo group who did not meet EE criteria crossed over to receive sirukumab at Week 24 through Week 52. From eek 24, based on the investigators discretion, all patients could adjust or initiate an additional DMARD (MTX, SSZ, hydroxycloroquine, chloroquine and or bucillamine) or oral corticosteroids. At Week 52, patients had the option to enroll into a long-term extension study (ARA3004) for an additional 4 years (total follow up 5 years).

Efficacy data through Week 52 is included in this submission.

5.4.2.2. Study Population A total of 878 patients were enrolled globally. The majority of patients were enrolled in North America (52.7%), followed by Europe (26.3%), Japan (13.2%), Latin America (4.1%) and Asia Pacific (3.6%).

Most of the patients completed 24 weeks of treatment either on their initial treatment or after having received escape therapy (Table 11). More patients in the sirukumab groups withdrew for adverse events than patients from the placebo group. Conversely, more patients in the placebo group met the criteria for escape therapy than in the sirukumab groups. Of the patients randomized to placebo, 158 (53.7%) remained on placebo through Week 24.

57 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 11: Summary of Patient Disposition at Week 24 (Study ARA3003) Sirukumab Placebo 50 mg q4w 100 mg q2w Patients randomized 294 292 292 Patients who met early escape criteria 94 (32%) 46 (16%) 44 (15%) Patients who discontinued study agent 42 (14%) 55 (19%) 46 (16%) Reason for discontinuation Adverse event 11 (26.2%) 19 (34.5%) 21 (45.7%) Lack of efficacy 15 (35.7%) 14 (25.5%) 8 (17.4%) Withdrawal of consent 12 (28.6%) 9 (16.4%) 9 (19.6%) Lost to follow-up 1 (2.4%) 3 (5.5%) 2 (4.3%) Physician decision 0 3 (5.5%) 1 (2.2%) Pregnancy 0 0 0 Death 0 0 0 Other 3 (7.1%) 7 (12.7%) 5 (10.9%) Continuing at Week 24 250 (85%) 237 (81%) 246 (84%)

At Week 24, patients in the placebo group who did not meet EE criteria crossed over (CO) to receive sirukumab 50 mg q4w or 100 mg q2w through Week 52. By Week 52, the number of patients who discontinue is similar across all 3 treatment arms (Table 12).

Table 12: Summary of Patient Disposition at Week 52 (Study ARA3003) Sirukumab PlaceboSirukumab 50 mg q4w 100 mg q2w Due to EE or CO Patients randomized 294 292 292 Patients who discontinued study agent 79 (27%) 88 (30%) 80 (27%) Reason for discontinuation Adverse event 29 (9.9%) 29 (9.9%) 36 (12.3%) Lack of efficacy 28 (9.5%) 27 (9.2%) 15(5.1%) Withdrawal of consent 12 (4.1%) 16 (5.5%) 12 (4.1%) Lost to follow-up 2 (0.7%) 4 (1.4%) 3 (1.0%) Physician decision 0 4 (1.4%) 2 (0.7%) Pregnancy 0 0 0 Death 0 0 2 (0.7%) Other 7 (2.4%) 8 (2.7%) 10 (3.4%) Completed study through 52 weeks 215 (73%) 204 (70%) 212 (73%)

Baseline disease characteristics were generally well balanced across the 3 treatment groups and were representative of a population of patients with moderately to severely RA despite previous treatment with anti-TNFα agents with unfavorable prognostics factors (Table 13).

Patients had to have been inadequate responders (documented lack of benefit) to treatment with 1 or more anti-TNFα agents or intolerant to 2 or more anti-TNFα agents as specified in the protocol. The most common reason for discontinuation of a prior anti-TNFα agent was lack of

58 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document efficacy (95.3% of patients. Patients could have been treated with more than 1 anti-TNFα agent; approximately 40% had taken 2 or more anti-TNFα agents. In addition, up to 41% of patients were also previously treated with biologics other than anti-TNFα agents.

At baseline 82% of patients were taking DMARDs (including approximately 75% taking MTX).

Table 13: Baseline Demographics and Disease Characteristics (Study ARA3003) Sirukumab Placebo 50 mg q4w 100 mg q2w Analysis Set: Randomized Patients 294 292 292

Female 240 (82%) 232 (80%) 240 (82%) Age (years) Mean (SD) 55.4 (12.3) 55.8 (11.9) 55.0 (12.3) Median 57.0 57.0 56.0 Range (18; 84) (21; 80) (20; 81) Weight (kg) Mean (SD) 75.8 (21.8) 76.7 (21.6) 76.9 (22.3) Median 73.1 73.0 72.6 Range (44.7; 174.0) (37.4; 160.2) (31.3; 159.9) Disease Duration (years) Mean (SD) 12.3 (9.3) 12.9 (9.0) 12.3 (8.4) Median 10.0 11.0 10.0 Range (0.6; 52.0) (0.8; 46.0) (0.8; 49.0) CRP (mg/dL) Mean (SD) 2.3 (2.8) 2.1 (2.3) 2.1 (2.4) Median 1.29 1.4 1.3 Range (0.01; 21.8) (0.01; 18.1) (0.03; 16.4) Rheumatoid Factor Positive 229 (78%) 221 (76%) 221 (76%) Anti-CCP Positive 230 (79%) 235 (81%) 242 (83%) DAS28 (CRP) Mean (SD) 5.8 (1.0) 5.9 (1.0) 5.9 (1.0) Median 5.9 6.0 5.9 Range (3.2; 8.3) (3.2; 8.3) (3.1; 8.2) HAQ disability index (0-3) Mean (SD) 1.57 (0.65) 1.65 (0.60) 1.61 (0.61) Median 1.63 1.75 1.63 Range (0.00; 3.00) (0.00; 3.00) (0.00; 3.00) Baseline DMARDs 243 (83%) 234 (80%) 235 (81%) Baseline Corticosteroids 184 (63%) 166 (57%) 183 (63%) ≥ 2 prior DMARDs 282 (96%) 282 (97%) 276 (95%) Prior anti-TNFα Use 294 (100%) 292 (100%) 292 (100%) 1 177 (60%) 180 (62%) 175 (60%) ≥2 117 (40%) 112 (38%) 117 (40%) Other biologic DMARDs in past 104 (35%) 119 (40%) 118 (41%)

5.4.2.3. Results

5.4.2.3.1. Signs and Symptoms Sirukumab demonstrated statistically significant and clinically meaningful reductions in signs and symptoms of RA over placebo. The primary endpoints, ACR 20 response at Week 16, as well as all 4 major secondary endpoints were met; statistical significance was shown for both

59 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document sirukumab doses (50 mg q4w and 100 mg q2w) compared with placebo based on pre-specified multiple testing procedures (Table 14). The onset of ACR response was rapid, with differences between sirukumab and placebo as early as Week 2 (the first scheduled assessment) for ACR 20 (Figure 16). ACR 20 response peaked within 12 weeks and was maintained thereafter.

Table 14: Primary and Major Secondary Endpoint (Study ARA3003) Sirukumab Placebo 50 mg q4w 100 mg q2w Primary Endpoints ACR 20 response at Week 16 294 292 292 Patients in response 71 (24.1%) 117 (40.1%) a 132 (45.2%) a Difference (95% CI)e 0.16 (0.09, 0.23) 0.21 (0.14, 0.29)

Major Secondary Endpoints Patients evaluable for change from baseline in HAQ-DId Score at Week 24 294 291 292 Mean (SD) -0.12 (0.49) -0.31 (0.54) a -0.33 (0.53) a LSMean Difference (95% CI)g -0.17 (-0.25, -0.09) -0.19 (-0.28, -0.11)

Patients evaluable for ACR 50 Response at Week 24 294 292 292 Patients in response 26 (8.8%) 61 (20.9%) a 63 (21.6%) a Difference (95% CI)e 0.12 (0.06, 0.18) 0.13 (0.07, 0.18)

Patients evaluable for DAS28 (CRP) ≤2.6 at Week 24 294 292 292 Patients in response 24 (8.2%) 56 (19.2%) a 63 (21.6%) a Difference (95% CI)e 0.11 (0.06, 0.17) 0.13 (0.08, 0.19)

Other Secondary Endpoints Patients evaluable for ACR 70 Response at Week 24 294 292 292 Patients in response 12 (4.1%) 25 (8.6%) c 29 (9.9%) c Difference (95% CI)e 0.05 (0.01, 0.08) 0.06 (0.02, 0.10)

Patients evaluable for change from baseline in CDAI d at Week 24 293 291 292 Mean (SD) -9.2 (16.5) -15.3 (17.5) a -16.8 (16.6) b LSMean Difference (95% CI)f -6.13 (-8.84, -3.41) -7.60 (-10.31, -4.89) a p value <0.001 compared with placebo b nominal p value 0.001 compared with placebo c nominal p value <0.05 compared with placebo d a negative change from baseline (i.e., a decrease) indicates improvement e the confidence intervals were based on Wald statistic. f the confidence intervals and p-values are based on ANOVA g the confidence intervals were based on ANCOVA. For ACR 20, ACR 50, ACR 70, MCR, DAS28 (CRP) ≤2.6: patients with missing data, treatment failure, or early escape were treated as non- responders For change in HAQ and CDAI: Patients with missing data or post early escape had values imputed by LOCF

60 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document mean change from baseline in HAQ-DI score at Week 24 were robust, with consistent findings across all planned sensitivity analyses (details provided in Appendix 9).

Table 15: HAQ-DI-related Endpoints (Study ARA3003) Sirukumab Placebo 50 mg q4w 100 mg q2w Patients evaluable for change from baseline in HAQ-DI c Score at Week 24 (major secondary endpoint) 294 291 292 Mean (SD) -0.12 (0.49) -0.31 (0.54) a -0.33 (0.53) a LSMean Difference (95% CI)d -0.17 (-0.25, -0.09) -0.19 (-0.28, -0.11)

Patients evaluable for HAQ-DI Response (Change of <-0.22 From Baseline) at 556 557 557 Week 24 Patients in response 110 (37.4%) 152 (52.2%) b 160 (54.8%) b Difference (95% CI)e 0.15 (0.07, 0.23) 0.17 (0.09, 0.25) a p value <0.001 compared with placebo b Nominal p value <0.001 compared with placebo c A negative change from baseline (i.e., a decrease) indicates improvement d The confidence intervals were based on ANCOVA. e The confidence intervals were based on Wald statistic. Patients with missing data or post early escape had values imputed by LOCF

5.4.2.5. Health Related Quality of Life In study ARA3003, mean baseline SF-36 PCS and MCS scores (~34 and 40 respectively) were below the reported mean for the general United States (US) population of 50 ± 1062 decreased health-related quality of life.

Consistent and clinically meaningful improvements in patient-reported health-related quality of life were demonstrated with sirukumab treatment compared with placebo. The magnitude of the improvement and the proportion of patients achieving clinically meaningful improvements in PCS and MCS were similar across sirukumab doses (Table 16).

62 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 16: SF-36-related Endpoints (Study ARA3003) Sirukumab Placebo 50 mg q4w 100 mg q2w Physical component summary (PCS) at baseline 294 291 292 Mean (SD) 33.2 (7.49) 31.8 (6.73) 32.4 (7.67)

Patients evaluable for change from baseline in PCS at Week 24 294 291 292 Mean (SD) 1.68 (6.65) 4.85 (7.10) a 5.06 (6.88) a LSMean Difference (95% CI)c 3.16 (2.05, 4.28) 3.38 (2.26, 4.49)

Patients evaluable for clinical ≥ 5-point improvement in PCS from baseline at week 24 294 292 292 Patients in response 86 (29.3%) 122 (41.8%) b 140 (47.9%) a Difference (95% CI)d 0.13 (0.05, 0.20) 0.19 (0.11, 0.26)

Mental component summary (MCS) at baseline 294 291 292 Mean (SD) 41.9 (11.12) 41.2 (11.79) 42.1 (11.15)

Patients evaluable for change from baseline in MCS at Week 24 294 291 292 Mean (SD) 1.08 (8.92) 3.92 (10.68) a 4.05 (9.28) a LSMean Difference (95% CI)c 2.84 (1.28, 4.41) 2.97 (1.41, 4.53)

Patients evaluable for clinical ≥ 5-point improvement in MCS from baseline at week 24 294 292 292 Patients in response 80 (27.2%) 114 (39.0%) b 109 (37.3%) b Difference (95% CI)d 0.12 (0.04, 0.19) 0.10 (0.03, 0.18) a Nominal p value <0.001 compared with placebo b Nominal p value <0.05 compared with placebo c The confidence intervals are based on ANOVA. d The confidence intervals are based on Wald statistic. Patients with missing data or post early escape had values imputed by LOCF

Clinically meaningful improvements compared with placebo were also noted in all 8 individual domains of the SF-36 at Week 24 (Figure 17).

63 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 17: Change in SF-36 Individual Domain Scores at Week 24 (Study ARA3003)

anominal p value <0.05compared with placebo Patients with missing data or post early escape had values imputed by LOCF

5.4.2.6. Fatigue Treatment with sirukumab was effective in reducing fatigue. A clinically meaningful improvement (≥4 point increase) in FACIT-fatigue were observed for the 50 mg q4w dose compared with placebo at Week 24 (Table 17).

64 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 17: FACIT-F-related Endpoints (Study 3003) Sirukumab Placebo 50 mg q4w 100 mg q2w Patients evaluable for change from baseline in FACIT-Fatigue Score at Week 24 294 291 292 Mean (SD) 1.85 (8.82) 6.60 (10.78) a 5.63 (9.11) a LSMean Difference (95% CI)b 4.74 (3.19, 6.30) 3.77 (2.22, 5.33)

Patients evaluable for ≥ 4-point improvement in FACIT-F from baseline at Week 24 294 291 292 Patients in response 119 (40.5%) 162 (55.7%) a 163 (55.8%) a Difference (95% CI)c 0.15 (0.07, 0.23) 0.15 (0.07, 0.23) a Nominal p value <0.001 compared with placebo bThe confidence intervals are based on ANOVA. cThe confidence intervals are based on Wald statistic Patients with missing data or post early escape had values imputed by LOCF

5.4.2.7. Prior Experience with Multiple Biologics It is now well described that patients with RA have multiple treatment options with non-biologic and biologic DMARDs, and that patients who do not obtain or maintain an adequate response to a treatment will try a different one. Patients included in ARA3003 reflected this real-world population.

In Study ARA3003, in addition to prior anti-TNFα treatment, approximately 39% of patients also received other biologic DMARDs prior to the study; predominantly abatacept, rituximab and tocilizumab.

In supportive subgroup analyses of study ARA3003, the efficacy of sirukumab versus placebo was observed in the reduction of signs and symptoms of RA for both sirukumab dose groups in patients previously treated with anti-TNFα agents only, as well as patients treated with other biologic DMARDs. For more difficult to achieve endpoints, such as ACR 50 and ACR 70, response rates were lower in patients who had received other biologic DMARDs than in the anti- TNFα agents only group (Table 18). This is not unexpected in that patients previously treated with multiple biologic DMARDs typically have lower responses with subsequent biologic DMARDs.40 The improvements in efficacy were similar between the sirukumab 50 mg q4w and 100 mg q2w groups

65 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 18: Improvement in Clinical Outcomes; Randomized Patients with Prior Use of Anti-TNFα Biologics Only and Patients With Prior Use of Other Biologic DMARDs (Study ARA3003) Anti-TNFα Biologics Only Other Biologic DMARDs Sirukumab Sirukumab Placebo 50 mg q4w 100 mg q2w Placebo 50 mg q4w 100 mg q2w Analysis sets: Randomized Patients: with No Prior Use of non-anti-TNFα Biologics; with Prior Use of non-anti- TNFα Biologics 189 173 173 104 119 118

ACR 20 response at Week 16a N 189 173 173 104 119 118 Patients in response 46 (24.3%) 68 (39.3%) 78 (45.1%) 25 (24.0%) 49 (41.2%) 54 (45.8%) Difference (95% CI)b 0.146 (0.051, 0.203 (0.107, 0.186 (0.068, 0.218 (0.097, 0.241) 0.298) 0.304) 0.339) p-valuec 0.003 < 0.001 0.003 < 0.001

ACR 20 response at Week 24a N 189 173 173 104 119 118 Patients with ACR 20 response 43 (22.8%) 80 (46.2%) 74 (42.8%) 33 (31.7%) 45 (37.8%) 51 (43.2%) Difference (95% CI)b 0.231 (0.137, 0.195 (0.101, 0.077 (-0.045, 0.129 (0.003, 0.326) 0.290) 0.199) 0.255) p-valuec <0.001 < 0.001 0.224 0.049

ACR 50 Response at Week 24a N 189 173 173 104 119 118 Patients with ACR 50 response 17 (9.0%) 42 (24.3%) 42 (24.3%) 9 (8.7%) 19 (16.0%) 21 (17.8%) Difference (95% CI)b 0.152 (0.076, 0.151 (0.075, 0.080 (-0.004, 0.101 (0.012, 0.228) 0.227) 0.165) 0.189) p-valuec < 0.001 < 0.001 0.069 0.030

ACR70 Response at Week 24a N 189 173 173 104 119 118 Patients with ACR70 response 9 (4.8%) 19 (11.0%) 22 (12.7%) 3 (2.9%) 6 (5.0%) 7 (5.9%) Difference (95% CI)b 0.061 (0.005, 0.078 (0.019, 0.025 (-0.027, 0.035 (-0.021, 0.116) 0.136) 0.077) 0.091) p-valuec 0.031 0.008 0.342 0.214 a Patients with missing data, treatment failure, or early escape were treated as non-responders bThe confidence intervals were based on Wald statistic. cThe nominal p-values were based on CMH test.

Sirukumab was effective in reducing signs and symptoms of RA compared with placebo regardless of the number of failed prior anti-TNFα therapies or number of biologic therapies previously received. Figure 18 shows all odds ratios were greater than 1.

66 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 18: ACR 20 Response at Week 16 by number of prior Anti-TNFs and Biologic Therapies (ARA3003)

In study ARA3003, a total of 103 patients (11.7%) had taken tocilizumab prior to the study (34, 29, and 40 patients in placebo, 50 mg q4w sirukumab, and 100 mg q2w sirukumab, respectively). The odds for a patient, with prior tocilizumab use, to achieve an ACR 20 response at Week 16 was consistently higher (odds ratio >1) in both sirukumab groups than in the placebo group (Figure 19).

67 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 19: ACR 20 Response at Week 16 by Prior Use of Tocilizumab (Study ARA3003)

Prior TCZ use (n): Placebo=34; SIR 50 mg q4w=29; SIR 100 mg q2w=40

5.5. Efficacy by Baseline Demographic and Disease Characteristics To examine the consistency of treatment effect for sirukumab in studies ARA3002 and ARA3003, odds ratios and corresponding 95% confidence intervals (CI) were calculated for the primary endpoint, ACR 20 response at Week 16, by pre-specified baseline demography and baseline disease characteristics. The treatment difference in the proportion of patients who achieved an ACR 20 response for each of the subgroups was analyzed using a logistic regression model.

Overall sirukumab treatment was shown to be effective across a wide range of subgroups.

5.5.1. Study ARA3002 In study ARA3002, sirukumab was effective in reducing signs and symptoms of RA compared with placebo in all subgroups evaluated. No notable differences in sirukumab efficacy were found among subgroups defined by baseline demography such as gender, weight, age, race, region, and baseline disease characteristics such as serological status and CRP.

The odds ratios and, with few exceptions, the 95% CIs were all greater than 1 (Figure 20).

In those subsets where the 95% CI contained 1 (Black or African American and geographic region of South Africa), the sample size was small (2.5% and 6% of overall study population respectively).

68 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 20: Odds Ratios (Sirukumab 50 mg, Placebo; Sirukumab 100 mg, Placebo) for Comparing the Proportion of Patients Who Achieved ACR 20 Response at Week 16; Full Analysis Set (Placebo Controlled Period) (Study ARA3002)

Patients with missing data, treatment failure, or early escape were treated as non-responders Odds ratio and confidence interval for odds ratio were based on logistic regression.

69 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

5.5.2. Study ARA3003 In study ARA3003, sirukumab was effective in reducing signs and symptoms of RA compared with placebo in subgroups evaluated. No notable differences in sirukumab efficacy were found among subgroups defined by baseline demography such as gender, weight, age, race, region, and baseline disease characteristics such as serological status and CRP.

In general, the odds ratios and 95% CIs were all greater than 1 (Figure 21).

In those subsets where the 95% CI contained 1 (Black or African American, geographic region of Latin America, age ≥65 and weight in 3rd and/or 4th quartile) the sample size of the subset was small (eg, black/African American and Latin America made up 6% and 4% of overall study population respectively) and the effect did not reflect a plausible pattern (eg, lack of correlation with increasing weight categories).

For age, the odds ratio of response versus placebo for patients aged ≥65 was close to one for 50 mg q4w. In ARA3003, approximately 22% of patients were 65 years or older at baseline. Of note, in study ARA3003 there was a higher placebo response for ACR 20 at Week 16 in the ≥65 age group (31.8%) compared with other age groups and the study overall (24.1%).

In order to further explore the effect of age, post hoc statistical analyses were performed on other endpoints and time points, and using age as a continuous variable rather than categorical to increase sensitivity. There was no consistent impact of age on the treatment effect across endpoints (ACR 20, ACR 50, or change in DAS28), visits (Week 16, Week 24) or dose of sirukumab suggesting the observation in the original analysis is not robust and likely an artifact of small numbers in the subgroup (Appendix 10).

70 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 21: Odds Ratios (Sirukumab 50 mg, Placebo; Sirukumab 100 mg, Placebo) for Comparing the Proportion of Patients Who Achieved ACR 20 Response at Week 16; Full Analysis Set (Placebo Controlled Period) (Study ARA3003)

Patients with missing data, treatment failure, or early escape were treated as non-responders Odds ratio and CI for odds ratio are based on logistic regression

71 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

5.6. Phase 3 Studies – Monotherapy The efficacy of sirukumab given as monotherapy is established by several lines of evidence

1) a subgroup analysis of patients treated with sirukumab without concomitant DMARDs in studies ARA3002 and ARA3003

2) a dedicated active comparator study (ARA3005) versus a commonly prescribed anti- TNFα therapy, adalimumab.

5.6.1. Sirukumab Received as Monotherapy in ARA3002 and ARA3003 Treatment with concomitant conventional DMARDs was permitted, but not required, in both the ARA3002 and ARA3003 studies.

A total of 299 (12% overall) patients in ARA3002 (n=133) and ARA3003 (n=166) received sirukumab treatment as monotherapy. Within each study, the proportion of patients not taking DMARDs was similar across treatment groups.

A pre-specified analysis was performed on the primary endpoint, ACR 20 at Week 16 (ARA3002 and ARA3003) and change from baseline in vdH-S score at Week 52 (ARA3002) by baseline DMARDs (yes/no).

In studies ARA3002 and ARA3003, both doses of sirukumab when given as monotherapy showed greater improvements in ACR20 response at Week 16 compared with placebo. In study ARA3002, sirukumab monotherapy also showed greater inhibition of radiographic progression compared with placebo (Table 19).

In supportive analyses, both doses of sirukumab when given as monotherapy showed greater improvements in ACR 50, DAS28 (CRP) ≤2.6, major clinical response, CDAI score, and HAQ- DI compared with placebo (Table 19).

For several endpoints, a numerically greater treatment response was observed with sirukumab 100 mg q2w compared with 50 mg q4w given as monotherapy across the studies; however, this was not observed consistently for the same endpoints or time points across studies.

72 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 19: Improvement in Signs and Symptoms and Physical Function; Randomized Patients With No Use of DMARDs at Baseline (Studies ARA3002, ARA3003) ARA3002 ARA3003 Sirukumab Sirukumab Placebo 50 mg q4w 100 mg q2w Placebo 50 mg q4w 100 mg q2w Analysis set: Randomized Patients With No Use of DMARDs at Baseline 48 39 46 51 58 57

ACR 20 response at Week 16a Patients in response 7 (14.6%) 18 (46.2%) 24 (52.2%) 7 (13.7%) 15 (25.9%) 22 (38.6%) Difference (95% CI)c 0.32 0.38 0.12 0.25 (0.13, 0.50) (0.20, 0.55) (-0.03, 0.27) (0.09, 0.41) p-value 0.001 < 0.001 0.115 0.004

ACR 50 Response at Week 24b Patients in response 2 (4.2%) 9 (23.1%) 9 (19.6%) 2 (3.9%) 9 (15.5%) 8 (14.0%) Difference (95% CI)c 0.19 0.15 0.12 0.10 (0.05, 0.33) (0.03, 0.28) (0.01, 0.22) (-0.004, 0.21) Nominal p-value 0.008 0.020 0.045 0.070

Major Clinical Response by Week 52b Patients with response 0 1 (2.6%) 4 (8.7%) NE NE NE Difference (95% CI)c 0.03 0.09 (-0.02, 0.08) (0.01, 0.17) Nominal p-value 0.264 0.037

DAS28 ≤2.6 (CRP) at Week 24b Patients in response 1 (2.1%) 10 (25.6%) 8 (17.4%) 3 (5.9%) 9 (15.5%) 9 (15.8%) Difference (95% CI)c 0.24 0.15 0.10 0.10 (0.09, 0.38) (0.04, 0.27) (-0.02, 0.21) (-0.02, 0.21) Nominal p-value 0.001 0.012 0.109 0.102

Change from baseline in CDAI at Week 24b Mean (SD) -7.8 (15.7) -14.5(14.8) -16.9 (17.1) -8.5 (17.3) -10.6 (19.3) -14.4 (17.5) LSMean Difference (95% -6.77 -9.16 -2.16 -5.94 CI)e (-13.57, 0.03) (-15.67, -2.65) (-9.02, 4.70) (-12.83, 0.96) Nominal p-value 0.051 0.006 0.535 0.091

Change from baseline in HAQ-DI Score at Week 24 Mean (SD) -0.10 (0.48) -0.25 (0.45) -0.51 (0.56) 0.01 (0.53) -0.23 (0.53) -0.38 (0.58) LSMean Difference (95% -0.15 -0.39 -0.19 -0.37 CI)d (-0.36, 0.06) (-0.59, -0.19) (-0.39, 0.01) (-0.57, -0.18) Nominal p-value 0.155 <0.001 0.057 <0.001

73 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 19: Improvement in Signs and Symptoms and Physical Function; Randomized Patients With No Use of DMARDs at Baseline (Studies ARA3002, ARA3003) ARA3002 ARA3003 Sirukumab Sirukumab Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment with No Use of DMARDs at Baseline 48 39 46 NE NE NE Change from baseline in vdH-S score at Week 52f Mean (SD) 3.81 (7.78) 1.25 (4.03) 0.11 (2.19) Median 0.50 0.50 0.00 Mean Difference -2.56 (-5.23- -3.70 (-6.15- (95% CI)b 0.16) 1.62) p-value 0.084 0.007 a pre-specified b supportive c The confidence intervals were based on Wald statistic. d The confidence intervals were based on ANCOVA e The confidence intervals were based on ANOVA f The 95% CI was based on the 2.5th and 97.5th percentiles of the mean differences from the bootstrap samples NE: not evaluated For ACR20, 50, 70, MCR, DAS28 (CRP) ≤2.6: patients with missing data, treatment failure, or early escape were treated as non-responders For change in HAQ, DAS28 and CDAI: Patients with missing data, treatment failure, or early escape had values imputed by LOCF

5.6.2. Study ARA3005 (Monotherapy)

5.6.2.1. Design Study ARA3005 was designed to demonstrate the superior efficacy of sirukumab monotherapy compared with adalimumab monotherapy in biologic-naïve patients who would qualify for sirukumab monotherapy on the basis of either safety issues or lack of efficacy with MTX. Active disease was defined as at least 8 of 68 tender joints and 6 of 66 swollen joints. In addition, patients must have had either a screening ESR ≥28 mm/hr or CRP level ≥10.00 mg/L.

A total of 559 patients were randomly assigned in a 1:1:1 ratio to receive treatment with sirukumab SC 50 mg q4w, sirukumab SC 100 mg q2w, or adalimumab 40 mg SC q2w (Figure 22).

74 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 22: Study Design - ARA3005

Patients in all treatment groups who had <20% improvement from baseline in both swollen and tender joint counts at Week 16 qualified for early escape (EE). Patients in the adalimumab 40 mg q2w group who met EE criteria received adalimumab 40 mg every week (qw) through Week 52. Patients in the sirukumab 50 mg q4w group who met EE criteria received sirukumab 100 mg q2w through Week 52. Patients in the sirukumab 100 mg q2w group who met EE criteria remained on their original, blinded treatment assignment through Week 52. The study remained blinded throughout. The study duration was 68 weeks (52 weeks of treatment plus 16 weeks of safety follow-up).

Efficacy data through week 24 is included in this submission.

5.6.2.2. Study Population A total of 559 patients were enrolled. Most of the patients were enrolled in Europe (73.7%), followed by North America (15.7%), Latin America (6.3%) and South Africa (4.3%).

Through Week 24, a slightly higher number of patients discontinued study treatment in the sirukumab arms compared with adalimumab. The most common reason for discontinuation of study agent was due to an AE (31 patients), with similar numbers of affected patients across treatment groups (Table 20).

75 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 20: Summary of Patient Disposition at Week 24 (Study ARA3005) Sirukumab Adalimumab 50 mg q4w 100 mg q2w Patients randomized 186 186 187 Patients who met early escape criteria 13 (7.0%) 17 (9.1%) 7 (3.7%) Patients who discontinued study agent 19 (10.2%) 30 (16.1%) 24 (12.8%) Reason for discontinuation Adverse event 9 (47.4%) 11 (36.7%) 11 (45.8%) Lack of efficacy 1 (5.3%) 4 (13.3%) 1 (4.2%) Withdrawal of consent 6 (31.6%) 8 (26.7%) 8 (33.3%) Lost to follow-up 0 1 (3.3%) 1 (4.2%) Physician decision 1 (5.3%) 0 0 Pregnancy 0 2 (6.7%) 1 (4.2%) Death 0 0 0 Other 2 (10.5%) 4 (13.3%) 2 (8.3%) Continuing at Week 24 167 (90%) 156 (84%) 163 (87%)

Baseline disease characteristics were generally well balanced across the 3 treatment groups and were representative of a population of biologic-naïve patients with moderately to severely active RA with unfavorable prognostic factors (Table 21).

Randomization was stratified by the reason for which patients had failed MTX. Approximately 54% of patients failed MTX purely for efficacy reasons. Approximately 46% of patients failed MTX in the face of tolerability issues (intolerance to MTX) or safety concerns (inappropriate for use of MTX). Across the study population, 41% of patients had taken ≥2 prior DMARDs.

76 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 21: Baseline Demographics and Disease Characteristics (Study ARA3005) Adalimumab Sirukumab 40mg q2w 50 mg q4w 100 mg q2w Analysis Set: Randomized Patients 186 186 187

Female 156 (84%) 157 (84%) 154 (82%) Age (years) Mean (SD) 52.6 (12.2) 52.5 (12.5) 49.8 (12.3) Median 54.5 54.5 49.9 Range (20; 82) (19; 82) (24; 79)

Weight (kg) Mean (SD) 75.5 (16.4) 74.9 (17.4) 74.6 (18.5) Median 74.5 72.9 72.0 Range (42.1; 138.0) (39.0; 150.0) (40.0; 133.0)

Disease Duration (years) Mean (SD) 6.2 (7.0) 6.9 (7.5) 6.8 (6.6) Median 4.0 4.2 4.6 Range (0.5; 44.0) (0.6; 48.0) (0.6; 36.0)

CRP (mg/dL) Mean (SD) 2.1 (3.1) 2.1 (2.6) 1.8 (2.3) Median 0.8 1.1 0.9 Range (0.01; 20.0) (0.02; 14.30) (0.01; 10.40)

Rheumatoid Factor Positive 130 (70%) 140 (75%) 134 (72%)

Anti-CCP Positive 142 (77%) 138 (75%) 141 (76%)

DAS28 (ESR) Mean (SD) 6.9 (0.9) 6.9 (0.9) 6.9 (0.9) Median 7.0 7.1 6.9 Range (4.4; 8.8) (4.8; 9.1) (4.4; 8.9)

HAQ disability index (0-3) Mean (SD) 1.7009 (0.62509) 1.7541 (0.55120) 1.6209 (0.61097) Median 1.7500 1.7500 1.6250 Range (0.000; 3.000) (0.000; 2.875) (0.000; 3.000)

Baseline Corticosteroids 113 (61%) 105 (57%) 109 (58%)

5.6.2.3. Results At Week 24, the 100 mg dose of sirukumab was significantly more effective than adalimumab in reducing disease activity as measured by the DAS28 (ESR). Given that significance was not achieved between the sirukumab 100 mg and adalimumab dose groups for ACR 50 response, formal testing within the pre-specified testing hierarchy stopped at this point (detailed in Appendix 8), and ll further analyses were considered supportive (Table 22). Note that the 50 mg dose of sirukumab achieved numerically greater reduction in disease activity as measured by the DAS28 (ESR) (nominal p=0.013). The proportion of patients achieving ACR 50 response for sirukumab ranged from 26.9% for 50 mg to 35.3% for 100 mg.

77 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

There was a trend for greater improvements in patients randomized to sirukumab that had failed MTX for any safety/tolerability reason compared with those who failed MTX for an efficacy reason alone (Table 22).

For endpoints that are considered higher clinical thresholds (DAS28 (CRP) ≤2.6 and ACR 50), there was a numerically greater treatment response in the sirukumab 100 mg q2w group compared with the sirukumab 50 mg q4w group at Week 24; however, this was not consistently observed with all endpoints. Importantly, both doses of sirukumab provide clinically meaningful benefit ie, relative to adalimumab, through Week 24 (Table 22).

Table 22: Summary of Primary and Key Secondary Endpoints; Full Analysis Set (Study ARA3005)

Adalimumab Sirukumab 40 mg q2w 50 mg q4w 100 mg q2w Analysis set: Full Analysis Set (Placebo Controlled Period) 186 186 187 Patients who failed MTX at baseline for efficacy reason 106 106 107 Patients who failed MTX at baseline for safety reason 80 80 80

Primary: Change from baseline in DAS28 (ESR) score at Week 24c Mean (SD) -2.19 (1.437) -2.58 (1.524) -2.96 (1.580) LS Mean Difference (95% CI)a -0.39 (-0.69; -0.08) -0.76 (-1.07; -0.46) p-value 0.013 f <0.001 Patients who failed MTX at baseline for efficacy reason Mean (SD) -2.19 (1.340) -2.39 (1.504) -3.01 (1.604) Patients who failed MTX at baseline for safety reason Mean (SD) -2.20 (1.564) -2.84 (1.521) -2.89 (1.557) ACR 50 at Week 24 Patients in response 59 (31.7%) 50 (26.9%) 66 (35.3%) % Difference (95% CI)b -4.8 (-14.1; 4.4) 3.6 (-6.0; 13.1) p-value 0.306 0.464 Patients who failed MTX at baseline for efficacy reason Patients in response 32 (30.2%) 25 (23.6%) 35 (32.7%) Patients who failed MTX at baseline for safety reason Patients in response 27 (33.8%) 25 (31.3%) 31 (38.8%) Major Secondary DAS28 (CRP) ≤2.6 at Week 24 Patients in response 14 (7.5%) 24 (12.9%) 38 (20.3%) % Difference (95% CI)b 5.4 (-0.7; 11.4) 12.8 (5.9; 19.7) ACR 20 at Week 24 Patients in response 105 (56.5%) 100 (53.8%) 110 (58.8%) % Difference (95% CI)b -2.7 (-12.8; 7.4) 2.4 (-7.6; 12.3) Other Secondary Endpointsc ACR 70 at Week 24 24 (12.9%) 22 (11.8%) 29 (15.5%) % Difference (95% CI)b -1.1 (-7.8; 5.6) 2.6 (-4.5; 9.7) Change from baseline in CDAI at Week 24 – Mean (SD) -25.9 (13.2) -23.0 (13.8) -26.8 (14.8) LS Mean Difference (95% CI)d 3.0 (0.0; 5.9) -0.9 (-3.9; 2.0) Change from baseline in HAQ-DI at Week 24 – Mean (SD) -0.5 (0.7) -0.5 (0.6) -0.5 (0.7) LS Mean Difference (95% CI)e 0.04 (-0.1; 0.2) -0.02 (-0.14; 0.10)

78 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 22: Summary of Primary and Key Secondary Endpoints; Full Analysis Set (Study ARA3005)

Adalimumab Sirukumab 40 mg q2w 50 mg q4w 100 mg q2w Change from baseline in Physical Component Score of SF-36 at Week 24 – Mean (SD) 6.4 (8.9) 6.2 (8.0) 6.5 (7.7) LS Mean Difference (95% CI)d -0.25 (-1.99; 1.49) 0.06 (-1.67; 1.79) Change from baseline in Mental Component Score of SF-36 at Week 24 – Mean (SD) 5.9 (11.3) 5.2 (10.0) 6.2 (10.5) LS Mean Difference (95% CI)d -0.72 (-2.97; 1.52) 0.23 (-2.00; 2.47) Change from baseline in FACIT-Fatigue Score at Week 24 – Mean (SD) 6.4 (11.2) 7.6 (9.5) 8.6 (11.6) LS Mean Difference (95% CI)d 1.2 (-1.1; 3.5) 2.2 (-0.1; 4.5) a The confidence intervals were based on ANCOVA. b The confidence intervals were based on Wald statistic. c other secondary endpoints not included in pre-specified hierarchy d The confidence intervals were based on ANOVA e The confidence intervals were based on MMRM f Nominal p value For change in DAS28: Patients with missing data were imputed using the observed baseline DAS28 (ESR) score [that is, imputed as no change from baseline in DAS28 (ESR) score]. For ACR 20, ACR 50, ACR 70 and DAS28 (CRP) ≤2.6: patients with missing data, treatment failure, or early escape were treated as non- responders. Change in CDAI, HAQ-DI, MCS, PCS and FACIT-F scores were based on observed data

79 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 23: Change from Baseline in DAS28 (ESR) by Visit through Week 24; Full Analysis Set (Study ARA3005)

Patients with missing data were imputed using the observed baseline DAS28 (ESR) score [that is, imputed as no change from baseline in DAS28 (ESR) score]. [GEFDASESR02.rtf] generated by /projects/jjprd214975/stats/interim/prog/figures/gefdasesr02.sas, 03JAN2016 21:53

80 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

5.7. Efficacy Exposure-Response Analyses Phase 3 data were analyzed for E-R relationships and incorporated into models to confirm that appropriate dose regimens were studied in Phase 3, as well as to determine the dose regimen with the optimal benefit-risk profile. The E-R analyses focused on the 2 pivotal placebo- controlled studies ARA3002 and ARA3003.

The E-R analysis was conducted by comparing response rates for major clinical efficacy endpoints (ie, ACR 20/ACR 50 responses and DAS28 [CRP] ≤2.6) across quartiles of steady- state trough serum sirukumab concentrations from the combined 50 mg q4w and 100 mg q2w groups in each Phase 3 study (ARA3002, ARA3003). Further efficacy E-R analysis was performed using a PK/PD modeling approach based on combined Phase 3 data from studies ARA3002 and ARA3003.

5.7.1. Efficacy by Sirukumab Trough Concentration Quartiles In the Phase 3 studies, ARA3002 and ARA3003, E-R analyses for ACR 20/ACR 50 responses at Week 16 showed that patients in the lowest trough sirukumab concentration quartile (mainly from the 50 mg q4w arm) consistently showed lower response rates compared with the 3 higher quartiles (Figure 24). A similar pattern was observed for ACR 20/ACR 50 responses at Week 24 (Appendix 4). In addition, this E-R relationship was also evident for DAS28 (CRP) ≤2.6 at Week 24 (Appendix 5).

Notably, in these Phase 3 studies, ARA3002 and ARA3003, patients in the 100 mg q2w group were mainly represented in the 2 higher trough concentration quartiles while patients in the 50 mg q4w group were mainly represented in the 2 lower trough concentration quartiles at both Week 16 and Week 24.

81 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 24: Proportion of Patients Who Achieved ACR 20 or ACR 50 Responses at Week 16 by Trough Serum Concentration Quartiles at Week 16 (Studies ARA3002 and ARA3003) ARA3002

ARA3003

This figure only includes patients treated with sirukumab 50 mg q4w or 100 mg q2w from Week 0. ACR responses were based on the observed data. Patients with missing sirukumab concentration, missing ACR20 status, or missing ACR50 status were excluded.

82 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

5.7.2. Efficacy Exposure-Response Modeling Analysis E-R modeling analyses were also performed based on the pooled data from the 2pivotal placebo-controlled Phase 3 clinical studies (ARA3002 and ARA3003).

Model-based simulations suggest a dose-response trend for sirukumab (25 mg q4w <50 mg q4w <100 mg q4w ≈ 50 mg q2w <100 mg q2w), where 50 mg q4w would produce near-maximum efficacy. Sirukumab steady-state exposure from 100 mg q2w corresponded to the plateau portion of the E-R curve; 50 mg q4w would produce clinical responses close to the maximum effect while exposure from 25 mg q4w was predicted to be associated with lower clinical responses compared with 50 mg q4w and 100 mg q2w doses (Figure 25).

Figure 25: Observed versus Predicted Week 16 ACR20/ACR50/ACR70 Responses Using Steady- State Trough Concentration as Exposure Metric (Pooled Data)

The observed ACR 20/50/70 responses were determined according to bins of the observed sirukumab trough concentrations at Week 16 corresponding to the placebo group (0 µg/mL) and the quartiles of trough sirukumab concentrations for patients receiving sirukumab treatment from studies ARA3002 and ARA3003. The points were plotted at the median concentration within each quartile. A 90% confidenceinterval around the observed data was computed based on the normal approximation for proportions. The colored dashed lines are the simulated median responses. The box plots were the observed sirukumab concentrations (25mgQ4w from C1377T04, 50mgQ4w and 100mgQ2w from ARA3002 and ARA3003) with box representing the median and 25th/75th percentiles and ends of whiskers representing the 5th/95th percentiles.

83 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Overall, drug exposure from sirukumab 50 mg q4w and 100 mg q4w in the Phase 3 studies were consistent with the Phase 2 PK data. The efficacy E-R analyses support the conclusion that the sirukumab 50 mg q4w dose regimen produces near maximum efficacy in patients with RA, while the 25 mg q4w regimen is predicted to result in suboptimal efficacy. The higher dose regimen of 100 mg q2w would produce maximum effect but the incremental benefit is small compared with 50 mg q4w. None of the covariates identified in the population PK and efficacy E-R modeling analyses, including body weight, diabetic comorbidity, race, baseline disease activity, or concomitant MTX use, warrant dose adjustment.

5.8. Efficacy Conclusions In the 2 pivotal Phase 3 placebo-controlled studies, ARA3002 (DMARD-IR study) and ARA3003 (anti-TNFα-IR study), benefits were demonstrated across a difficult-to-treat patient population representing the full spectrum of moderately to severely active adult RA, ie, patients naive to biologic treatment who had responded inadequately to conventional DMARDs through to those who have failed to respond to multiple biologics.

 Improvement in signs and symptoms Consistent clinically and statistically significant improvements were demonstrated in ACR 20 as well as higher thresholds of efficacy, including ACR 50 response, major clinical response (MCR) and DAS28 (CRP) ≤2.6. Within each study, ACR 20 response was consistent across a range of demographic and baseline disease subgroups  Inhibition of structural damage Robust and significant inhibition of progression of structural damage as measured by change in Van der Heijde-modified Sharp (vdH-S) at Week 52 and seen as early as Week 24 in ARA3002  Improvement in physical function Statistically significant and clinically meaningful improvements in HAQ-DI  Improvement in patient reported outcomes Clinically meaningful improvements in SF-36 physical and mental scores, in all 8 individual domains of the SF-36 as well as clinical relevant improvements in FACIT-fatigue Subpopulation data from studies ARA3002 and ARA3003 in patients treated with sirukumab without concomitant DMARDs, and data from the monotherapy study ARA3005 in biologic-naïve patients with active RA established the efficacy of sirukumab as monotherapy. Whilst in the monotherapy subgroup a small incremental benefit of 100 mg q2w over 50 mg q4w was observed, it is not considered sufficient to justify recommending sirukumab 100 mg q2w.

84 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Overall, both dose regimens of sirukumab 50 mg every 4 weeks (q4w) and 100 mg every 2 weeks (q2w) were efficacious for the treatment of RA in combination with DMARDs and in monotherapy.

The 50 mg q4w dose regimen is recommended as the optimal dose schedule as if offers near maximum efficacy with 4-fold less exposure.

85 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

6. SUMMARY OF CLINICAL SAFETY An overview of safety observed in the sirukumab clinical development program is presented in the sections below.

6.1. General Approach to Evaluating and Managing Safety in the Sirukumab Development Program The clinical program for sirukumab was designed to evaluate the safety of sirukumab in patients with RA and also to evaluate patient selection and risk mitigation plans that could be used in product labeling. Safety analyses provided an assessment of all adverse events and focused in greater detail on adverse events of interest that are relevant for (i) IL-6 pathway inhibitors, (ii) immunosuppressive drugs, and (iii) risks that are relevant for the RA population:

 IL-6 pathway inhibitors (eg, tocilizumab) may increase the risk of infections, including opportunistic infections; gastrointestinal (GI) perforations, mainly lower GI perforations; and certain laboratory abnormalities, including elevations in lipids and aminotransferases and decreases in neutrophils and platelets. These events and laboratory parameters were considered events of special interest for additional safety analyses, and the clinical studies included risk mitigation strategies that may be appropriate for product labeling to inform physicians how to monitor and manage treatment with the drug.  Immunosuppression, in addition to increasing the risk of infections, may also increase the risk of certain malignancies; therefore, malignancies were also considered events of special interest for additional safety analyses, and clinical studies included risk mitigation strategies that may be appropriate for product labeling.  Patients with RA have a higher risk of certain comorbidities due to the underlying inflammatory burden of RA and/or medications used in RA treatment. a. The risk of CV disease is approximately 1.5 times higher in the RA population than the general population and thought to be partly attributable to traditional CV risk factors.3,35,63 Inflammatory cytokines increased in RA (including TNFα, IL-1, and IL-6) are thought to contribute either independently or through interactions with traditional CV risk factors to result in a heightened cardiac disease risk for this population.11,38,42

b. Epidemiologic studies have found a higher rate of certain malignancies in patients with RA relative to the general population, mainly an elevated rate of hematologic malignancies including lymphomas.

6.2. Comorbidities and Concomitant Medications of Study Population Baseline comorbidities and concomitant medication use in studies ARA3002 and ARA3003 were balanced between treatment groups. A high proportion of patients had cardiovascular risk factors, in particular, hypertension (39% overall). Overall, 12% of patients in the studies had latent tuberculosis, and appropriate treatment was initiated before they began dosing. The majority of patients were receiving methotrexate or other DMARDs, corticosteroids, and NSAIDs (Table 23).

86 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

In addition, the 120-day Safety Update (cut-off: 29 July 2016) provided an additional 4 months of safety data.

6.4. Overview of Safety Analysis Overall assessment of Sirukumab safety included assessment of all adverse events, all adverse events leading to treatment discontinuation, serious adverse events, and events with a fatal outcome (Table 25 and Table 27).

Safety analyses in this document captured all events that occurred within 16 weeks after the last dose of sirukumab, a period which accounts for the systemic elimination based on its PK.

MACE, GI perforations, and hepatobiliary events were independently adjudicated. Note that in the ongoing review of safety data for this program, the sponsor identified data errors in adjudication outcome for some events (MACE and GI perforations). The adjudication outcome errors were corrected, and the database was subsequently corrected; the results provided here reflect the final validated data.

6.4.1. Studies ARA3002 and ARA3003 Most analyses focus on data pooled from the placebo-controlled studies ARA3002 and ARA3003 and their common long-term extension (ARA3004) and are described as follows:

(1) Placebo-controlled analyses, which show data pooled from the 18-week placebo-controlled periods of studies ARA3002 and ARA3003. These analyses represent true placebo-controlled analyses and data are shown in 3 columns that represent safety events that occurred in the 3 populations of patients who were randomized to (i) placebo; (ii) sirukumab 50 mg q4w; and (iii) sirukumab 100 mg q2w (Table 25).

(2) 52-Week analyses, which includes all data from the 18-week placebo-controlled period as well as data beyond Week 18 and through Week 52. Key analyses of these data include 5 columns as follows (Table 25):

a. Placebo – data from patients randomized to placebo, some of whom received placebo up to Week 24 in ARA3003 and up to Week 52 in ARA3002 (ie, does not include time after early or late escape or after crossover to sirukumab). b. Sirukumab 50 mg q4w randomized population (excludes patients who early or late escaped to sirukumab or patients who crossed over to sirukumab). c. Sirukumab 100 mg q2w randomized population (excludes patients who early or late escaped to sirukumab or patients who crossed over to sirukumab). d. Sirukumab 50 mg q4w combined population (includes patients originally randomized to sirukumab 50 mg q4w as well as patients randomized to placebo after early or late escape or crossover to sirukumab 50 mg).

88 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

e. Sirukumab 100 mg q2w combined population (includes patients originally randomized to sirukumab 100 mg q2w as well as patients randomized to placebo after early or late escape or crossover to sirukumab 100 mg).

(3) Summary of Clinical Safety (SCS) cutoff analyses, which show all data pooled from the controlled and uncontrolled periods of studies ARA3002, ARA3003, and their long-term extension study ARA3004 through the SCS Cutoff date of 02 February 2016. These analyses are shown in 2 columns as follows (Table 25):

1. Sirukumab 50 mg q4w combined population (includes patients originally randomized to sirukumab 50 mg q4w as well as patients randomized to placebo after early or late escape or crossover to sirukumab 50 mg).

2. Sirukumab 100 mg q2w combined population (includes patients originally randomized to sirukumab 100 mg q2w as well as patients randomized to placebo after early or late escape or crossover to sirukumab 100 mg).

Limitations of Placebo Group Comparisons Beyond Week 18

Comparisons of sirukumab versus placebo beyond 18 weeks have the following limitations:

 Patients who showed less than 20% improvement in tender and swollen joints could qualify for early escape from the placebo arm in both studies ARA3002 and ARA3003  Patients could also late escape in study ARA3002.  All placebo patients in study ARA3003 crossed over to active sirukumab at Week 24; therefore, beyond Week 24, the placebo population was only represented by the ARA3002 population and only 49% of those ARA3002 patients randomized to placebo were able to tolerate placebo for 52 weeks. Thus, from 18 weeks onwards, the composition of the placebo group is altered and the initial randomization properties are no longer preserved after Week 18. In addition, the duration of observation of placebo subjects (average of 7.3 months) is reduced relative to the sirukumab treatment groups (average of 19.4 months), and unless hazards are constant over time, this creates additional bias.

As a result of the addition of the early and late escape subjects to the combined sirukumab arms, the combined sirukumab arms include a mixture of 2 distinct populations: a. Subjects who were initially randomized to sirukumab, and b. Early/late escape subjects with greater inflammatory disease burden at the time of escape/conversion to sirukumab compared with subjects who were randomized to sirukumab at the start of the studies. At the same time, the placebo group became less enriched for inflammatory disease burden due to the escape of patients with greater inflammatory burden. Since disease burden has been identified as an important covariate affecting the risk of death

89 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

(Appendix 11), the combined sirukumab arms constitute a heterogeneous patient population with respect to the risk of death. Finally, placebo experience is skewed towards shorter follow up which will impact assessment of adverse events that may be expected to occur as a function of longer duration of observation. Therefore, comparisons between the combined sirukumab arms and placebo are biased and any comparisons to placebo after Week 18 must be interpreted with caution.

6.4.2. Study ARA3005 Study ARA3005 is described separately because the study population and comparator were different from the placebo-controlled studies. Data are included through BLA cutoff of 02 February 2016. Analyses of safety data from study ARA3005 are presented for the 3 populations of patients who were randomized to (i) adalimumab, (ii) sirukumab 50 mg q4w, and (iii) sirukumab 100 mg q2w.

6.4.3. 120-day Safety Update In the 120-day Safety Update, the Sponsor provided updated safety information through a cutoff date of 29 July 2016 (ie, approximately 5.5 months since the cutoff for the SCS). Relative to data included in the SCS, data presented in the 120-day Safety Update included an approximately 910 additional patient-years of exposure to sirukumab across all the Phase 3 RA studies including ARA3001 and ARA3005, representing an approximately 21% increase (Section 6.10 and Table 36).

6.5. Adverse Events

6.5.1. Studies 3002 and 3003 Through 18-week placebo-controlled period, treatment-emergent AEs were reported in higher proportions of patients in the sirukumab treatment groups compared with the placebo group, and slightly higher AE rates were reported in the 100 mg q2w group than in the 50 mg q4w group (Table 25 and Table 26). The differences in overall AE rates between the sirukumab and placebo groups were primarily driven by higher rates of AEs in the Investigations System-Organ Class (SOC) (increases in liver chemistry levels and decreases in leukocytes, neutrophils, and platelets) and the General disorders and administration site conditions SOC (mostly injection site reactions). Differences between the 100 mg q2w sirukumab group and the 50 mg q4w group resulted mostly from higher rates of injection site reactions (mostly injection-site erythema and pruritus).

Through the SCS cutoff date, overall AE rates did not increase disproportionate to the increased time of follow-up, and there was no dose relationship in proportions of patients with AEs reported overall between the 2 sirukumab dose regimens; however, there were 2 exceptions in the 100 mg q2w dose of sirukumab: there were more frequent injection-site reactions and a marginally higher number of hypersensitivity reactions.

90 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 25: Treatment-emergent AEs in the DMARD-IR and TNFα-Failure Studies ARA3002, ARA3003, and ARA3002 and ARA3003 ARA3002 and ARA3003 ARA3004 Through 18 weeks of exposure Through 52 weeks of exposure Through SCS cutoff Combined3 Combined4 Combined3 Combined4 PBO 50 mg1 100 mg2 PBO 50 mg1 100 mg2 50 mg 100 mg 50 mg 100 mg N=850 N=848 N=850 N=850 N=848 N=850 N=1214 N=1217 N=1214 N=1217 Total patient-years of exposure5 292.3 292.3 293.5 519.5 786.9 784.4 1109.4 1111.1 1963.8 1974.6 Average duration of exposure (Weeks)6 17.94 17.99 18.01 31.89 48.42 48.15 47.68 47.64 78.33 78.73 Patients with ≥1: 444 515 545 703 695 969 997 AE, N (%) 548 (64.5%) 1022 (84.2%) 1050 (86.3%) (52.2%) (60.7%) (64.1%) (82.9%) (81.8%) (79.8%) (81.9%) AEs leading to 22 (2.6%) 34 (4.0%) 45 (5.3%) 31 (3.6%) 76 (9.0%) 80 (9.4%) 100 (8.2%) 123 (10.1%) 142(11.7%) 172(14.1%) discontinuation N (%) 112 SAE, N (%) 27 (3.2%) 41 (4.8%) 46 (5.4%) 56 (6.6%) 95 (11.2%) 151 (12.4%) 152 (12.5%) 237 (19.5%) 246 (20.2%) (13.2%) Rate/100 PY (95% 14.36 11.07 15.05 12.69 9.4 (6.17, (10.30, 16.14 (11.82, (8.36, (12.39, (10.27, 14.33 14.43 13.5 14 (12.3,15.86) CI) 13.61) 19.48) 21.53) 14.37) 18.11) 15.51) (12.14,16.81) (12.22,16.91) (11.84,15.34) Deaths, N 1 1 1 1 4 6 10 12 15 13 0.34 (0.01, 0.34 (0.01, 0.34 (0.01, 0.19 0.51 0.76 0.90 1.08 0.76 0.66 Rate/100 PY (95%) 1.91) 1.91) 1.90) (0.00,1.07) (0.14,1.3) (0.28,1.66) (0.43,1.66) (0.56,1.89) (0.43,1.26) (0.35,1.13) 1. Only includes patients randomized to sirukumab 50 mg q4w and does not include patients initially randomized to placebo who EE/LE/CO to sirukumab 50 mg q4w 2. Only includes patients randomized to sirukumab 100 mg q2w and does not include patients initially randomized to placebo who EE/LE/CO to sirukumab 100 mg q2w. 3. All patients who received at least 1 dose of sirukumab 50 mg q4w through the noted exposure time. This includes patients who were initially randomized to sirukumab 50mg q2w and patients randomized to placebo who EE/LE/CO to sirukumab 50 mg q4w. 4. All patients who received at least 1 dose of sirukumab 100 mg q2w through the noted exposure time. This includes patients who were initially randomized to sirukumab 100 mg q2w and patients randomized to placebo who EE/LE/CO to sirukumab 100 mg q2w. 5. Total patient-years of exposure is calculated as the total amount of safety follow up in the given window with censoring due to lost to follow up, completion of planned follow up, window cutoff, or death. Abbreviations: SCS=Summary of Clinical Safety; PBO=placebo; EE=early escape; LE=late escape; CO=crossover; AE=adverse event; SAE=serious adverse event.

91 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Adverse reactions occurring in 2% or more of patients on sirukumab 50 mg and at least 1% greater than placebo during the placebo-controlled period are summarized in Table 26

Table 26: Adverse Reactions Occurring in at Least 2% or More of Patients on Sirukumab 50 mg and at Least 1% Greater than Placebo 18-Week Placebo-Controlled Period Incidence (%) Placebo Sirukumab 50 mg Sirukumab 100 mg Preferred Term (N=850) (N=848) (N=850) Increased 2.9% 13.0% 14.6% aminotransferase a Injection site reactions b 2.1% 8.1% 16.0% Neutropenia 0.4% 5.3% 2.7% Leukopenia 0.9% 4.4% 4.2% a Includes ALT increased, AST increased, Hepatic enzyme increased, Liver function test abnormal, Transaminases increased, Alanine aminotransferase abnormal, Aspartate aminotransferase abnormal, and Hepatic enzyme abnormal b Predominantly included injection-site erythema, pruritus, swelling, and rash.

Other infrequent and medically-relevant adverse reactions occurring at an incidence less than 2% in patients treated with sirukumab included: thrombocytopenia, gastrointestinal perforation, serious hypersensitivity reaction, cellulitis, intervertebral discitis, necrotizing fasciitis, osteomyelitis, pneumonia, sepsis, soft tissue abscess, blood bilirubin increased, hypercholesterolemia, blood triglycerides increased.

6.5.1.1. Adverse Events Leading to Treatment Discontinuation Most adverse events were mild, self-limited, and did not require treatment discontinuation. The proportions of AEs that lead to discontinuation of study agent are shown in Table 26. As shown, during the placebo-controlled period, AEs leading to treatment discontinuation were reported in higher proportions of patients in the sirukumab treatment groups compared with the placebo group. The disparity in AEs leading to study agent discontinuation was, for the most part, attributable to AEs in the Investigations SOC (protocol discontinuation rules for specific laboratory abnormalities, particularly aminotransferase abnormalities), injection site reactions in the sirukumab 100 mg group, and infections.

Through the SCS cutoff, the rates of AEs leading to treatment discontinuation did not increase disproportionate to the increased time of follow-up. The most frequent AEs leading to discontinuation were infections, followed by AEs in the Investigations SOC. It is notable that the majority of investigations requiring treatment discontinuation occurred during the placebo-controlled period, which suggests that monitoring patients more closely during this timeframe will identify patients who require treatment discontinuation.

6.5.2. Study 3005 Generally similar adverse event rates were observed in all treatment groups. Rates of serious adverse events were higher in the 50 mg sirukumab group compared with either the 100 mg group or adalimumab group, and this disparity was largely explained by more serious infections 92 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 26: Rate of Serious Adverse Events per 100 PY*

* Safety populations presented here as per description in Section 6.4 (Approach to Safety Analysis): Placebo-controlled, Week 52 refer to studies ARA3002 and ARA3003 only, SCS Cutoff refers to studies ARA3002 and ARA3003, and their long-term extension study ARA3004 and the 120-day Cutoff refers to all studies (ARA3001, ARA3002, ARA3003, ARA3004, and ARA3005).

6.6.1. Deaths All-cause mortality rates were evaluated during each study period.

Through the 18 week placebo-controlled period in studies ARA3002 and ARA3003 (Table 25), one death occurred in each treatment group: Acute Respiratory Distress Syndrome (ARDS) related to infection in 1 patient in the placebo group, sudden cardiac death in 1 patient in the sirukumab 50 mg q4w group, and GI hemorrhage in 1 patient in the sirukumab 100 mg q2w group hospitalized for uncontrolled hypertension and a myocardial infarction (MI). These deaths resulted in mortality rates of 0.34 deaths per 100 patient years in each of the 3 treatment groups (Figure 27).

Through 52 weeks of exposure in studies ARA3002 and ARA3003, an additional 3 deaths occurred in patients randomized to sirukumab 50 mg q4w and an additional 5 deaths in patients randomized to sirukumab 100 mg q2w (Table 25 and Figure 27). The rates were 0.51 and 0.76 deaths per 100 patient years, respectively, in patients originally randomized to the sirukumab 50 mg and 100 mg treatment groups and 0.19 with cumulative placebo exposure (ie with additional placebo exposure beyond the 18 week placebo-controlled period).

95 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Through the SCS cutoff with the additional exposures accrued in the ARA3004 long-term extension, a total of 29 deaths were reported in relation to patients from studies ARA3002 and ARA3003 (Table 25), resulting in mortality rates of 0.76 and 0.66 deaths per 100 patient years, respectively, in patients receiving sirukumab 50 mg q4w and 100 mg q2w.

Further, through the SCS cut-off in the active control study ARA3005 (average follow-up: approximately 45 weeks), a single fatality was reported. The patient was in the sirukumab 100 mg q2w group and died from a hemorrhagic stroke. No fatalities were reported in the adalimumab or sirukumab 50 mg q4w groups. There were no fatalities in study ARA3001.

Through the 29 July 2016 cutoff date for the 120-day Safety Update, an additional 8 deaths relative to the SCS cutoff were reported for sirukumab-treated patients who participated in the RA development program. The mortality rates in the Phase 3 study program (ARA3001, ARA3002, ARA3003, ARA3004, and ARA3005) through the 120-day Safety Update cutoff date was 0.68 and 0.71 deaths per 100 patient-years, respectively, in patients receiving sirukumab 50 mg q4w and 100 mg q2w. An additional death (sirukumab 50 mg q4w group) from cerebrovascular accident occurred during the Safety Update period but was reported late, after the 29 July 2016 cutoff, and thus is not included in the above incidence rate (Figure 27).

Figure 27: Rate of Deaths per 100 PY*

96 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Beyond the 16 week safety follow up window after the last dose of study agent for all the phase 3 studies, 4 more deaths occurred: 2 in study ARA3002, 1 in study ARA3003 and 1 in study ARA3005. These patients are not included in Figure 27.

In addition, 1 death occurred in the Phase 2 study C1377T04. This patient is also not included in Figure 27.

6.6.1.1. Causes of Death Cumulatively through the SCS cutoff date (02 Feb 2016), there was a total of 30 deaths through 16 weeks after the last administration of study agent reported for all patients who participated in the Phase 3 sirukumab RA clinical studies (1 death in a placebo-treated patient due to an ARDS related to infection and 29 deaths in sirukumab-treated patients). Among the 29 patients treated with sirukumab, the majority of deaths resulted from MACE (13/29), infections (7/29), or malignancy (4/29), which are the leading causes of death in the RA population32,53 and in other RA drug development programs.8,9,10 Each of the fatal cardiovascular events involved patients with at least 2 cardiovascular risk factors in addition to RA (Section 6.7.3), and each of the fatal infections (Section 6.7.1) involved patients with 1 or more risk factors. The causes of the remaining 5 fatalities included: intestinal ischemia/infarction, road traffic accident, respiratory failure related to pulmonary fibrosis, aortic dissection, and gastrointestinal hemorrhage.

Four additional deaths occurred beyond the 16 week safety follow-up of the respective studies: 2 in study ARA3002, 1 in study ARA3003 and 1 in study ARA3005. These patients developed malignancies during the studies and subsequently died up to 1.5 years post follow up.

The causes of deaths among the 9 sirukumab-treated patients who died between the cut off dates for the SCS and the 120-day Safety Update (including the death reported after the 29 July 2016 cutoff date; see Section 6.6.1) were consistent with the main causes of deaths reported through the SCS cutoff date as described above. Specifically, 4 of the 9 additional sirukumab-treated patient deaths involved a fatal infection (sepsis [n=2], meningitis pneumococcal/pneumonia, and erysipelas), and 2 of the additional deaths were adjudicated as MACE (sudden death, cerebral infarction). The causes of death for the remaining 3 additional sirukumab-treated patient deaths were cerebrovascular accident (adjudicated as Undetermined cause of death), respiratory failure, and unknown cause.

In addition, 1 death occurred in the Phase 2 study due to a non-adjudicated brain aneurysm.

6.6.1.2. Risk Factors Associated with Mortality The causes of death varied and were consistent with the rates and causes of death seen in an RA population treated with biologics. The CV and infection-related deaths had one or more risk factors associated with them.

To evaluate covariates associated with mortality, 3 additional sets of analyses were conducted. The results are summarized below:

97 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

1. Multivariate logistic regression analyses showed that older age, male gender, smoking, previous MI, Latin America location, and baseline corticosteroid use were associated with all-cause mortality regardless of treatment group. These risk factors have been associated with mortality in other biologic-treated cohorts and are not unique to the RA population or treatment.28,39,41 2. Marginal structural modeling identified baseline characteristics of older age, corticosteroid use, and a comorbidity of hypertension as risk factors for mortality. 3. Additionally, higher average inflammatory burden during the study as measured by HAQ, or CRP were associated with increased risk of mortality. It is important to note that sirukumab was not identified as significantly associated with mortality by logistic regression or marginal structural modelling. Lastly, since subjects with higher inflammatory burden or disease activity are more likely to escape early to sirukumab treatment arms, there is inherent bias in comparing sirukumab arms directly to placebo after Week 18. Thus, analyses of the difference between placebo and sirukumab over 52 weeks, adjusted for important risk factors, were done using Poisson regression and are detailed in Appendix 12. These analyses show reduced differences between placebo and sirukumab with increased precision after adjustment.

6.6.1.3. Mortality Rates Over Time Mortality rates were evaluated by 6-month increments of exposure to sirukumab to determine if cumulative or duration of exposure was associated with additional risk (Figure 28). These analyses showed no increase in mortality rate with prolonged exposure and no dose effect in rates of death. Moreover, the rates of events for MACE, infections and malignancies, which were the most common causes of mortality, also remained constant over time.

98 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 28: Analysis of Death Over Time (SCS Cut-off)

6.6.1.4. Mortality Rates Compared with Published Clinical Trial Data As discussed in Section 6.1, patients with RA have a higher risk of certain comorbidities (eg, CV disease and hematologic malignancies) due to the underlying inflammatory burden of RA and/or medications used in RA treatment, thus leading to a higher mortality rate compared with the general population.

To examine the mortality rates observed in patients in the sirukumab Phase 3 program relative to the rates reported in clinical development programs of other agents used in the treatment of RA, indirect comparisons were used (Figure 29). The mortality rates were generally consistent across RA clinical development programs, and the rates observed in sirukumab-treated patients were consistent with rates in other programs. More variability was observed among placebo-treated patients across RA development programs, likely due to comparatively smaller amount cumulative follow up with placebo-treated patients.

99 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 29: Mortality rates from the sirukumab RCT program and published rates from comparator RCT programs

Exposure-adjusted mortality rates from sirukumab randomized controlled study (RCT) program and published rates from RCTs/RA development programs for anti-TNFα agents (golimumab, certolizumab, adalimumab), tofacitinib, abatacept, tocilizumab, and rituximab. Sirukumab point estimate is 0.66 for combined sirukumab groups across the 5 Phase 3 studies through the SCS cutoff date; placebo point estimate in sirukumab Phase 3 program is 0.19. Error bars represent 95% CI.

Rates of mortality among sirukumab-treated patients were also within the range of rates previously reported in the general RA population from epidemiology studies, which range from 1.7 to 3.2 per 100 patient-years.17,36,54,66 Combined, these observations suggest that mortality rates in sirukumab-treated patients are broadly consistent with those observed for patients with RA in general or patients treated with other drugs used in treating RA.

6.7. Adverse Events of Special Interest Adverse events of special interest are summarized in Table 29.

100 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 29: AEs of Interest: Incidence per 100 Patient-Years in the DMARD-IR and TNFα-Failure Studies ARA3002, ARA3003, and ARA3002 and ARA3003 ARA3002 and ARA3003 ARA3004 Through 18 weeks of exposure Through 52 weeks of exposure Through SCS cutoff Combined3 Combined4 Combined3 Combined4 PBO 50 mg1 100 mg2 PBO 50 mg1 100 mg2 50 mg 100 mg 50 mg 100 mg N=850 N=848 N=850 N=850 N=848 N=850 N=1214 N=1217 N=1214 N=1217 Total patient-years of exposure5 292.3 292.3 293.5 519.5 786.9 784.4 1109.4 1111.1 1963.8 1974.6 7 (0.8%) 16 (1.9%) 14 (1.6%) 14 (1.6%) 41 (4.8%) 36 (4.2%) 54 (4.4%) 54 (4.4%) 89 (7.33%) 95 (7.81%) Serious infection 2.4 5.52 4.81 2.71 5.29 4.65 4.94 4.93 4.67 5.00 N (%) Rate/100 PY (95% CI) (0.97, 4.95) (3.15, 8.96) (2.63, 8.07) (1.48, 4.55) (3.79, 7.17) (3.26,6.44) (3.71,6.44) (3.71, 6.44) (3.75, 5.75) (4.05, 6.11) 0 1 (0.1%) 3 (0.4%) 1 (0.1%) 2 (0.2%) 4 (0.5%) 3 (0.2%) 6 (0.5%) 6 (0.5%) 8 (0.7%) GI Perforations 0.00 0.34 1.02 0.19 0.25 0.51 0.27 0.54 0.31 0.41 N (%) Rate/100 PY (95% CI) (0, 1.02) (0.01, 1.91) (0.21, 2.99) (0, 1.07) (0.03, 0.92) (0.14, 1.31) (0.06, 0.79) (0.2, 1.18) (0.11, 0.67) (0.18, 0.8) Upper GI Perforations 0 1(0.1%) 1(0.1%) 1 (0.1%) 1 (0.1%) 2 (0.2%) 1 (0.1%) 2 (0.2%) 1 (0.1%) 2 (0.2%) N (%) 0.00 0.34 0.34 0.19 0.13 0.26 0.09 0.18 0.05 0.1 Rate/100 PY (95% CI) (0.00, 1.02) (0.01, 1.91) (0.01, 1.90) (0, 1.07) (0, 0.71) (0.03, 0.92) (0, 0.5) (0.02,0.65) (0.00, 0.28) (0.01, 0.37) Lower GI Perforations 0 0 2 (0.2%) 0 1 (0.1%) 2 (0.2%) 2 (0.2%) 4 (0.3%) 5 (0.4%) 6 (0.5%) N (%) 0.00 0.00 0.68 0.00 0.13 0.26 0.18 0.36 0.25 0.3 Rate/100 PY (95% CI) (0.00, 1.02) (0.00, 1.02) (0.08, 2.47) (0, 0.58) (0, 0.71) (0.03, 0.92) (0.02, 0.65) (0.1, 0.92) (0.08, 0.6) (0.11, 0.66) MACE6 1 (0.1%) 2 (0.2%) 1 (0.1%) 2, 0.39 20, 6 N (%) 0.34 0.68 0.34 (0.047, 9, 1.15 3, 0.38 14, 1.27 4, 0.36 1.02 0.30 Rate/100 PY (95% CI) (0.009, 1.91) (0.083, 2.47) (0.009, 1.89) 1.39) (0.52, 2.18) (0.08, 1.12) (0.69, 2.12) (0.1, 0.92) (0.62, 1.58) (0.11, 0.66) 1 (0.1%) 1 (0.1%) 3(0.4%) 1 (0.1%) 4 (0.3%) 1 (0.1%) 6 (0.5%) 1 (0.1%) Non-fatal MI 1 (0.1%) 0 0.34 0.19 0.38 0.13 0.36 0.09 0.31 0.05 N (%) 0.34 0.00 Rate/100 PY (95% CI) (0.01, 1.91) (0.00, 1.02) (0.01, 1.90) (0.00, 1.07) (0.08, 1.12) (0.00, 0.71) (0.10, 0.93) (0.00, 0.50) (0.11, 0.67) (0.00, 0.28)

0 1 (0.1%) 4(0.5%) 1 (0.1%) 7 (0.6%) 2 (0.2%) 9 (0.7%) 3 (0.2%) Non-fatal stroke 0 1 (0.1%) 0.00 0.19 0.51 0.13 0.63 0.18 0.46 0.15 N (%) 0.00 0.34 Rate/100 PY (95% CI) (0.00, 1.02) (0.01,1.91) (0.00, 1.02) (0.00, 1.07) (0.14, 1.30) (0.00, 0.71) (0.25, 1.30) (0.02, 0.65) (0.21, 0.87) (0.03, 0.44) 0 0 2(0.2%) 2 (0.2%) 6 (0.5%) 3 (0.2%) 8 (0.7%) 4 (0.3%) CV Death 0 1 (0.1%) 0.00 0.00 0.25 0.25 0.54 0.27 0.41 0.20 N (%) 0.00 0.34 Rate/100 PY (95% CI) (0.00, 1.02) (001, 1.91) (0.00, 1.02) (0.00, 0.58) (0.03, 0.92) (0.03, 0.92) (0.20, 1.18) (0.06, 0.79) (0.18, 0.80) (0.06, 0.52)

101 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 29: AEs of Interest: Incidence per 100 Patient-Years in the DMARD-IR and TNFα-Failure Studies

ARA3002 and ARA3003 ARA3002 and ARA3003 ARA3002, ARA3003, and ARA3004 Through 18 weeks of exposure Through 52 weeks of exposure Through SCS cutoff Combined3 Combined4 Combined3 Combined4 PBO 50 mg1 100 mg2 PBO 50 mg1 100 mg2 50 mg 100 mg 50 mg 100 mg N=850 N=848 N=850 N=850 N=848 N=850 N=1214 N=1217 N=1214 N=1217 1 (0.1%) 7 3 (0.4%) 11 (1.3%) 3 (0.4%) 16 (1.3%) 5 (0.4%) 24 (2%) 7 (0.6%) MACE plus 1 (0.1%) 3 (0.4%) 0.34 0.58 1.4 0.38 1.45 0.45 1.23 0.35 N (%) 0.34 1.03 Rate/100 PY (95% CI) (0.01, 1.91) (0.21, 3) (0.01, 1.9) (0.12, 1.69) (0.7, 2.51) (0.08, 1.12) (0.83, 2.35) (0.15, 1.05) (0.79, 1.84) (0.14, 0.73) 1 (0.1%) 3 (0.4%) 8 (0.9%) 6 (0.7%) 11 (0.9%) 13 (1.1%) 20 (1.65%) 19 (1.6%) Malignancy 2 (0.2%) 1 (0.1%) 0.34 0.58 1.02 0.77 0.99 1.17 1.03 0.97 N (%) 0.68 0.34 Rate/100 PY (95% CI) (0.08, 2.47) (0.01, 1.91) (0.01, 1.91) (0.12, 1.69) (0.44, 2.01) (0.28, 1.67) (0.5, 1.78) (0.62,2.01) (0.63, 1.58) (0.58, 1.51) NMSC7 1 (0.1%) 1 (0.1%) 0 2 (0.2%) 3 (0.4%) 1 (0.1%) 4 (0.3%) 2 (0.2%) 6 (0.5%) 4 (0.3%) N (%) 0.34 0.34 0.00 0.39 0.38 0.13 0.36 0.18 0.31 0.20 Rate/100 PY (95% CI) (0.01, 1.91) (0.01, 1.91) (0.00, 1.02) (0.05, 1.39) (0.08, 1.12) (0.00, 0.71) (0.10, 0.92) (0.02, 0.65) (0.11, 0.67) (0.06, 0.52) Other Malignancies8 1 (0.1%) 0 1 (0.1%) 1 (0.1%) 5 (0.6%) 5 (0.6%) 7 (0.6%) 11 (0.9%) 14 (11.3%) 15 (1.2%) N (%) 0.34 0.00 0.34 0.19 0.64 0.64 0.63 0.99 0.71 0.76 Rate/100 PY (95% CI) (0.01, 1.91) (0.00, 1.02) (0.01, 1.90) (0.00, 1.07) (0.21, 1.49) (0.21, 1.49) (0.25, 1.30) (0.50, 1.77) (0.39, 1.20) (0.43, 1.25) 3. Only includes patients randomized to sirukumab 50 mg q4w and does not include patients initially randomized to placebo who EE/LE/CO to sirukumab 50 mg q4w. 4. Only includes patients randomized to sirukumab 100 mg q2w and does not include patients initially randomized to placebo who EE/LE/CO to sirukumab 100 mg q2w. 5. All patients who received at least 1 dose of sirukumab 50 mg q4w through the noted exposure time. This includes patients who were initially randomized to sirukumab 50mg q2w and patients randomized to placebo who EE/LE/CO to sirukumab 50 mg q4w. 6. All patients who received at least 1 dose of sirukumab 100 mg q2w through the noted exposure time. This includes patients who were initially randomized to sirukumab 100 mg q2w and patients randomized to placebo who EE/LE/CO to sirukumab 100 mg q2w. 7. Total patient-years of exposure is calculated as the total amount of safety follow up in the given window with censoring due to lost to follow up, completion of planned follow up, window cutoff, or death. 8. MACE is defined as CV death, MI, and stroke 9. MACE plus includes non-fatal myocardial infarction (MI), non-fatal stroke, unstable angina (UA) requiring hospitalization, transient ischemic attack (TIA) requiring hospitalization, and cardiovascular (CV) death 10. Nonmelanoma skin cancers (NMSC) and malignancies other than NMSC (Other malignancies) were analyzed separately.

102 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

6.7.1. Infections

6.7.1.1. Patient Selection as Risk Minimization for Infections Since sirukumab treatment may increase the risk of infection, patient selection criteria and routine monitoring for infections were implemented as risk mitigation measures. Patients who had a severe infection in the past 2 months, an opportunistic infection in the past 6 months, had a history of chronic or recurrent infectious disease, were infected with HIV, hepatitis B, or hepatitis C were excluded from the studies. Immunization with live viral or bacterial vaccine within 3 months (12 months for BCG) of first study agent administration, during the study, or within 4 months after the last administration of study agent, was not permitted. Patients were screened for tuberculosis to ensure that patients with active or untreated latent TB did not receive sirukumab. Patients with latent TB could participate after initiation of appropriate therapy.

During the study, sirukumab was discontinued in any patient who developed an opportunistic infection. Treatment was interrupted for serious infections until the infection resolved, and Investigators were required to consider discontinuing sirukumab. These risk mitigation measures and the risk of serious infections is reflected in the proposed sirukumab US Prescribing Information.

6.7.1.2. Infections in Sirukumab Clinical Studies In placebo-controlled analyses, the overall frequency of infections (both serious and non-serious) was similar between the placebo and sirukumab groups in studies ARA3002 and ARA3003, but serious infections occurred more commonly in patients receiving sirukumab (Table 29 and Figure 30).

103 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 30: Rate of Serious Infections per 100 PY*

Through the SCS cut-off, the rate per 100 patient-years of follow-up of serious infection remained generally stable through Week 52 and also through the SCS cutoff suggesting that the rate of serious infections did not increase over time, and the rates of serious infections were similar regardless whether patients were receiving concomitant DMARDs. The most common serious infections were of bacterial origin, and the specific infections that occurred with highest frequency were pneumonia and cellulitis.

The rates of serious infections through the cutoff date for the 120-day Safety Update were very similar to those reported through the SCS cutoff date (4.76 and 4.67 patients per 100 patient years of exposure, respectively).

Overall, 11% of patients had latent TB and required initiation of treatment prior to initiating study agent. Across all studies, 2 cases of pulmonary TB occurred in sirukumab-treated patients (1 case of TB reactivation in the 50 mg group in ARA3005; and 1 de novo case in the 100 mg group in ARA3002 in a patient who screened negative for TB at study entry), while 1 case was seen in an adalimumab patient, and no cases in placebo. Both sirukumab-treated patients recovered from their infections. These observations suggest that TB screening and initiation of treatment for latent TB prior to initiation of sirukumab provides effective risk mitigation.

104 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

An impact of sirukumab on viral infections was not apparent. Rates of common viral infections such as upper respiratory tract infections and nasopharyngitis were not higher in sirukumab-treated patients than in placebo-treated patients, and the incidence of herpes zoster was similar between sirukumab 50 mg q4w, sirukumab 100 mg q2w, and placebo indicating that sirukumab treatment does not lead to an increased incidence of varicella-zoster virus reactivation. There were no cases of disseminated herpes zoster reported during the clinical studies.

Opportunistic infections were uncommon in sirukumab clinical studies. Four non-serious opportunistic infections were reported: One case of herpes zoster in the ophthalmic distribution of the trigeminal nerve (Placebo EE  100 mg treatment group), 1 case of herpes ophthalmic (zoster or simplex not specified) (100 mg treatment group) and 2 cases of esophageal candidiasis (1 in 100 mg treatment group, 1 in placebo EE to 50 mg treatment group), all of whom recovered with antiviral or antifungal treatment. One event of localized herpes zoster in the eye (50 mg treatment group) was reported as a SAE since it led to hospitalization, which was mild in intensity, and resolved with treatment. A serious fungal infection (retro-orbital Aspergillus) (100 mg treatment group) was reported after the SCS cutoff and a case reported as “indeterminate colitis” prior to the SCS cutoff was subsequently determined to be CMV colitis (50 mg treatment group) and a serious opportunistic infection. Both patients recovered after sirukumab discontinuation and appropriate treatment.

6.7.1.3. Impact of Neutropenia on Infections Treatment with sirukumab was associated with a decrease in neutrophil counts (Section 6.7.6). To determine if changes in neutrophil count were associated with an increased risk of infection, the proportions of patients with an infection or serious infection and absolute neutrophil count (ANC) less than the lower limit of normal (LLN; 1.96 x 103/µL) were evaluated in each treatment group during the placebo-controlled period (Table 30). Rates were higher in each sirukumab group than in placebo, though conclusions are limited since the proportions of patients with ANC

Therefore, additional analyses were conducted to evaluate infection rates in patients whose ANC decreased to less than the LLN (Table 30). Overall rates of infections were generally comparable among sirukumab-treated patients than in placebo-treated patients in the subpopulation of patients with ANC

105 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

In placebo-controlled analyses, GI perforations were observed in 0.1% and 0.4% of patients in the 50 mg q4w and 100 mg q2w groups, respectively, versus 0 for placebo patients. Through the SCS cutoff, rates of GI perforations remained low and generally stable over time (Table 29 and Figure 31). Rates per 100 PY were higher in sirukumab-treated patients than in placebo-treated patients, with this disparity resulting in higher rates of lower GI perforations in sirukumab- treated patients (Table 29). A dose effect was not apparent.

The overall incidence rates of GI perforation through the 120-day Safety Update cutoff date (0.30 and 0.41 per 100 patient-years of exposure for the sirukumab 50 mg q4w and 100 mg q2w groups, respectively) were unchanged relative to those presented through the SCS cutoff date.

Overall, the incidence of GI perforation seen with sirukumab is similar to that seen in long term safety with tocilizumab (see benefit risk section), which appears to be associated with a small increased risk of lower GI perforation.55

6.7.3. MACE

6.7.3.1. Cardiovascular Disease in RA Since cardiovascular disease is a common comorbidity in RA, major adverse cardiovascular events (MACE) were followed closely in the sirukumab development program for RA. MACE was defined as nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular death. A broader definition of ‘MACE plus’, additionally incorporating softer cardiovascular endpoints

107 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document such as hospitalization for unstable angina, and hospitalization for transient ischaemic attack (TIA) was also analyzed. All serious adverse events that could represent a MACE were adjudicated by an independent, blinded expert clinical endpoint committee, the Cleveland Clinic Coordinating Center for Clinical Research (C5 Research) Clinical Events Committee, and categorized by MACE component.

6.7.3.2. MACE in the Sirukumab Program Sirukumab has an acceptable cardiovascular safety profile. Small numbers of MACE were reported in the sirukumab clinical development program (Table 29). During the 18 week placebo-controlled period for pivotal studies ARA3002 and ARA3003, MACE as defined by first occurrence of non-fatal MI, non-fatal stroke or CV death, were reported in 1 (0.1%) patient in the placebo group, 2 (0.2%) in the sirukumab 50 mg q4w group, and one (0.1%) patient in the sirukumab 100 mg q2w group (Table 29 and Figure 32). In 52 week analyses and through the SCS cutoff, overall incidence of MACE per 100 patient-years remained low and generally stable over time (placebo 0.39, sirukumab 50 mg q4w: 1.15, sirukumab 100 mg q2w: 0.38; Table 29). The overall incidence rates of MACE through the 120-day Safety Update cutoff date (0.99 and 0.34 per 100 patient-years of exposure for the sirukumab 50 mg q4w and 100 mg q2w groups, respectively) were similar to those presented through the SCS cutoff date (Table 29 and Figure 32).

Figure 32: Rate of MACE per 100 PY*

108 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

The majority of patients with MACE had at least one cardiovascular risk factor at baseline. Although sirukumab is associated with lipid elevations, on-treatment lipid levels were similar between patients with and without MACE (Section 6.7.7). Note that body weight, blood pressure and blood glucose do not change with sirukumab therapy.

Incidence of MACE (including MACE components of non-fatal MI, non-fatal stroke and CV death) was numerically lower for placebo and sirukumab 100 mg q2w compared to sirukumab 50 mg q4w (Table 29 and Figure 32). The dose difference is not related to lipid levels (see Section 6.7.7) or duration of sirukumab exposure. Although the number of events is small, baseline and on-treatment cardiovascular risk factors, inflammation and disease activity were evaluated to further investigate a potential explanation. However, the data did not reveal any clear reason for this dose difference.

Overall, the incidence of MI and stroke seen with sirukumab is similar to that observed with tocilizumab (MACE incidence rates overall have not been reported for tocilizumab; Figure 33), and similar or lower than rates reported in large epidemiological controlled studies including patients with RA. Combined, these data show that no excess risk of MACE has been identified on sirukumab compared with the RA population.

Figure 33: Indirect comparison of the incidence of MI and stroke on sirukumab and tocilizumab

109 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

6.7.4. Malignancies

6.7.4.1. Patient Selection as Risk Minimization for Malignancy Since immunosuppression may increase the risk of malignancy, patients were excluded from study participation if they had a known malignancy or a history of malignancy within the previous 5 years, with the exception of nonmelanoma skin cancers. In addition, study agent administration was discontinued in any patient who developed a malignancy other than a nonmelanoma skin cancer.

6.7.4.2. Malignancies in Sirukumab Clinical Studies In the placebo controlled period, rates of malignancies were low in all treatment groups (Table 25) and no differences were observed between the placebo and sirukumab groups.

Through the SCS cutoff, a total of 41 patients developed malignancies, 3 patients with placebo, 21 with 50 mg q4w, and 17 with 100 mg q2w. The most frequently reported malignancies were cancers of the skin, breast, and lung. The rate of malignancies remained constant over time through the SCS cutoff and was comparable in patients administered sirukumab 50 mg q4w and sirukumab 100 mg q2w (Table 25 and Figure 34). As expected, the frequency of malignancies was highest in the group aged ≥75 to <85 years. No consistent pattern was seen in the incidence of malignancies when comparing patients in the Phase 3 studies who were and were not on DMARDs at baseline through the SCS cutoff date.

Figure 34: Rate of Malignancies per 100 PY*

110 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document extension study ARA3004 and the 120-day Cutoff refers to all studies (ARA3001, ARA3002, ARA3003, ARA3004, and ARA3005).

Rates of malignancies other than NMSC observed in all Phase 3 studies of sirukumab through the SCS cutoff were compared with expected rates adjusted for age, gender, and race based on data available in the National Institutes of Health SEER (Surveillance, Epidemiology, and End Results) database (2012). The standardized incidence ratios of 1.01 and 0.91 for the sirukumab groups approximated 1, which suggests that the observed number of malignancies was similar to that expected in the general population (Table 31).

Table 31: Malignancies in Phase 3 sirukumab studies compared with the expected number in the general population according to the SEER database PBO SIR 50 mg q4w SIR 100 mg q2w (n=850) (n=1461) (n=1465) 521 PY 2196 PY 2215 PY Observed Malignancies other than 1 17 15 NMSC, N Expected number of malignancies a 3.84 16.91 16.55 Rate/100 PY (95% CI) 0.19 (0.00, 1.07) 0.78 (0.45, 1.24) 0.68 (0.38, 1.12) Standardized Incidence Ratio b (95% CI) 0.26 (0.01, 1.45) 1.01 (0.59, 1.61) 0.91 (0.51, 1.50)

Observed Lymphomas, N 0 2 2 Expected number of lymphomas a 0.15 0.67 0.65 Rate/100 PY (95% CI) 0.00 (0.00, 0.58) 0.09 (0.01, 0.33) 0.09 (0.01, 0.33) Standardized Incidence Ratio b (95% CI) 0.00 (0.00, 19.96) 3.01 (0.36, 10.86) 3.09 (0.37, 11.16) a The expected number of patients with malignancies is based on the SEER Database (2012), adjusted for age, gender, and race. b Standardized Incidence Ratio = observed number of patients with malignancy divided by expected number of patients with malignancy

Patients with RA are known to have an increased risk of lymphoma and lung cancer compared with the general population.47,50 Lymphomas were reported in 2 patients in each sirukumab group, giving standardized incidence ratios that approximated 3. While the 95% confidence intervals overlapped 1, the standardized incidence ratio of 3 is consistent with the elevated risk reported in patients with RA, and consistent with the standardized incidence ratios reported in patient populations receiving other biologics used in treating RA.43,50,65 Lymphomas rates increased 1.75-12x in patients with RA compared with the general population.48

Combined, these results do not suggest an impact of sirukumab on overall rates of malignancies. As with other biologic agents, there is uncertainty whether sirukumab contributed to the increased risk of lymphoma, or whether the higher rate compared with the general population resulted from the underlying disease. As with other immunosuppressive agents used in treating RA, recommended prescribing information notes that caution should be exercised when considering sirukumab use in patients with a history of malignancy since immunosuppression may affect host immune response to malignancies.

111 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

6.7.5. Aminotransferase Abnormalities Aminotransferase abnormalities have been reported in patients with RA receiving DMARDs, especially methotrexate, and agents that block the IL-6 pathway, eg tocilizumab, an anti-IL6R inhibitor. Therefore, aminotransferases were followed closely in the sirukumab development program for RA, and guidelines were provided for interrupting or discontinuing sirukumab.

Table 32: Aminotransferase Abnormalities in Sirukumab Phase 3 Studies ARA3002 and ARA3003 ARA3005 Through 18 weeks of exposure Through SCS Cutoff PBO SIR 50 mg SIR 100 mg ADA SIR 50 mg SIR 100 mg N=850 N=848 N=850 N=186 N=186 N=187 ALT Abnormalities ALT >ULN 180 (21.2%) 494 (58.3%) 485 (57.1%) 55 (29.6%) 106 (57.0%) 100 (53.5%) ALT≥3x ULN 11 (1.3%) 53 (6.3%) 70 (8.2%) 10 (5.4%) 7 (3.8%) 14 (7.5%) ALT≥5x ULN 5 (0.6%) 14 (1.7%) 18 (2.1%) 3 (1.6%) 1 (0.5%) 3 (1.6%) ALT≥8xULN 2 (0.2%) 4 (0.5%) 7 (0.8%) 1 (0.5%) 0 1 (0.5%)

AST Abnormalities AST >ULN 138 (16.2%) 378 (44.6%) 380 (44.7%) 40 (21.5%) 66 (35.5%) 69 (36.9%) AST≥3x ULN 6 (0.7%) 20 (2.4%) 29 (3.4%) 3 (1.6%) 5 (2.7%) 6 (3.2%) AST≥5x ULN 3 (0.4%) 2 (0.2%) 6 (0.7%) 1 (0.5%) 0 1 (0.5%) AST≥8xULN 2 (0.2%) 0 1 (0.1%) 1 (0.5%) 0 1 (0.5%) Aminotransferase abnormalities requiring study agent discontinuation a 2 (0.2%) 7 (0.8%) 7 (0.8%) 2 (1.1%) 1 (0.5%) 2 (1.1%) Patients with any event of total bilirubin >ULN 10 (1.2%) 80 (9.4%) 100 (11.8%) 6 (3.2%) 26 (14.0%) 27 (14.4%) a Patients with any of the following criteria: (i) ALT or AST ≥8x ULN; ALT or AST ≥5x ULN for 2 or more weeks; ALT or AST ≥3x ULN and total bilirubin ≥2x ULN (>35% direct bilirubin) or INR >1.5; ALT or AST ≥3x ULN accompanied by clinical symptoms. PBO=placebo; ULN=upper limit of normal; ALT=alanine transaminase; AST=aspartate transaminase

In placebo-controlled analyses, the proportion of patients with aminotransferase abnormalities was higher with sirukumab than placebo (Table 32). Most of the ALT and AST elevations were transient, asymptomatic, < 3 x ULN and returned to normal with sirukumab treatment. A small dose effect was observed in rates of aminotransferase abnormalities. Patients receiving concomitant DMARDs at baseline were more likely to experience aminotransferase abnormalities than patients not receiving concomitant DMARDs. Overall, 7 (0.8%) patients in the sirukumab 50 mg q4w group and 7 (0.8%) in the sirukumab 100 mg q2w groups had abnormalities that required study agent discontinuation per protocol, compared with 2 (0.2%) patients in the placebo group. Rates of aminotransferase abnormalities and discontinuations due to aminotransferase abnormalities were similar in patients treated with sirukumab versus adalimumab in study ARA3005 (Table 32).

Total bilirubin increases were commonly observed with sirukumab treatment, which were generally asymptomatic increases in indirect (unconjugated) bilirubin.

112 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

6.7.5.1. Adjudicated Hepatobiliary Events According to the Draft FDA Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical Evaluation, patients with a 3-fold or greater elevation above the ULN for ALT or AST who also have elevations in serum total bilirubin to > 2x ULN, without initial findings of cholestasis (serum alkaline phosphatase activity of > 2x ULN) and where no other reason can be found to explain the combination of increased aminotransferases and total bilirubin, such as viral hepatitis A, B, or C, pre-existing or acute liver disease, or another drug capable of causing the observed injury, may have an increased risk of liver injury (Hy’s Law).16

All cases of ALT or AST elevation ≥3 x ULN and associated total bilirubin elevation ≥2 x ULN were submitted for adjudication to determine whether any fulfilled the third criterion of Hy’s law. Additionally, (i) all SAEs within hepatobiliary system-organ class (excluding gall bladder disorders without liver involvement); and (ii) all cases of ALT or AST >20 x ULN (toxicity Grade 4) were submitted for adjudication.

Ten cases were adjudicated in a blinded manner for causality by three expert hepatologists: 3 in placebo-treated patients, 1 in the sirukumab 50 mg q4w group, and 6 patients in the sirukumab 100 mg q2w group. Abnormalities in a patient receiving 50 mg q4w were attributed to nonalcoholic steatohepatitis. Among patients receiving 100 mg q2w, two patients had cholelithiasis, two patients had hepatitis E infection, one patient had initiated INH simultaneously for latent TB, and one patient had nonalcoholic fatty liver disease complicated with concomitant MTX and corticosteroid use. Additional details on these cases are found in Appendix 6.

No cases met the third criterion of Hy’s Law (ie, all cases had alternative explanations).

Since IL-6 pathway inhibitors are known to impact neutrophil and platelet counts, these laboratory parameters were monitored during sirukumab clinical studies and guidelines were provided for parameters requiring interruption or discontinuation of sirukumab.

6.7.6. Neutrophil and Platelet Counts Since IL-6 pathway inhibitors are known to impact neutrophil and platelet counts, these laboratory parameters were monitored during sirukumab clinical studies and guidelines were provided for parameters requiring interruption or discontinuation of sirukumab.

6.7.6.1. Patient Selection Patients with an absolute neutrophil count (ANC) below the lower limit of normal (<1950 cells/mm3) at baseline were excluded. Treatment was interrupted if a patient developed an ANC between 500 and 1000 cells/mm3 during a clinical study. Treatment could be restarted when the ANC was greater than 1000 cells/mm3. Sirukumab treatment was permanently discontinued if a patient developed an ANC less than 500 cells/mm3.

Patients with a platelet count below the lower limit of normal (<140,000 cells/mm3) at baseline were excluded. Treatment was interrupted if a patient developed a platelet count between 50,000 113 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document and 100,000 cells/mm3 during a clinical study. Treatment could be restarted when the platelet count was greater than 100,000 cells/mm3. Sirukumab treatment was permanently discontinued if a patient developed a platelet count less than 50,000 cells/mm3.

6.7.6.2. Neutrophil and Platelet Counts in Sirukumab Clinical Studies In placebo-controlled analyses, the proportions of patients with low neutrophil and platelet counts were higher with sirukumab than placebo (Table 33). Most decreases in neutrophils to <1000 cells/mm3 or platelets to <100,000 cells/mm3 were transient, and resolved within the dosing interval such that no change in dose schedule was required. Through Week 52 across the Phase 3 studies, <1% of patients discontinued sirukumab because of decreased neutrophils, or decreased platelets.

Table 33: Number of patients with post-baseline values by maximum toxicity grade for hematology lab parameters through 18 weeks of exposure Randomized Treatment Groups in ARA3002 and ARA3003 Sirukumab Placebo 50 mg q4w 100 mg q2w Patients evaluated, N 842 843 846 Lowest neutrophil count

Lowest platelet count 841 (98.9%) 843 (99.4%) 845 (99.4%)

LLN=lower limit of normal; q2w=every 2 weeks; q4w=every 4 weeks.

6.7.7. Lipids Elevations in lipid levels (total cholesterol, low-density lipoprotein (LDL) cholesterol, high- density lipoprotein (HDL) cholesterol, and fasting triglycerides) have been observed with agents inhibiting the IL-6 pathway including sirukumab. These lipid elevations are considered to reflect resolution of inflammation, as patients with active untreated RA have low lipid levels which may increase or normalize with anti-inflammatory treatment including biologic DMARDs.6.18,29 Overall, lipid elevations with sirukumab were similar to those observed with tocilizumab. Increases in both LDL and HDL were observed with sirukumab compared with placebo from

114 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Week 8 and remained stable thereafter with no dose difference (Figure 35). The majority of patients on sirukumab did not shift ATP III lipid thresholds for LDL and triglycerides (Table 34).

Figure 35: Mean LDL and HDL changes over time with sirukumab

115 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 34: Shift in LDL and triglycerides from baseline to highest post-baseline value through 18 weeks (Studies 3002 and 3003 pooled) Placebo (N=850) Sirukumab 50 mg q4w Sirukumab 100 mg q2w (N=848) (N=850) LDL (mg/dL) <130 to ≥130 15.0% 39.4% 40.9% <160 to ≥160 5.9% 20.9% 27.5% <190 to ≥190 3.5% 9.5% 12.4%

Triglycerides (mg/dL) <150 to ≥150 17.4% 32.2% 32.7%

Atherogenic indices such as total cholesterol:HDL ratio and ApoB:A1 ratio are considered more reliable lipid markers in RA as they are less susceptible to variation in inflammatory burden and disease activity than individual lipid parameters in RA.7 The mean total cholesterol:HDL ratio increased slightly in sirukumab-treated patients from Week 8, with similar results for both sirukumab doses through Week 24, while the ApoB:A1 ratio remained unchanged through Week 24. These results are similar to those observed for tocilizumab.31

In the 7.9% of patients that started statin therapy on sirukumab, lipids including LDL improved to baseline levels with statins (Figure 36).

Figure 36: Baseline, Pre- and Post-Lipid Lowering Agent (LLA) LDL Cholesterol for Patients Starting LLAs Post-Baseline (N=205) Sirukumab Combined (50mg q4w and 100mg q2w)

116 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

For the time period of observation in the clinical trials, the lipid elevations on sirukumab were not associated with an increased risk of MACE, as on-treatment lipid levels were similar in patients with and without MACE on sirukumab (Figure 37).

Figure 37: Change from baseline in total cholesterol in patients with or without MACE on sirukumab 50 mg (red) and 100 mg (blue).

Although lipid elevations on sirukumab were not associated with an increased incidence of MACE, the proposed label contains wording to help clinicians manage lipid elevations on sirukumab. Prescribers are advised to assess lipid parameters approximately 8 weeks after start of sirukumab therapy, then monitor and manage patients according to clinical guidelines (eg, National Cholesterol Educational Program [NCEP]).

6.7.8. Injection-site Reactions During the placebo-controlled period, injection-site reactions (ISR) were reported more frequently in sirukumab-treated than placebo-treated patients (Table 25). The most frequent ISRs were erythema, pruritus, swelling, and rash. Reactions were generally mild to moderate in severity and led to withdrawal of study agent in a small number of patients (<1%) through Week 52. Most ISR occurred during the first 18 weeks of treatment. The incidence of antibodies to sirukumab was low and there was no apparent association between the presence of antibodies

117 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

to sirukumab and ISRs. Rates of ISRs were higher in the sirukumab 100 mg q2w group and higher in patients who were not using DMARDs at baseline.

6.7.9. Hypersensitivity Reactions The narrow hypersensitivity Standardized MedDRA Query (SMQ) was programmatically applied to identify hypersensitivity reactions excluding local injection site reactions. During the placebo-controlled period, hypersensitivity reactions were reported in 29 (3.4%), 38 (4.5%) and 47 (5.5%) patients in the placebo, sirukumab 50 mg q4w and sirukumab 100 mg q2w, respectively (Table 35 and Appendix 7). The most common reactions were rash, eczema, urticaria, and allergic dermatitis, most of which were mild, self-limited and did not require treatment discontinuation and occurred more frequently in the first 6 months. Serious hypersensitivity reactions were uncommon, and most were considered by the investigator as not related to study agent. Serious hypersensitivity reactions considered possibly related to study agent by the investigator included the terms: allergic dermatitis, drug hypersensitivity, bronchospasm, laryngeal edema, and Stevens-Johnson syndrome (details on these cases can be found in Table 25). Of note, the case of bronchospasm was reported in a patient with emphysema who experienced acute bronchitis. Laryngeal edema was reported in a patient who discontinued sirukumab due to oropharyngeal discomfort, and 26 days later, experienced hoarseness and was diagnosed with vocal cord edema. Similar vocal cord edema occurred twice after the patient was treated with etanercept. The event of Stevens Johnsons Syndrome was reported as “SJS of the mouth” and was limited to oral involvement in a patient who previously experienced aphthous ulcers after treatment with tocilizumab. No events of anaphylaxis were reported (per Sampson criteria).44 There was one event of reported serum sickness 3 days after the 2nd dose of sirukumab 100 mg in a patient who developed swollen hands, face and lips and discontinued study drug. The investigator considered the event possibly related to sirukumab. The event was reported as mild, nonserious, and resolved without any treatment. There was no apparent association between the presence of antibodies to sirukumab and hypersensitivity reactions.

Table 35: Hypersensitivity reactions excluding injection site reactions Studies ARA3002, ARA3003, Studies ARA3002 and ARA3003 and ARA3004 Through 18 weeks of exposure Through SCS cutoff Combined Combined PBO 50 mg 100 mg 50 mg 100 mg N=850 N=848 N=850 N=1214 N=1217 Patients with ≥1 event, N (%) Hypersensitivity reactions 29 (3.4%) 38 (4.5%) 47 (5.5%) 129 (10.6%) 143 (11.8%) Moderate or Severe 3 (0.4%) 6 (0.7%) 8 (0.9%) 26 (2.1%) 35 (2.9%) Hypersensitivity reactions Serious Hypersensitivity reactions 0 (0.0%) 0 (0.0%) 2 (0.2%) 4 (0.3%) 9 (0.7%)

118 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

6.8. Safety in Subpopulations The safety profile of sirukumab was similar across subpopulations, irrespective of DMARD use, age, sex, race, ethnicity, weight, study population (DMARD-IR or TNFα-IR). As expected, among elderly patients, the proportions who experienced AEs, SAEs, serious infections, MACE, malignancies, and mortality was increased, but it was increased in both the sirukumab and placebo groups.

6.9. Exposure-Response Analysis for Safety The E-R relationship between systemic exposure to sirukumab and the occurrence of selected safety events in adult patients with RA were evaluated based on data from four Phase 3 studies (ie, data from ARA3001 and ARA3002 through Week 52 and data from ARA3003 and ARA3005 through Week 24). The safety events of interests include serious infection (SINF), and clinical laboratory abnormalities of neutropenia, ALT elevation, LDL cholesterol elevation, total cholesterol elevation, abnormal HDL and triglyceride elevation. In addition, safety events of death, MACE, malignancy through the BLA safety cut-off date were included to assess exposure-response relationship for these rare events. Model-predicted PK metrics derived from the final population PK model using individual post hoc PK parameter estimates and the actual dosing information for each patient, was used to correlate sirukumab exposure with safety events.

Across the four Phase 3 studies, no apparent relationships were identified between sirukumab exposure metrics (ie, cumulative AUC and/or steady-state Cmax, Cmin, and Cave) and the occurrence of serious infection, death, MACE, malignancy, or triglyceride level. Weak correlations between sirukumab exposure and neutropenia, ALT, LDL elevation, total cholesterol elevation, or abnormal HDL were observed. However, the observed small ER trends for neutropenia, ALT elevation and abnormal lipid parameters in RA patients receiving SC sirukumab treatment were consistent with the known modulation effects of anti-IL6 agents as reported for other anti-IL-6 biologics in patients with RA.

6.10. 120-day Safety Update The results presented in the 120-Day Safety Update were consistent with the results presented in the SCS. No new safety issues were noted. Additionally, no new adverse drug reactions (ADR) or meaningful increases in the incidences of previously-reported ADRs were identified (Table 36).

119 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 36: Incidence rate (patient-based per 100 patient years of exposure) of deaths, serious infections, GI perforations, MACE, malignancy, and hepatobiliary abnormalities during the sirukumab- controlled period: comparison of data through the SCS and 120-day safety update cutoff dates Thru SCS Cutoff Thru Safety Update Cutoff 50 mg q4w 100 mg q2w Combined 50 mg q4w 100 mg q2w Combined Sirukumab-controlled 1461 1465 2926 1461 1465 2926 analysis set Death Total subj-yrs of exposure 2193.3 2210.6 4403.9 2638.4 2675.0 5313.4 Incidence per 100 subj-yrs 0.68 0.63 0.66 0.68 0.71 0.70 of exposure (95% CI) (0.38, 1.13) (0.35, 1.06) (0.44, 0.95) (0.40, 1.08) (0.43, 1.11) (0.49, 0.96) Serious infections Total subj-yrs of exposure 2144.7 2160.5 4305.3 2571.2 2605.1 5176.3 Incidence per 100 subj-yrs 4.76 4.67 4.72 4.59 4.84 4.71 of exposure (95% CI) (3.88, 5.77) (3.81, 5.68) (4.09, 5.41) (3.80, 5.50) (4.03, 5.76) (4.14, 5.34) GI perforations Total subj-yrs of exposure 2192.0 2208.2 4400.2 2637.2 2671.9 5309.1 Incidence per 100 subj-yrs 0.32 0.36 0.34 0.30 0.41 0.36 of exposure (95% CI) (0.13, 0.66) (0.16, 0.71) (0.19, 0.56) (0.13, 0.60) (0.21, 0.74) (0.22, 0.56) MACE Total subj-yrs of exposure 2178.5 2209.3 4387.9 2619.7 2673.6 5293.4 Incidence per 100 subj-yrs 1.15 0.41 0.77 1.07 0.37 0.72 of exposure (95% CI) (0.74, 1.69) (0.19, 0.77) (0.54, 1.08) (0.71, 1.54) (0.18, 0.69) (0.51, 0.99) Malignancies Total subj-yrs of exposure 2183.9 2204.0 4387.9 2627.4 2665.9 5293.3 Incidence per 100 subj-yrs 1.05 0.86 0.96 0.91 1.05 0.98 of exposure (95% CI) (0.67, 1.58) (0.52, 1.35) (0.69, 1.29) (0.59, 1.36) (0.70, 1.52) (0.73, 1.29) Hepatobiliary abnormalities Total subj-yrs of exposure 2189.7 2205.9 4395.6 2634.9 2669.6 5304.5 Incidence per 100 subj-yrs 0.37 0.77 0.57 0.34 0.71 0.53 of exposure (95% CI) (0.16, 0.72) (0.45, 1.23) (0.37, 0.84) (0.16, 0.65) (0.43, 1.11) (0.35, 0.76)

6.11. Sirukumab Safety with Indirect Reference to Other Drugs Used for Rheumatoid Arthritis Mortality rates and rates of adverse events of interest were indirectly compared with rates observed in clinical programs and trials of other agents used in treating rheumatoid arthritis. While recognizing the limitations of such comparisons, the populations recruited in the comparator programs had generally similar definitions of moderate to severe rheumatoid arthritis. Rates of serious infections, malignancies, MACE, MI, and stroke, as well as mortality rates, were generally similar in the sirukumab program as reported in comparator RA development programs and trials (Figure 38). Thus, for these events of interest, sirukumab safety appeared to be generally similar that of other agents used in treating rheumatoid arthritis.

120 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 38: Rates of mortality and events of interest in the Sirukumab Phase 3 program with a summary of data from RCTs/ RA development programs

Data includes sirukumab and published incidence rates from RCTs/RA development programs for anti-TNFs (golimumab, certolizumab, adalimumab, etanercept), rituximab, abatacept, tocilizumab, and tofacitinib. Sirukumab point estimates (solid circles) are for the combined sirukumab groups across the 5 Phase 3 studies, and Placebo point estimates are shown as solid squares. Data are through the SCS cutoff. Error bars on sirukumab and placebo Phase 3 rates represent 95% CI. The incidence rate point estimates in comparator compound-treated patients (open circles) and placebo patients (open squares) for RCTs/RA development programs of other approved compounds are presented with the number (n) of point estimates plotted shown below the x-axis.

6.12. Safety Conclusions The safety of sirukumab in the RA population was evaluated in a total of 3428 patients participating in 7 studies, representing 4548 patient-years of follow-up in sirukumab treated patients with a median duration of treatment of 1.33 years.

Important identified risks for sirukumab are serious infections, GI perforation, injection-site and hypersensitivity reactions, and certain laboratory abnormalities:

 Laboratory abnormalities were commonly observed in sirukumab-treated patients, including decreases in neutrophils, leukocytes, and platelets, and increases in aminotransferases, unconjugated bilirubin, and lipids, including cholesterol and triglycerides.  Decreases in neutrophils, leukocytes, and platelets were consistent with the anti- inflammatory effects of blocking IL-6, and most did not require dose interruption or treatment discontinuation.  Increases in aminotransferases and unconjugated bilirubin were, in general, asymptomatic and did not require dose interruption or treatment discontinuation.  Increases in lipids were not associated with substantial changes in atherogenic indices, and responded to treatment with lipid lowering agents. Important potential risks for sirukumab were similar to those observed with other biologics used to treat moderate to severely active RA and include cardiovascular events and malignancy. Major adverse cardiovascular events (MACE) and malignancies were observed in clinical studies of sirukumab, and rates of these events were consistent with expected rates in patients with RA.

 No dose relationship was observed between the sirukumab 50 mg q4w and 100 mg q2w dose regimens and the types or frequencies of AEs, with the exception of injection-site reactions, which occurred more frequently in the sirukumab 100 mg group, and numerically higher rates of hypersensitivity reactions and laboratory abnormalities in the 100 mg group.  The safety profile of sirukumab was similar in patients on baseline DMARDs and those who were not on DMARDs.  Across most subgroups, including sex, race, ethnicity, weight, DMARD-inadequate responders, or anti-TNFα-inadequate responder populations, no consistent differences in the safety of sirukumab were seen. The exception was age, where, as expected, the proportion of elderly patients with AEs, SAEs, serious infections, MACE, malignancies, and mortality was increased in both the sirukumab and placebo treatment groups.  Immunogenicity and incidence of anti-sirukumab antibodies were uncommon with a very low incidence of anti-sirukumab antibodies. During the placebo-controlled periods of the clinical studies, 1 death was reported in each treatment group. With longer-term follow-up in the controlled and uncontrolled portions of clinical studies after escape and group cross-overs were permitted, combined mortality rates were consistent with the rates observed in clinical studies of other drugs developed for RA. The causes of death varied and were consistent with the rates and causes of death seen in an RA population treated with biologics. No dose relationship was observed.

122 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document and rheumatologists are accustomed to monitoring and treating these side effects. The clinical studies of sirukumab demonstrated that these AEs can be managed through careful evaluation by the treating physician, and follow-up guidance that has been included into the proposed product labeling. Additionally, the Sponsor is committed to continued evaluation of the benefits and risks of sirukumab by way of:

 Safety data from the 5-year ARA3004 long-term extension (LTE) of the ARA3002 and ARA3003 studies with an estimated 8500 patient-years of follow-up,  A proposed observational study evaluating the risk of uncommon events such as serious infections (including TB and opportunistic infections), MACE, malignancy, and all-cause mortality, established registries in the US and EU, and  A pregnancy outcomes study using an established US pregnancy registry.

123 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

7. DOSE RECOMMENDATION The recommended dosage of sirukumab for the treatment of patients with RA is 50 mg administered subcutaneously q4w. This dose recommendation was based on the following considerations:

1. Both dose regimens of sirukumab 50 mg q4w and 100 mg q2w were efficacious for the treatment of RA in combination with DMARDs and in monotherapy. 2. In two large placebo-controlled studies, sirukumab 50 mg q4w and 100 mg q2w showed overall comparable efficacy across multiple endpoints and different RA populations. There were numerically better efficacy results in some subpopulations (eg, anti-TNF inadequate responders and patients receiving monotherapy) for clinical endpoints (particularly higher threshold endpoints) with 100 mg q2w dose regimen; still, the incremental benefit with 100 mg q2w versus 50 mg q4w is considered to be small. 3. E-R analyses based on Phase 3 data showed that sirukumab 50 mg q4w resulted in near-maximum efficacy. These E-R analyses also provided confirmatory evidence that dose regimens lower than 50 mg q4w (eg, 25 mg q4w) would not produce robust efficacy for the treatment of RA. 4. The safety profile observed for sirukumab in the RA Phase 3 studies was comparable between the 50 mg q4w and 100 mg q2w dose groups, with no evidence of dose effect in safety events (except for injection-site reactions, which occurred more frequently in the 100 mg q2w group). 5. The higher dose regimen of sirukumab100 mg q2w as monotherapy appeared slightly more effective than 50 mg q4w monotherapy, however, the magnitude of the incremental benefit is not considered sufficient to justify recommending sirukumab 100 mg q2w for monotherapy use. 6. None of the covariates identified in the population PK and efficacy ER modeling analyses, including body weight, diabetic comorbidity, race, baseline disease activity, or concomitant MTX use, warrant dose adjustment. Based on the totality of the data reviewed above across multiple RA populations, both sirukumab 50 mg q4w and 100 mg q2w demonstrated a favorable benefit to risk profile. Given that both dose regimens had overall similar efficacy except for small incremental efficacy gain with 100 mg q2w, and the 4-fold exposure difference between the two dose regimens, sirukumab 50 mg q4w administered subcutaneously q4w is recommended for the treatment of RA.

124 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

8. BENEFIT-RISK ASSESSMENT Rheumatoid arthritis is a common, chronic, life-long, autoimmune disease affecting approximately 1.3 million people in the US. Although it primarily affects joints and is a leading cause of disability when left untreated, RA also has extra-articular manifestations with systemic effects including cardiovascular morbidity, fatigue, and depression. Despite multiple treatment options being available, many patients still fail to achieve control of their disease and sustained disease remission is uncommon. As a result, patients frequently discontinue and/or switch between several agents due to inadequate or loss of response and adverse effects. Thus there still remains a considerable unmet need in this chronic disease that requires lifelong therapy. In addition to the currently approved biologic therapies, new safe, effective and convenient therapies are required to improve the signs and symptoms of the disease, slow down joint structural damage, and address the systemic manifestations of RA to improve the overall quality of life for patients.

Sirukumab shows consistent and clinically meaningful improvement of signs and symptoms, physical function, inhibition of progressive joint damage. Perhaps of greater importance to the patient is the statistically significant positive impact of sirukumab treatment on all domains of patient-reported health-related quality of life across a full spectrum of moderately to severely active RA including significant improvement in fatigue. The once every 4 weeks dosing regimen that can be self-administered by the patient or a family member at home or a healthcare provider in the clinical setting offers further flexibility to the patient. Risks were generally consistent with those seen in other biological DMARDs in randomized clinical studies and now commonly recognized by the rheumatology community, are generally not treatment limiting, and are consistent with the known safety profile of other IL-6 pathway inhibitors or other classes of biologic DMARDs.

As delineated below, these data collectively indicate that sirukumab has a positive benefit-risk that addresses an existing unmet medical need in the treatment paradigm of RA.

8.1. Overall Assessment To facilitate the benefit-risk assessment, a structured approach was applied to the analysis of the Phase 3 sirukumab program to present efficacy and safety data side by side. The results are presented in a Forest plot (Figure 39). The focus is on the proposed dose of 50 mg q4w.

The benefits of sirukumab treatment were defined as primary and important secondary categorical endpoints assessing signs and symptoms, physical function, joint damage, and health related reported quality of life. Efficacy data are presented as a proportion per 100 persons (%) for sirukumab 50 mg q4w in studies ARA3002 and ARA3003, individually or integrated, for:

 Signs and symptoms: Improvement from baseline as measured ACR 20 at Week 16, ACR 50 at Week 24, DAS28 remission at Week 24, and major clinical response (MCR, Week 52)

125 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

 Physical function: The proportion of patients with clinically relevant improvements in functional ability (a change of <-0.22 in HAQ-DI at Week 24)  Reduction of joint damage: The proportion of patients with no progression in structural damage (a change of ≤0 from baseline in vdH-S score at Week 52)  Quality of life: The proportion of patients with clinically relevant improvements in SF-36 (increase from baseline of ≥5 in PCS and MCS at Week 24) and FACIT-fatigue (increase from baseline of ≥4 at Week 24) The Sponsor depicted identified risks and potential risks as adverse events of interest that had the potential to be severe or fatal, and included MACE, malignancy, serious infection, and GI perforation. To date, other risks listed in Section 2 (eg, hepatobiliary abnormalities, elevated lipids, abnormal hematologic laboratory values) have only rarely resulted in significant clinical sequelae, and due to the rarity of these events, they are not depicted in Figure 39. Integrated safety data are presented for sirukumab 50 mg q4w as incidence rates per 100 patient-years (PY) through 18 weeks and 52 weeks of exposure in pooled studies ARA3002 and ARA3003. Figure 39 includes patients initially randomized to sirukumab 50 mg q4w but does not include patients who early escaped/late escaped/crossed over from placebo to sirukumab 50 mg q4w.

Figure 39: Risk Differences for Key Benefits and Key AEI: Studies ARA3002 and ARA3003

NOTE: Pooled efficacy and safety data are from Phase 3 Studies ARA3002 and ARA3003 50 mg q4w.

126 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

For efficacy, across all endpoints, sirukumab 50 mg q4w showed a clear improvement compared with placebo (positive proportion differences all favor sirukumab; Figure 39). For example, when treating 100 patients who were inadequate responders to conventional nonbiologic DMARDs and/or anti-TNFα, relative to placebo, 24.0 more patients would show ACR 20 improvement at Week 16 and at Week 24, and 15.8 more patients would show ACR 50 improvement (Figure 39). Additionally, clinically meaningful improvements in health-related quality of life, including SF-36 physical and mental scores and FACIT-Fatigue, were observed for sirukumab versus placebo in both ARA3002 and ARA3003. For FACIT-Fatigue, 17.5 and 15.2 more patients showed a clinically relevant improvement at Week 24 (studies ARA3002 and ARA3003, respectively). Results for the primary endpoints were consistent across the subgroups examined including DMARD-IR and anti-TNFα IR patients, patients who received sirukumab monotherapy, patients’ ≥65 years of age, and patients with high body weight or diabetes comorbidity.

The safety of sirukumab is established on the basis of 7 studies in the RA clinical development program that included 3,120 sirukumab-treated patients with a median duration of treatment of 1.38 yrs. With respect to risks, rates of MACE, malignancy, and GI perforation events per 100 PY for sirukumab are generally low at Week 18 and Week 52, with 95% CIs vs. placebo that overlap 0. As expected for this mechanism of action, rates of serious infection are numerically higher in sirukumab-treated patients relative to placebo. In the 18-week, true placebo-controlled period, mortality rates were identical in the placebo- and sirukumab-treated patients. In the Week 52 analyses, (ie, patients who remained in their originally assigned randomized treatment group through Week 52), there was a numerical imbalance in exposure-adjusted mortality rates between sirukumab and placebo randomized treatment groups. However, the number of deaths was low. The limited placebo-exposure relative to sirukumab exposure makes interpretation of mortality difficult.

Taken together, the observed safety profile reflected events expected in IL-6 pathway inhibitor class. Additional risks identified, but not depicted in Figure 39 included serious hypersensitivity reactions, hepatic enzyme elevations, thrombocytopenia, and neutropenia. These risks are consistent with the known safety profile of IL-6 pathway inhibition and are routinely managed by rheumatologists who use other biologic DMARDs. Suggested language included in the proposed labeling text provides guidance on the mitigation and management of these risks. Subgroup analyses show that there were no consistent differences in the safety profile of sirukumab, with the exception of increasing age (more patients with SAEs, serious infections, or malignancies in older patients), consistent with the increased risk of these events with increased with age. The rates of these events by age were comparable to those in both the general and RA population. The incidence of antibody development to sirukumab was low through Week 52 with no apparent association with loss of response or safety events.

8.2. Postmarketing Safety Surveillance Plan The pharmacovigilance activities for sirukumab include AE collection and regulatory reporting, aggregate data review for periodic safety reporting, signal detection, and surveillance. The

127 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Sponsor will systematically review, on a regular basis, the ongoing clinical studies and postmarketing safety data from multiple sources to detect and evaluate any changes in the safety profile of sirukumab or potential safety signals. Based on these safety evaluations, the Sponsor will determine the appropriate safety-related actions to be taken with respect to the product based on its benefit risk profile for patients in the ongoing clinical studies and for patients treated with the product in a postmarketing setting.

The Sponsor is proposing to monitor and evaluate risks of interest among patients exposed to sirukumab and comparator treatments (including conventional nonbiologic and/or biologic DMARDs) in existing biologics registries in the EU and the US, such as RABBIT (“Rheumatoid Arthritis Observation of Biologic Therapy”, based in Germany), ARTIS (“Anti-Rheumatic Treatment in Sweden”), and a large US-based registry. In addition to these registries, the Sponsor proposes to evaluate safety outcomes of interest related to sirukumab using real-world data from electronic health records (EHR) and health insurance claims databases.

The postmarketing safety surveillance plan includes a framework for a prospective meta- analysis: primary and secondary analyses are conducted within each data source mentioned above separately, and if feasible and scientifically appropriate, results will be pooled. Safety outcomes of interest to be evaluated in patients exposed to sirukumab versus other biologics include serious infection, malignancy, and MACE. All-cause mortality will also be evaluated. The proposed meta-analysis aims to aggregate effect estimates not only from individual studies conducted as part of post-marketing surveillance efforts, but also from other independently published studies on the topic.

Pregnancy outcomes will be assessed via a sirukumab pregnancy exposures study using data from an existing pregnancy and drug registry, based in the United States and Canada. This registry is evaluating the safety of medications used to treat autoimmune diseases, including RA, when used during pregnancy. The data collected include information on the health status of pregnant women exposed to the medication, as well as birth outcome data on their infants through one year of age.

8.3. Benefit-risk Conclusions In conclusion, the data demonstrate a favorable benefit to risk profile for sirukumab in combination with DMARDs or as monotherapy. Sirukumab 50 mg administered subcutaneously q4w leads to clinical responses within 12 weeks of treatment and maintained through 1 year, robust inhibition of radiographic progression, improvement in physical and mental function, and improvements in additional patient-reported outcome measures such as fatigue. Benefits were demonstrated across a number of populations representing the full spectrum of moderately to severely active adult RA who should receive a biologic DMARD, from MTX-inadequate response patients to patients who have failed 2 or more conventional nonbiologic DMARDs to those who have failed multiple biologics. Risks of sirukumab treatment are generally consistent with the known safety profile of an IL-6 pathway inhibitor.

128 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

9. CONCLUSIONS In conclusion, the efficacy and safety data presented here support the use of sirukumab 50 mg given as an SC injection every 4 weeks for the treatment of adult patients with moderately to severely active RA.

The sirukumab clinical program was designed to study the broad range of patients encountered in current clinical practice in whom the drug would most likely be used, including patients who had previously been treated with multiple prior biologic agents.

Sirukumab at doses of 50 mg q4w and 100 mg q2w was highly efficacious in reducing the symptoms, delaying the progression of structural damage, and improving patient reported outcomes, including in patients for whom other therapies failed or were otherwise inappropriate. These benefits of sirukumab are achieved with a safety profile that is similar to other biologics currently used in the management of RA. Appropriate warnings and precautions for use and advice on the management of patients treated with sirukumab have been included in the proposed labelling. Long-term monitoring and evaluation of adverse events of interest will continue to be performed as described.

Since both doses were efficacious in this broad range of patients, the four-fold lower dose was considered optimal to minimize exposure and the potential for AEs. The recommended dosage for adult patients with RA is 50 mg q4w, given as a SC injection. Sirukumab will be available in 2 different presentations, either a PFS or an AI. Sirukumab represents an important addition to the treatment options for patients with RA and can make a meaningful difference in their lives by not only improving the signs and symptoms of RA but also the systemic manifestations of RA that are important to patients such as physical and mental function and fatigue.

129 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

REFERENCES 1. Aletaha D, Smolen J. The simplified disease activity index (SDAI) and the clinical disease activity index (CDAI): A review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol. 2005; 23(Suppl 39):S100-S108. 2. Ali NS, Hashem AHH, Hassan AM, Saleh AA, El-Baz HN. Serum interleukin-6 is related to lower cognitive functioning in elderly patients with major depression. Aging Ment Health. 2017;24:1-7. 3. Avina-Zubeita JA et al. Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta- analysis of observational studies. Ann Rheum Dis. 2012;71(9):1524-9. 4. Baillet, A., Gossec, L., Paternotte, S., & et al. (2015). Evaluation of serum interleukin-6 level as a surrogate marker of synovial inflammation and as a factor of structural progression in early rheumatoid arthritis: results from a French national multicenter cohort. Arthritis Care Res, 65(7), 905-912. 5. Brennan, F. M., & McInnes, I. B. (2008). Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest, 118(11), 3537–3545. 6. Brooks, P. M. (2006). The burden of musculoskeletal disease – a global perspective. Clin Rheumatol, 25(6), 778-781. 7. Calin D. Popa, Elke Arts, Jaap Fransen, and Piet L. C.M. van Riel. Atherogenic Index and High-Density Lipoprotein Cholesterol as Cardiovascular Risk Determinants in Rheumatoid Arthritis: The Impact of Therapy with Biologicals. Mediators Inflamm. 2012;2012:785946. Epub 2012 Sep 6. 8. CDER. Clinical review: Tocilizumab (TCZ) subcutaneous (SC) in a pre-filled syringe (PFS). Available at: http://www.accessdata fda.gov/drugsatfda_docs/nda/2013/125472Orig1s000MedR.pdf, accessed 24 July 2016. 9. CDER. Medical review: Tocilizumab (Clinical review of complete response). Available: http://www.accessdata fda.gov/drugsatfda_docs/nda/2010/125276s000MedR.pdf, accessed 24 July 2016. 10. CDER. Medical review: Tofacitinib (Clinical review; Addendum to primary clinical review). Available at: http://www.accessdata fda.gov/drugsatfda_docs/nda/2012/203214Orig1s000MedR.pdf, accessed 24 July 2016. 11. Choy E, Ganeshalingam K, Semb AG, et al. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology. 2014;53 (12): 2143-2154. 12. Clough JD. The Cleveland Clinic Guide to Arthritis. New York, NY: Kaplan Publishing; 2009. 13. Cohen, S. B., Moreland, L. W., Cush, J. J., & et al. (2004). A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis, 63(9), 1062-1068. 14. Curtis, J. R., Xie, F., Chen, L., & et al. (2011). The incidence of gastrointestinal perforations among rheumatoid arthritis patients. Arthritis Rheum, 63(2), 346-351. 15. Dougados M, Soubrier M, Antunez A, Balint P, Balsa A, Buch MH, Casado G, Detert J, El-Zorkany B, Emery P, Hajjaj-Hassouni N, Harigai M, Luo SF, Kurucz R, Maciel G, Mola EM, Montecucco CM, McInnes I, Radner H, Smolen JS, Song YW, Vonkeman HE, Winthrop K, Kay J. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis. 2014;73(1):62-68. 16. Draft FDA Guidance for Industry on Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 17. Engler H, Brendt P, Wischermann J, Wegner A, Röhling R, Schoemberg T, Meyer U, Gold R, Peters J, Benson S, Schedlowski M. Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms. Mol Psychiatry. 2017 Jan 31. doi: 10.1038/mp.2016.264. 18. Fiest KM, Hitchon CA, Bernstein CN,et al. Systematic Review and Meta-analysis of Interventions for Depression and Anxiety in Persons With Rheumatoid Arthritis. J Clin Rheumatol. 2017 Feb 17. 19. Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis. Am J Manag Care 2012;18:S295-302.

130 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

20. Gottenberg, J-E, Brocq, O, Perdriger, A et al. Non-TNF-Targeted Biologic vs a Second Anti-TNF Drug to Treat Rheumatoid Arthritis in Patients With Insufficient Response to a First Anti-TNF Drug A Randomized Clinical Trial. JAMA. 2016;316(11):1172-1180. 21. Gout, T., Ostor, A. J., & Nisar, M. K. (2011). Lower gastrointestinal perforation in rheumatoid arthritis patients treated with conventional DMARDs or tocilizumab: a systematic literature review. Clinical Rheumatol, 30, 1471- 1474. 22. Hashizume, M., & Mihara, M. (2011). The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis, 2011:765624. 23. Jansen LM, van der Horst-Bruinsma IE, van Schaardenburg D, Bezemer PD, Dijkmans BA. Predictors of radiographic joint damage in patients with early rheumatoid arthritis. Ann Rheum Dis. 2001 Oct;60(10):924-7. 24. Karlsson JA, Kristensen LE, Kapetanovic MC, Gülfe A, Saxne T, Geborek P. Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register. Rheumatology (Oxford). 2008;47(4):507-513. 25. Karpouzas GA, Dolatabadi S, Moran R, Li N, Nicassio PM, Weisman MH. Correlates and predictors of disability in vulnerable US Hispanics with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012 Sep;64(9):1274-1281. 26. Karpouzas GA, Draper T, Moran R, Hernandez E, Nicassio P, Weisman MH, Ormseth S. Trends in Functional Disability and Determinants of Clinically Meaningful Change Over Time in Hispanic Patients With Rheumatoid Arthritis in the US. Arthritis Care Res (Hoboken). 2017;69(2):294-298. 27. Köhler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, Stubbs B, Solmi M, Veronese N, Herrmann N, Raison CL, Miller BJ, Lanctôt KL, Carvalho AF. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017 May;135(5):373-387. 28. Koike T, Harigai M, Inokuma S. Postmarketing surveillance of tocilizumab for rheumatoid arthritis in Japan: interim analysis of 3881 patients. Ann Rheum Dis. 2011; 70(12): 2148–2151. 29. Lavebratt C, Herring MP, Liu JJ, Wei YB, Bossoli D, Hallgren M, Forsell Y. Interleukin-6 and depressive symptom severity in response to physical exercise.Psychiatry Res. 2017;252:270-276. 30. Matcham F, Rayner L, Steer S, Hotopf M. The prevalence of depression in rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology (Oxford). 2013 Dec;52(12):2136-2148. 31. McInnes IB, et al. Ann Rheum Dis 2015;74:694–702. 32. Mikuls TR, Saag KG, Criswell LA, et al. Mortality risk associated with rheumatoid arthritis in a prospective cohort of older women: results from the Iowa Women’s Health Study. Ann Rheum Dis. 2002; 61:994–999. 33. Moreland, L. W., & Curtis, J. R. (2009). Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms. Semin Arthritis Rheum, 39(2), 132–143. 34. Mullberg J, Schooltink H, Stoyan T, et al. The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol. 1993;23(2):473-480. 35. Nadkarni A, You M, Resuehr H, Curtis JR. The Risk for Cardiovascular Events Associated with Hyperlipdemia among Patients with and Without Rheumatoid Arthritis. J Arthritis 2015 Dec;4(4). pii: 178. 36. Ogdie, A., Haynes, K., Troxel, A. B., Love, T. J., & et al. (2014). Risk of mortality in patients with psoriatic arthritis, rheumatoid arthritis and psoriasis: a longitudinal cohort study. Ann Rheum Dis, 73(1), 149-153. 37. Papadopoulos NG, Alamanos Y, Papadopoulos IA, Tsifetaki N, Voulgari PV, Drosos AA. Disease modifying antirheumatic drugs in early rheumatoid arthritis: a longterm observational study. J Rheumatol. 2002 Feb;29(2):261-266. 38. Patompong, Ungprasert. Update in cardiovascular disease in patients with rheumatic diseases. Journal of Nature and Science. 2015;1(3):e59. 39. Radovits BJ, Fransen J, Al Shamma S, Eijsbouts AM, van Riel PL, Laan RF. Excess mortality emerges after 10 years in an inception cohort of early rheumatoid arthritis. Arthritis Care Res (Hoboken). 2010; 62(3):362-370.

131 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

40. Rendas-Baum R, Wallenstein GV, Koncz T, et. al. Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors. Arthritis Res Ther. 2011,13(1):1-15. 41. Richter A, Listing J, Schneider M, et al. Impact of treatment with biologic DMARDs on the risk of sepsis or mortality after serious infection in patients with rheumatoid arthritis. Ann Rheum Dis. Published online first: 13 Nov 2015; doi:10.1136/ annrheumdis-2015-2078382015. 42. Ridker PM. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving Upstream To Identify Novel Targets for Atheroprotection.Circ Res. 2016 Jan 8;118(1):145-56. 43. Rubbert-Roth A, Sebba A, Brockwell L, et al. Malignancy rates in patients with rheumatoid arthritis treated with tocilizumab. RMD Open 2016;2:e000213. doi:10.1136/rmdopen-2015-000213. 44. Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117(2):391-397. 45. Scheller, J., Chalaris, A., Schmidt-Arras, D., & Rose-John, S. (2011). The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta, 1813(5), 878–888. 46. Schiff, M. H., Kremer, J. M., Jahreis, A., Vernon, E., Isaacs, J. D., & van Vollenhoven, R. F. (2011). Integrated safety in tocilizumab clinical trials. Arthritis Res Ther, 13(5), R141. 47. Simon TA, Thompson A, Gandhi KK, et al. Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Research & Therapy. 2015; 17:212. 48. Simon TA, Thompson A, Gandhi KK, Hochberg MC, Suissa S. Erratum to: Incidence of malignancy in adult patients with rheumatoid arthritis: a meta-analysis. Arthritis Res Ther. 2016 May 4;18(1):100. 49. Singh, J. A., Saag, K. G., Bridges, S. L., Aki, E. A., Bannuru, R. R., Sullivan, M. C., et al. (2016). 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care and Research, 68(1), 1-25. 50. Smitten AL, Simon TA, Hochberg MC, et al. A meta-analysis of the incidence of malignancy in adult patients with rheumatoid arthritis. Arthritis Res Ther 2008;10:R45. 51. Smolen JS , Aletaha D , Bijlsma JW , Breedveld FC , Boumpas D, Burmester G , et al . Treating rheumatoid arthritis to target: recommendations of an international task force . Ann Rheum Dis. 2010; 69(4):631-637 . 52. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. Oct 2016 ;388(10055):2023-2038. 53. Sparks JA, Chang SC, Liao KP, et al. Rheumatoid arthritis and mortality among women during 36 years of prospective follow-up: results from the Nurses' Health Study. Arthritis Care Res. 2016; 68 (6):753–762. 54. Sparks, J. A., Chang, S. C., Liao, K. P., & et al. (2016). Rheumatoid arthritis and mortality among women during 36 years of prospective follow-up: results from the Nurses' Health Study. Arthritis Care Res, 68(6), 753–762. 55. Strangfeld, A., Richter, A., Siegmund, B., & et al. (2016). Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis, 1-7. 56. Svensson B, Andersson ML, Bala SV, Forslind K, Hafström I; BARFOT study group. Long-term sustained remission in a cohort study of patients with rheumatoid arthritis: choice of remission criteria. BMJ Open. 2013 Sep 10;3(9):e003554. 57. Tanaka, T., & Kishimoto, T. (2014). The biology and medical implications of interleukin-6. Cancer Immunol Res, 2(4), 288–294. 58. Tanaka, Y., & Martin Mola, E. (2014). IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab. Ann Rheum Dis, 73(9), 1595-1597. 59. Taylor PC, Moore A, Vasilescu R, Alvir J, Tarallo M. A structured literature review of the burden of illness and unmet needs in patients with rheumatoid arthritis: a current perspective. Rheumatol Int. May 2016;36(5):685-95.

132 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

60. U.S. Food and Drug Administration; Guidance for Industry; Rheumatoid Arthritis: Developing Drug Products for Treatment, May 2013; https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm354468.pdf (accessed 20May2017). 61. van Gestel A., Haagsma C., van Riel P. Validation of rheumatoid arthritis improvement criteria that include simplified joint counts. Arthritis and Rheumatism. 1998;41(10):1845–1850. 62. Ware, JE Jr. SF-36 Health Survey Update. Spine. 2000;25(24):3130–3139. 63. Watson DJ, Rhodes T, Guess HA. All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol 2003 Jun;30(6):1196-202. 64. Withers M, Moran R, Nicassio P, Weisman MH, Karpouzas GA. Perspectives of vulnerable U.S Hispanics with rheumatoid arthritis on depression: awareness, barriers to disclosure, and treatment options. Arthritis Care Res (Hoboken). 2015 Apr;67(4):484-492. 65. Wolfe F, Michaud K, Arthritis & Rheumatism, Vol. 56, No. 9, September 2007, pp 2886–2895. 66. Zhang, Y, Lu, N, Peloquin, C, et al. (2016). Improved survival in rheumatoid arthritis: a general population- based cohort study. Ann Rheum Dis, 1-6.

133 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

APPENDICES Appendix 1: PFS-U and PFS-AI...... 135 Appendix 2:Proportion of Patients who Achieved DAS28 (CRP) Good Responses or DAS28 (CRP) ≤2.6 by Visit (Study C1377T04 Part B)...... 140 Appendix 3: Proportion of Patients Who Achieved DAS28 (CRP) ≤2.6 at Week 24 by Trough Serum Sirukumab Concentration Quartiles (Study C1377T04 Part B) ...... 141 Appendix 4: Proportion of Patients Who Achieved ACR 20 or ACR 50 Responses at Week 24 by Trough Serum Concentration Quartiles (Studies ARA3002 and ARA3003) ...... 142 Appendix 5: Proportion of Patients Who Achieved DAS28 (CRP) ≤2.6 at Week 24 by Trough Serum Concentration Quartiles (Studies ARA3002 and ARA3003)...... 143 Appendix 6: Adjudicated Hepatobiliary Events ...... 144 Appendix 7: Serious Hypersensitivity Reactions (Excl. Injection Site Reactions) in Studies ARA3002 and ARA3003 Considered Possibly Related by Investigator (through SCS cutoff) ...... 148 Appendix 8: Efficacy Endpoints ...... 150 Appendix 9: Summary of Statistical Methods for 3002/3003/3005...... 152 Appendix 10: Analysis of the number of Patients who Achieved ACR 20, ACR 50 and DAS28 Responses by Age; Study ARA3003 ...... 165 Appendix 11: Week 18 Measures of Inflammation in Patients Randomized to Placebo in ARA3002 and ARA3003 ...... 169 Appendix 12: Additional Modeling Results for Death...... 171 Appendix 13: Definition of Subgroups in Studies ARA3002 and ARA3003...... 174

134 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 1: PFS-U and PFS-AI

PFS-U The PFS-U features the UltraSafe Passive® Needle Guard X100L (NG, Figure 1), a commercially available platform product marketed by Becton-Dickinson Medical– Pharmaceutical Systems. The NG is cleared in the US under the 510(k) numbers K011369, K060743. The NG has been supplied to biopharmaceutical manufacturers as an accessory to PFS since 2001 (used with more than 10 drugs) and is considered the industry standard. Janssen currently markets the NG globally (including US) with EPREX®, STELARA®, and SIMPONI®. Janssen has manufactured and distributed over 100 million doses using the NG in global markets. Both available strengths of PLIVENSIA™ are clearly distinguishable from other rheumatoid arthritis drugs by the color of the plunger in addition to appropriate device and carton labeling.

Figure 1: PLIVENSIA™ PFS-U

135 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

The NG activates automatically, preventing unintentional needle-stick injuries to the user, healthcare professionals, and persons assisting the patient with injections. Human factors and usability studies supported the development of appropriate Instructions for Use (IFU) for the combination product. The IFU is picture-based and designed to facilitate readability and ease of use. The IFU provides an intuitive organization of the injection steps based on whether they occur before, during or after injection to provide a clear and easy to understand sequence of steps. Critical information is written in bold red text, providing further emphasis.

The assembly and labeling process for the PFS has been validated to ensure that the final product is safe, effective, and performs as intended. Design validation activities also included usability testing to support that the NG can be correctly, safely and effectively used by the intended user audience to deliver a subcutaneous injection. Usability of the PFS-U was successfully validated during extensive and robust usability testing including 2 summative human factors studies. Both studies were conducted by human factors experts in accordance with FDA and other international standards organizations’ HFS guidances with observed simulated injections into injection pads placed on recommended subcutaneous injection sites. Between the 2 studies, 75 patients were evaluated, including trained, untrained, and inexperienced patients. Across all participants, 100% successfully prepared and injected the full dose. There were no observed patterns of failures, difficulties or use errors. The IFU was well received, highly rated, and facilitated successful learning of the PFS-U and injection procedure by first-time users.

PFS-AI The PFS-AI presentation is a disposable, fixed-dose, single-dose combination product consisting of a needle-based injection system, and a PLIVENSIA™ PFS constituent portion (Figure 2).

Janssen currently markets the PFS-AI platform globally (including US) with SIMPONI®. With PLIVENSIA™, Janssen would be the only company offering two RA drugs in the same autoinjector. This creates a potential patient benefit as users can switch between Janssen RA drugs without additional autoinjector training. For former Simponi patients who are still switching between other RA drugs to maximize effectiveness, they can now switch back to an anti-IL-6 therapy with a device they are already familiar with. The PFS-AI also hides the needle at all times to reduce anxiety associated with receiving a needle-based injection. The PFS-AI was specifically designed for RA patients and has been optimized over an 8-year history of proven safe and effective clinical use. A second generation SmartJect was introduced in 2013 specifically to enhance usability for Simponi and is now benefitting PLIVENSIA™ patients as well. With these improvements, along with improvements to the IFU, SmartJect complaints and reported use errors have decreased by >75% over its 8 years of patient use to become a “best-in- class” autoinjector.

136 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Well over 5 million units have been manufactured and distributed. The PFS-AI presentation consists of the PFS assembled into the AI forming a single unit that is not to be separated. Both available strengths of PLIVENSIA™ are clearly distinguishable from each other by device and carton labeling and from other RA drugs by the color of the cap and button in addition to appropriate device and carton labeling. Based on SIMPONI distribution data, autoinjectors are the preferred presentation for RA patients as opposed to prefilled syringes with needle guards.

Figure 2: PLIVENSIA™ PFS-AI

Development was performed in accordance with requirements of CFR 21 Part 820.30 design controls, risk management (ISO 14971), and biocompatibility (ISO 10993-1). In addition, the PFS-AI fulfills requirements related to needle-based injection systems (ISO 11608-1, ISO 11608-5) ensuring dose accuracy. Safety and effectiveness were demonstrated during design verification and validation.

137 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

The PFS-AI has an ergonomic design that facilitates use and handling by users with impaired dexterity. Early focus group and voice of the customer reviews resulted in a form factor with an oversized grip and push button to best accommodate RA patients who may have hand impairment. The design of the PFS-AI ensures a minimum of handling steps to simplify PLIVENSIA™ administration. A large clear area allows inspection of the drug product integrity prior to injection. To perform an injection, the user removes the cap and presses the PFS-AI against the injection site, which triggers needle penetration and injection. Audible and visual feedback informs the user about the injection progress. The needle retracts back into the PFS-AI to protect from unintentional needle-stick injuries. Human factors and usability studies supported the development of appropriate IFU for the combination product. The IFU is picture-based and designed to facilitate readability and ease of use. The IFU provides an intuitive organization of the injection steps based on whether they occur before, during or after injection to provide a clear and easy to understand sequence of steps. Critical information is written in bold red text, providing further emphasis.

The PFS-AI assembly and labeling process has been validated to ensure that the final product is safe, effective, and performs as intended. Design validation activities, including both non- interventional and interventional studies, were also conducted. As summarized below, usability of the autoinjector was successfully validated during extensive and robust usability testing including 2 summative human factors studies, as well as a separate clinical usability study in PLIVENSIA™ clinical studies. A summary of the successful bioavailability and PK comparison studies is provided in Section 4.

Human factors studies Both studies were conducted by human factors experts in accordance with FDA and other international standards organizations’ HFS guidances with observed simulated injections into injection pads placed on recommended subcutaneous injection sites. Between the 2 studies, 76 patients were evaluated, including trained, untrained, and inexperienced patients. Across all participants, 100% successfully prepared and injected the full dose. There were no observed patterns of failures, difficulties or use errors. The IFU was well received, highly rated, and facilitated successful learning of the PFS-AI and injection procedure by first-time users.

Clinical usability study A clinical usability study was conducted to evaluate the real-life handling and use experience of the PFS-AI in patients with RA over their first 16 weeks of dosing in the long-term extension study (CNTO136ARA3004). This study enrolled 110 English-speaking patients from the United States. All patients received training on the use of the PFS-AI via a demonstration with a trainer device, as well as a review of the Instructions for Use (IFU). At Weeks 2 and 4 (first and second doses), patients injected themselves using the PFS-AI and were assessed by site personnel for successful completion of essential tasks in the injection process. Patients able to self-dose were then allowed to continue q2w self-injections at home from weeks 6-14, and use-related data were collected via an e-diary (phone or computer) regarding success or failure of their injections. Patients were also interviewed at the end of the study regarding success or difficulties with their injections. A descriptive statistical approach was used for these analyses, without formal 138 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document hypothesis testing. Success of the study was based on observations of success or failure of self- injection at the week 2 and 4 visits. A high proportion of patients (99%) were able to successfully self-inject at Week 4 (second self-injection). This study, in addition to the Human Factors studies, demonstrated that the PFS-AI as designed, together with appropriate training and the written IFU, is well-suited for self-administration of sirukumab in patients with RA. No new patient risks relating to autoinjector use were identified. The study also indicated high patient confidence which is among the highest patient-reported needs for self-administration devices.

139 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 2:Proportion of Patients who Achieved DAS28 (CRP) Good Responses or DAS28 (CRP) ≤2.6 by Visit (Study C1377T04 Part B)

140 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 3: Proportion of Patients Who Achieved DAS28 (CRP) ≤2.6 at Week 24 by Trough Serum Sirukumab Concentration Quartiles (Study C1377T04 Part B)

This figure only includes patients treated with Sirukumab 25 mg q4w, 50 mg q4w, 100 mg q4w or 100 mg q2w from Week 0. DAS remission was based on the observed data. Patients with missing Sirukumab concentration or missing DAS28 status were excluded.

141 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 4: Proportion of Patients Who Achieved ACR 20 or ACR 50 Responses at Week 24 by Trough Serum Concentration Quartiles (Studies ARA3002 and ARA3003) ARA3002

ARA3003

142 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 5: Proportion of Patients Who Achieved DAS28 (CRP) ≤2.6 at Week 24 by Trough Serum Concentration Quartiles (Studies ARA3002 and ARA3003) ARA3002

ARA3003

143 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 6: Adjudicated Hepatobiliary Events

Hepatologist Adjudication Aminotransferase Hepatobiliary Consensus – (IU/L) / T Bili (mg/dL) Case Study Dose Event Day of Event Alternate Causes Levels Sequelae Details HB#1 ARA3002 Placebo SAE – Hepatic 154 Unlikely – Hepatic 16 / 0.3 Resolved/None 55 year old woman in whom fatty Cyst cyst liver and a liver cyst were incidentally noted while being evaluated for rib trauma. HB#2 ARA3002 Placebo ALT/AST 61 Possibly – INH + 711 / 0.4 Resolved/None 33 year old woman who >20xULN Diclofenac experienced ALT > 20x ULN with mild increase in fatigue. She was also receiving concomitant isoniazid for latent TB and Diclofenac. HB#3 ARA3002 Placebo ALT/AST 89 Probably – 427 / 0.4 Resolved/None 29 year old man receiving MTX >20xULN Methotrexate and prednisone who developed ALT > 20x ULN after three months of treatment with study drug HB#4 ARA3002 50 mg SAE – 141 Unlikely – NASH 175 / 0.6 ALT and AST levels 63 year old man prednisone with Nonalcoholic continued to waxing and waning serum steatohepatitis fluctuate after elevations of ALT > AST. withdrawal of study Hepatic steatosis was noted on agent ultrasound. The patient had risk factors for NASH, and a liver biopsy showed NASH. Other causes of liver diseases were largely ruled out. Event was considered to likely be background NASH. HB#5 ARA3002 100 mg ALT/AST >3xULN 451 Unlikely – 312 / 3.1 Resolved/None 27 year old woman on study drug & Bilirubin Cholelithiasis for more than one year with a >2xULN three episodes of elevated ALT/AST, with the last including increased serum bilirubin, vomiting and “abdominal”(presumably pain). Evaluation revealed cholelithiasis, and she underwent cholecystectomy.

144 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 6: Adjudicated Hepatobiliary Events

Hepatologist Adjudication Aminotransferase Hepatobiliary Consensus – (IU/L) / T Bili (mg/dL) Case Study Dose Event Day of Event Alternate Causes Levels Sequelae Details HB#6 ARA3002 Pbo  100 ALT/AST >3xULN 379 (Day 20 Unlikely – 345 / 3.0 Resolved/None 65 year old man experienced mg & Bilirubin Sirukumab) Cholelithiasis abdominal pain, elevations in >2xULN ALT, AST, and bilirubin. Abdominal ultrasound revealed a multitude of small calculi and normal bile ducts. He was diagnosed with abdominal acute calculous cholecystitis in remission, reactive hepatitis. Symptoms and abnormal liver chemistries were considered consistent with passing a gall stone. HB#7 ARA3004 100 mg SAE and ALT/AST 365 Unlikely – Acute 3549 / 0.6 Resolved/None 54 year old woman with marked >20xULN Hepatits E elevation in serum ALT and documented acute Hepatitis E infection, with resolution over the next month. HB#8 ARA3002 100 mg ALT/AST >3xULN 15 Possibly – Isoniazid 169 / 3.1 Resolved/None 51 year old obese woman & Bilirubin hepatotoxicity receiving MTX and steroids for >2xULN RA and isoniazid for latent TB experienced elevated ALT and serum Bilirubin approximately 2 weeks after initiating study agent. The abnormalities resolved after discontinuation of INH and study drug. HB#9 ARA3005 100 mg ALT/AST 323 Possibly – Hepatitis 969 / 3.7 ALT/AST elevations 58 year old woman was observed >20xULN E resolved 6 months to have abrupt increase in after study agent aminotransferases on week 44 of withdrawal therapy. Two weeks later, she experienced upper abdominal pain, decreased appetite, and a slightly flatulent abdomen, and was found to be positive for Hepatitis E IgM(+). ALT and AST peaked at >20x ULN and total bilirubin was >3x ULN (3.7

145 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 6: Adjudicated Hepatobiliary Events

Hepatologist Adjudication Aminotransferase Hepatobiliary Consensus – (IU/L) / T Bili (mg/dL) Case Study Dose Event Day of Event Alternate Causes Levels Sequelae Details mg/dL). Ultrasound findings included liver texture to be mildly grained, inhomogeneous, and concluded chronic hepatitis. No liver biopsy was performed. A follow up MRI was reported to show signs of hepatic cirrhosis with multiple regeneration nodes. The investigator considered the condition doubtfully related to study agent but rather due to previous oral toxicant(s) (nutritional, medication, other), and eventually termed the event chronic hepatitis. HB#10 ARA3002 Pbo  100 ALT/AST >3xULN 373 (Day 15 Probably – ALT 32 & AST 106 / 3.1 Persistent mild 41 year old female patient mg & Bilirubin sirukumab) Underlying NAFLD ALT/AST elevations randomized to placebo who had >2xULN and steatosis normal ALT (10 IU/L), AST (14 IU/L), and bilirubin (0.5 mg/dL) at baseline. Risk factors included obesity and concomitant methotrexate and corticosteroids. While on placebo, aminotransferases and bilirubin progressively increased (maximum ALT = 68 IU/L; maximum AST = 94 IU/L; and maximum bilirubin = 1.3 mg/dL). After crossover to Sirukumab, aminotransferases and bilirubin continued to increase (maximum ALT = 75 IU/L; maximum AST = 203 IU/L; and maximum bilirubin = 11.9 mg/dL). Patient developed jaundice and persistent vomiting. The liver biopsy showed marked steatosis and

146 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 6: Adjudicated Hepatobiliary Events

Hepatologist Adjudication Aminotransferase Hepatobiliary Consensus – (IU/L) / T Bili (mg/dL) Case Study Dose Event Day of Event Alternate Causes Levels Sequelae Details steatohepatitis consistent with methotrexate-associated hepatic injury (but would also fit with non-alcoholic steatohepatitis), which had progressed to stage 3 (bridging) fibrosis. In addition, the biopsy is notable for a predominantly portal, mixed inflammatory infiltrate including mononuclear cells (lymphocytes and plasma cells) and neutrophils, as well as canalicular cholestasis. These latter findings are not typical of methotrexate injury (or non-alcoholic steatohepatitis) and suggested a possibly superimposed secondary process, such as drug effect. Sirukumab, methotrexate, and corticosteroids were withdrawn, and aminotransferase elevations decreased to 2-3x ULN and bilirubin elevations resolved over approximately 6 months.

147 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 7: Serious Hypersensitivity Reactions (Excl. Injection Site Reactions) in Studies ARA3002 and ARA3003 Considered Possibly Related by Investigator (through SCS cutoff) Case # Age, Sex Randomized Event Event Description Relationship to Severity Dose Study Drug/ Group Outcome

Case#1 63, F Sirukumab Dermatitis Patient developed whole body rash, itching papules, and Very likely/ Severe 50 mg SC allergic difficulty breathing 16d after last dose (dose 8) and was treated Resolved q4w with loratadine, ranitidine, and cetirizine, palmitoylethanolamide (Physiogel AI cream) and methylprednisolone. Case#2 31, F PBO EE to Stevens 4 days after dose 6 patient had swelling of the mouth with a Possible/ Moderate Sirukumab Johnson single "bubble" covering the whole mouth with skin changes Resolved 100 mg SC Syndrome around the lips and oral cavity. No other parts of the skin were q2w involved. Patient was diagnosed with Stevens-Johnson Syndrome. Of note, approximately 2 weeks prior to initiating sirukumab therapy, patient presented with mild inflammation of the mouth characterized by redness affecting the mucous membranes with no bullous lesions that resolved following treatment with Socoseryl hemodiasylate. Medical history included the patient developed aphtosis ulcer of the mouth cavity during tocilizumab treatment, which resolved after application of antifungal treatment. Case#3 56, F Sirukumab Drug Patient presented with symptoms of acute urticaria and erythema Very likely/ Moderate 100 mg SC hypersensitivity multiforme, and esophageal spasm 13 days after last dose (dose Resolved q2w 33). Investigator initially indicated that the event was related to medications (omeprazole, drotaverine) for treatment of an earlier episode of non-serious AE of esophageal spasm and duodenal ulcer. Subsequently the investigator reconsidered his decision. Case#4 65, M Sirukumab 50 Broncho-spasm Patient with a history of emphysema was hospitalized with acute Possible/ Moderate mg SC q4w bronchitis with bronchospasm 2 days after last dose (dose 19). Resolved

148 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Case#5 47, F Sirukumab Laryngeal The patient developed swelling and redness at the injection site, Possible/ Moderate 100 mg SC oedema cough, and a strange sensation in the pharynx, received Resolved q2w chlorphenamine and fexofenadine and was hospitalized for observation (day of injection- dose 10). 26 days after last dose patient developed hoarseness. Plicae ventricularis and vocal cord edema was diagnosed by ENT. Patient subsequently had 2 similar events with plicae ventricularis and vocal cord edema after taking etanercept.

149 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 8: Efficacy Endpoints

RA Signs and Symptoms Assessments

ACR 20, ACR 50, ACR 70 The American College of Rheumatology’s ACR 20 criteria for assessing response to treatment and improvement in RA are defined as at least a 20% improvement in tender and swollen joint counts and at least a 20% improvement in 3 of the 5 remaining ACR-core set: patient and physician global assessments, pain, disability and an acute phase reactant (CRP was used in this program). ACR 50 and ACR 70 are calculated with the respective percent improvement.

Major clinical response is a continuous 6 month period of achieving an ACR 70 response.

Disease Activity Score (DAS28) DAS28 is a continuous measure of disease activity with frequently utilized score targets of ≤2.6 and ≤3.2. Components of DAS28 score include tender and swollen joint count (28), patient’s global assessment of disease and an acute phase reactant (CRP or ESR). A score of >5.1 represents high disease activity.61

Clinical Disease Activity Index (CDAI) The Clinical Disease Activity Index (CDAI) is a continuous measure of RA disease activity. CDAI is defined as the sum of 28TJC, 28SJC, Patient’s Global Assessment of Disease Activity, and Physician’s Global Assessment of Disease Activity. Unlike other measures, CDAI does not include the use of an acute phase reactant (CRP or ESR). A CDAI score of >22 is represents high disease activity whilst a score <10 is considered low disease activity.1

Radiographic Assessment of Joint Damage Radiographs of hands and feet were performed at baseline and at specified time points during study ARA3002. Radiographs were scores using the van der Heijde modfied Sharp method by two independent central assessors who were blinded to patient assignment and acquisition sequence. The scores recorded by these two readers were averaged and compared by timepoint to determine radiographic progression. Data through 1 year are included.

Physical Function The Health Assessment Questionnaire Disability Index (HAQ-DI) is a patient-completed questionnaire specific for RA, which assesses the degree of difficulty a patient has experienced in 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and other activities. A decrease from baseline in HAQ-DI score indicates improvement; a change of <-0.22 is considered to be clinically meaningful

150 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Patient Reported Outcomes Additional measures of patient reported outcomes included SF-36 Health Survey and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale. The SF-36 is a health-related, quality of life assessment. Questions are divided into 8 domains: four for physical health (physical health, bodily pain, physical functioning and physical role limitations) and four for mental health (mental health, vitality, social functioning and emotional role limitation). An increase of at least 5 points in the physical and mental component summary (PCS and MCS) scores is deemed a clinically relevant improvement for either subscore.

FACIT-Fatigue The FACIT-fatigue, a questionnaire, assesses self-reported tiredness, weakness, and difficulty conducting usual activities due to fatigue. The total FACIT-fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. In rheumatology, a change of 4 points is considered clinically meaningful and has been used as a response definition in the RA population.

151 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 9: Summary of Statistical Methods for 3002/3003/3005

1. ANALYSIS SETS

Efficacy Analysis Sets

Efficacy Full Analysis Set (for analyses of non-radiographic efficacy endpoints) For ARA3002 and ARA3003, the efficacy full analysis set (placebo controlled period) includes all patients who were randomized into the study, i.e., the Intent-to-Treat (ITT) Population. For ARA3005, the efficacy Full Analysis Set (FAS) includes all randomized patients who received at least 1 (partial or complete) dose of study agent, ie, the modified Intent-to-Treat (mITT) population.

In the efficacy analyses, patients were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

Efficacy Full Analysis Set (for analyses of radiographic efficacy endpoints in ARA3002) The efficacy full analysis set (placebo controlled period) for radiographic assessment includes all randomized patients who received at least 1 (partial or complete) dose of study agent and who had non-missing baseline vdH-S score. In the radiographic efficacy analyses, patients were analyzed according to the randomized treatment groups they were assigned to, regardless of the treatments they actually received.

Safety Analysis Set The safety analysis set includes all patients who received at least 1 (partial or complete) dose of study agent, i.e., the treated Population. In the safety analyses, patients were analyzed according to the treatment they actually received, regardless of the treatments they are randomized to.

2. DATA HANDLING RULES

Treatment Failure Criteria The following are the TF criteria for Week 0 through Week 52 in 3002 and 3005 and through Week 24 in 3003): 1. Initiate treatment with DMARDs, systemic immunosuppressives, and/or biologics for RA. 2. Increase dose of MTX for RA above the baseline dose (does not apply to 3005).

152 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

3. Initiate treatment with oral corticosteroids for RA, increase the dose of oral corticosteroids for RA above the baseline dose, or receive intravenous or intramuscular administration of corticosteroids for RA. 4. Discontinue study agent injection due to any reason(s). The following are the TF criteria for Week 24 through Week 52 in 3003: 1. Discontinue study agent injection due to any reason(s).

Missing Data

ACR 20 For the primary signs and symptoms endpoint of ACR 20 at Week 16 for both ARA3002 (Table 1) and ARA3003 (Table 2), the pre-specified primary statistical approach considered all patients who were treatment failures (TF) or had missing data to be non-responders. The tables below display the numbers with imputed data by study. The amount of imputed data was similar across treatment groups, albeit somewhat higher in ARA3003 compared with ARA3002.

Table 1: Summary of Observed and Imputed ACR 20 Response at Week 16; Full Analysis Set (Placebo Controlled Period) (ARA3002) Sirukumab Placebo 50 mg q4w 100 mg q2w Analysis set: Full Analysis Set (Placebo Controlled Period) 556 557 557

Patients evaluable for ACR 20 response at Week 16a 556 557 557

Number of Observed ACR 20 500(89.9%) 511(91.7%) 496(89.0%) Number of Imputed ACR 20 56(10.1%) 46(8.3%) 61(11.0%) TF (NR) 56(10.1%) 42 (7.6%) 55 (9.9%) Missing (Not TF) 0 4 (0.7%) 6(1.1%)

a Patients who were Treatment Failures (TF) or had missing data were treated as NR=Non-responder

153 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document radiographs were retaken; however, the retaken images were outside of analytical window, (4) radiographs were not performed at scheduled visit due to a missed visit or discontinuation of treatment.

While the amount of imputed data due to missing was similar across treatment groups, 33.8% of patients in the placebo group had data imputed due to Early Escape.

Table 4: Summary of Observed and Imputed change from baseline in vdH-S score at Week 52; Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment (ARA3002) Sirukumab Placebo 50 mg q4w 100 mg q2w Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment 550 553 551

Number with observed vdH-S score 288 (52.4%) 460 (83.2%) 467 (84.8%) Number with imputed vdH-S score 262 (47.6%) 93 (16.8%) 84 (15.2%) EE and Linear Extrapolation 186 (33.8%) NA NA Missing and Linear Extrapolation 76 (13.8%) 93 (16.8%) 84 (15.2%)

a Patients in the placebo group who Early Escape at Week 18 had subsequent values set to missing. Then all patients across all groups with missing endpoint data had their value imputed by linear extrapolation If there were no post-baseline measurements for the linear extrapolation, baseline was carried forward.

3. SENSITIVITY ANALYSIS

ACR20 response at week 16 (ARA3002 and ARA3003) To evaluate the robustness of the primary analysis, the following pre-planned sensitivity analyses were performed:

1. An analysis similar to the primary analysis, however, based on all randomized patients who receive at least 1 (partial or complete) dose of study agent. Note that this sensitivity analysis was not performed since all randomized patients received study treatment. 2. An analysis similar to the primary analysis, however, based on data without TF Rules applied. 3. An analysis similar to the primary analysis, however, based on data that patients who discontinue study treatment prior to Week 16 due to reasons other than an unsatisfactory therapeutic effect are not considered TF. 4. An analysis similar to the primary analysis, however, based on data without Missing Data Rules applied. 5. An analysis similar to the primary analysis, however, based on observed data (ie, data without TF or Missing Data Rules applied).

Change from baseline in vdH-S score at Week 52 (ARA3002) An analysis of variance (ANOVA) model was used to test the difference between a sirukumab group (50 mg q4w or 100 mg q2w) and the placebo group. In the model, the dependent variable was the van der Waerden normal score of change from baseline in vdH-S score at Week 52 and the independent variables were treatment group and use of MTX at baseline.

155 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Data Handling Rules for Primary Analysis

1. For patients in the placebo group who met EE criteria at Week 18, all the scores after Week 18 (such as scores at Weeks 24 and 52) were set to missing and linear extrapolation used to impute missing data 2. For patients in all treatment groups with missing vdH-S score at Week 52, the missing score at Week 52 was imputed by linear extrapolation, ie, the predicted score using a linear regression model based on all observed scores prior to Week 52 (including baseline score) or set to baseline score if only baseline score was available.

To evaluate the robustness of the above analysis, the following pre-planned sensitivity analyses were performed:

1) An analysis similar to the primary analysis, however, based on data with vdH-S score at Week 52 imputed as follows:

a. For patients in all treatment groups who met EE criteria at Week 18, all the scores after Week 18 were set to missing.

b. For patients in all treatment groups with missing vdH-S score at Week 52, the missing score at Week 52 was imputed by linear extrapolation, i.e., the predicted score using a linear regression model based on all observed scores prior to Week 52 (including baseline score) or set to baseline score if only baseline score is available (Table 5).

2) An analysis similar to the primary analysis, however, based on data with missing vdH-S score at Week 52 imputed as follows:

a. For patients in the placebo group who met EE criteria at Week 18, all the scores after Week 18 were set to missing.

b. For patients in all treatment groups with missing vdH-S score at Week 52, the missing score at Week 52 was imputed using the last non-missing observed score prior to Week 52 (including baseline score), ie, last observation carry forward (LOCF) (Table 5).

3) An analysis similar to the primary analysis, however, based on observed data with post-escape data excluded from patients who escaped from the placebo to the sirukumab groups and without EE or Missing Data Rules applied (Table 5).

4) An analysis similar to the primary analysis, however, based on data with Missing Data Rules applied and EE Rules not applied. In this analysis, the post-escape data was included (Table 5).

5) An analysis, similar to the primary analysis, however, based on data from all randomized patients, i.e., Efficacy Full Analysis Set (Placebo Controlled Period). In this analysis, for patients with missing baseline scores, the change from baseline in vdH-S score at Week 52 was imputed by the median value of change from baseline in vdH-S score at Week 52 among all patients in the same 156 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

randomization stratum (use of MTX at baseline: 0 mg/week, > 0 to < 12.5 mg/week, or ≥ 12.5 mg/week) (Table 5).

Per request of the FDA, the following additional sensitivity analyses were performed:

A. In this analysis, all the observed vdH-S scores through week 52 (excluding the post-EE data from the placebo patients) were used to estimate the on-treatment slopes using a mixed effects model and the confidence intervals for differences in on-treatment slopes between a sirukumab group and the placebo group were obtained via a bootstrap method (Table 5).

B. This analysis was similar to the above sensitivity analysis, however, the post-EE data from the placebo patients were included (Table 5).

C. In this analysis, the post-EE data from the placebo patients were excluded. The missing vdH-S scores at Week 52 were accounted for using Inverse Probability Weighting (IPW) methods. The confidence intervals were created via bootstrap sample distribution of treatment differences (Table 5).

D. In this analysis, the post-EE data from the placebo patients were excluded. The missing vdH-S scores at Week 52 were imputed using Multiple Imputation (MI) methods (Table 5).

E. In this analysis, the post-EE data from the placebo patients were excluded. The missing vdH-S scores at Week 52 were imputed using MI and then Tipping Point analysis was performed (Table 6).

Table 5: Summary of Change From Baseline in vdH-S Score at Week 52; Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment (Study CNTO136ARA3002) Sirukumab Analysis Method Placebo 50 mg q4w 100 mg q2w Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment 550 553 551 Primary Method N 550 553 551 Mean (SD) 3.69 (9.245) 0.50 (2.961) 0.46 (3.258) Median 1.00 0.00 0.00 Range (-22.1; 98.0) (-9.5; 25.0) (-23.6; 24.0) IQ range (0.00; 4.03) (-0.50; 1.00) (-0.50; 1.00) p-valuea < 0.001 < 0.001 Sensitivity 1 N 550 553 551 Mean (SD) 3.69 (9.245) 0.51 (3.080) 0.41 (3.325) Median 1.00 0.00 0.00 Range (-22.1; 98.0) (-9.5; 25.0) (-23.6; 24.0) IQ range (0.00; 4.03) (-0.50; 1.00) (-0.50; 1.00) p-valuea < 0.001 < 0.001

157 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 5: Summary of Change From Baseline in vdH-S Score at Week 52; Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment (Study CNTO136ARA3002) Sensitivity 2 N 550 553 551 Mean (SD) 2.57 (7.098) 0.50 (2.701) 0.39 (2.604) Median 0.50 0.00 0.00 Range (-4.5; 98.0) (-9.5; 25.0) (-13.5; 24.0) IQ range (0.00; 2.50) (-0.50; 1.00) (-0.50; 1.00) p-valuea < 0.001 < 0.001 Sensitivity 3 N 288 460 467 Mean (SD) 3.54 (9.050) 0.60 (2.861) 0.38 (2.724) Median 1.00 0.00 0.00 Range (-4.5; 98.0) (-9.5; 25.0) (-13.5; 24.0) IQ range (0.00; 3.50) (-0.50; 1.00) (-0.50; 1.00) p-valuea < 0.001 < 0.001 Sensitivity 4 N 550 553 551 Mean (SD) 2.88 (7.722) 0.50 (2.961) 0.46 (3.258) Median 0.50 0.00 0.00 Range (-22.1; 98.0) (-9.5; 25.0) (-23.6; 24.0) IQ range (0.00; 3.00) (-0.50; 1.00) (-0.50; 1.00) p-valuea < 0.001 < 0.001 Sensitivity 5 N 556 557 557 Mean (SD) 3.65 (9.203) 0.50 (2.950) 0.46 (3.241) Median 0.98 0.00 0.00 Range (-22.1; 98.0) (-9.5; 25.0) (-23.6; 24.0) IQ range (0.00; 4.02) (-0.50; 1.00) (-0.50; 1.00) p-valuea < 0.001 < 0.001 FDA Analysis A N 288 460 467 Mean (SD) 3.54 (9.050) 0.60 (2.861) 0.38 (2.724) Median 1.00 0.00 0.00 Range (-4.5; 98.0) (-9.5; 25.0) (-13.5; 24.0) IQ range (0.00; 3.50) (-0.50; 1.00) (-0.50; 1.00) On-treatment slope per yearb(SE) 4.12 (0.28) 0.6 (0.25) 0.51 (0.26) Difference (95% CI)c -3.52, (-4.26, -2.78) -3.61, (-4.34, -2.89) FDA Analysis B N 447 460 467 Mean (SD) 3.06 (8.003) 0.60 (2.861) 0.38 (2.724) Median 0.55 0.00 0.00 Range (-4.5; 98.0) (-9.5; 25.0) (-13.5; 24.0) IQ range (0.00; 3.50) (-0.50; 1.00) (-0.50; 1.00) On-treatment slope per yearb(SE) 3.27 (0.24) 0.6 (0.24) 0.5 (0.24) Difference (95% CI)c -2.67, (-3.28, -2.06) -2.77, (-3.37, -2.18) FDA Analysis C N 288 460 467 Mean (SD) 3.54 (9.050) 0.60 (2.861) 0.38 (2.724) Median 1.00 0.00 0.00 Range (-4.5; 98.0) (-9.5; 25.0) (-13.5; 24.0) IQ range (0.00; 3.50) (-0.50; 1.00) (-0.50; 1.00) IPW-based Mean 5.98 0.73 0.74 Difference (95% CI)d -5.25, (-9.06, -2.72) -5.25, (-9.06, -2.67)

158 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Table 5: Summary of Change From Baseline in vdH-S Score at Week 52; Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment (Study CNTO136ARA3002) FDA Analysis D N 288 460 467 Mean (SD) 3.54 (9.050) 0.60 (2.861) 0.38 (2.724) Median 1.00 0.00 0.00 Range (-4.5; 98.0) (-9.5; 25.0) (-13.5; 24.0) IQ range (0.00; 3.50) (-0.50; 1.00) (-0.50; 1.00) MI-based Mean 3.15 0.52 0.46 Difference (95% CI) -2.62, (-3.35, -1.9) -2.69, (-3.4, -1.97) p-value <.0001 <.0001 a The p-values were based on van der waerden ANOVA b 1 Year = 52 Weeks. cThe confidence intervals are based on bootstrap method. dThe confidence interval is based on the 2.5th and 97.5th percentiles from the bootstrap sample distribution of treatment difference.

Table 6: Summary of Treatment Difference in Change From Baseline in Vdh-S Score at Week 52 Based on a Multiple Imputation (MI) and Tipping Point Method; Full Analysis Set (Placebo Controlled Period) for Radiographic Assessment (Study CNTO136ARA3002) Sirukumab 50 mg q4w 100 mg q2w Mean (p-value) Mean (p-value) Tipping amount (Δ) 95% CI 95% CI Δ=-5 -0.93 (0.015) -0.99 (0.0093) (-1.69, -0.18) (-1.74, -0.25) Δ=-4 -1.27 (0.0008) -1.33 (0.0004) (-2.01, -0.53) (-2.07, -0.59) Δ=-3 -1.61 (<.0001) -1.67 (<.0001) (-2.34, -0.87) (-2.4, -0.94) Δ=-2.5 -1.78 (<.0001) -1.84 (<.0001) (-2.51, -1.05) (-2.57, -1.11) Δ=-2 -1.95 (<.0001) -2.01 (<.0001) (-2.68, -1.22) (-2.73, -1.28) Δ=-1.5 -2.12 (<.0001) -2.18 (<.0001) (-2.84, -1.39) (-2.9, -1.46) Δ=-1 -2.28 (<.0001) -2.35 (<.0001) (-3.01, -1.56) (-3.07, -1.63) Δ=-0.5 -2.45 (<.0001) -2.52 (<.0001) (-3.18, -1.73) (-3.24, -1.8) Δ=0 -2.62 (<.0001) -2.69 (<.0001) (-3.35, -1.9) (-3.4, -1.97) Δ=0.5 -2.79 (<.0001) -2.85 (<.0001) (-3.52, -2.07) (-3.57, -2.14) Δ=1 -2.96 (<.0001) -3.02 (<.0001) (-3.69, -2.24) (-3.74, -2.3)

Post-hoc sensitivity analyses to explore de facto estimands (utilizing all observed data, including data collected after escape or treatment discontinuation) for all Primary and key Secondary endpoints from ARA3002 and ARA3003 were conducted, along with Tipping Point analyses of 159 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document those de facto estimands. The Tipping Point analyses varied assumptions about expected outcomes among patients with missing data, with the goal of evaluating the plausibility of assumptions about the missing data under which the conclusions change, i.e., under which there is no longer evidence of a treatment effect. The tipping point analyses were two- dimensional, ie, allowed assumptions about the missing outcomes on the two arms being compared with vary independently and included scenarios where dropouts on treatment have worse outcomes than dropouts on control.

4. MAJOR SECONDARY ENDPOINT METHODS (ARA3002 AND ARA3003) Change from Baseline in HAQ-DI Score at Week 24 Change from baseline in HAQ-DI score is a measure of the change in the functional status, where a negative change reflects an improvement and a positive change reflects a worsening. The HAQ-DI score will not be computed if the patient does not have scores for at least 6 of the 8 categories. Data from all randomized patients, i.e., Efficacy Full Analysis Set (Placebo Controlled Period), was included and analyzed according to the randomized treatment groups. To compare the differences between treatment groups, an analysis of covariance (ANCOVA) model was used with change from baseline in HAQ-DI score at Week 24 as the dependent variable, and treatment group, use of MTX at baseline (0 mg/week, > 0 to < 12.5 mg/week, or ≥ 12.5 mg/week) and baseline HAQ-DI score as the independent variables. The model included data from all 3 treatment groups. The treatment difference between a sirukumab group (50 mg q4w or 100 mg q2w) and the placebo group was estimated by difference in the least squares means (LSmeans) between the 2 groups compared. The 95% CIs for differences in LSmeans between the sirukumab and the placebo groups and p-values were calculated based on contrast test statistics. Imputation Rules  Patients with missing HAQ-DI score at baseline were excluded from the analysis.  For patients who met EE criteria Week 18, HAQ-DI score at Week 24 was replaced by the observed score at Week 18 or, if Week 18 score is missing, by the last non-missing observed HAQ-DI score prior to Week 18.  For patients with missing HAQ-DI score at Week 24, HAQ-DI score at Week 24 was imputed using the last non-missing observed HAQ-DI score prior to Week 24. Sensitivity Analyses To evaluate the robustness of the above analysis, the following sensitivity analyses were performed: 1. An analysis was performed using Mixed-Effect Model Repeated Measure (MMRM) model based on observed data with post-escape data excluded from patients who escaped from the placebo group to the sirukumab groups and with no EE or Missing Data Imputation rules applied. The fixed terms of this model are treatment group, use of MTX at baseline, baseline value of HAQ–DI score, visit, and an interaction of treatment and visit. An unrestricted (UN) variance-covariance matrix for repeated measure within a patient was used. The model

160 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

included data from all 3 treatment groups. The treatment difference between a sirukumab group (50 mg q4w or 100 mg q2w) and the placebo group was estimated by difference in LSmeans between the 2 groups compared. The 95% CIs for differences in LSmeans between the sirukumab and the placebo groups and p-values were calculated based on contrast test statistics. 2. An analysis similar to the above sensitivity analysis 1, however, based on observed data including the post-escape data and with no EE or Missing Data Imputation rules applied.

Proportion of patients who achieve an ACR 50 response at Week 24 Proportion of patients who achieve an ACR 50 response at Week 24 was analyzed at Week 52 DBL. In this analysis, data from all randomized patients, i.e., Efficacy Full Analysis Set (Placebo Controlled Period), was included and analyzed according to the randomized treatment groups. A CMH test stratified by the use of MTX at baseline (0 mg/week, >  t  .5 mg/week, or ≥ 12.5 mg/week) was used to test treatment difference between a sirukumab group (50 mg q4w or 100 mg q2w) and the placebo group on proportion of patients who achieve an ACR 50 response at Week 24. The 95% CIs for the treatment differences were calculated based on the Wald statistics. Imputation rules:  Patients who met TF criteria prior to Week 24 or who met EE criteria at Week 18 were considered as non-responders.  Patients who had missing data at Week 24 were considered non-responders.

Proportion of patients with DAS28 (CRP) remission at Week 24 If any of the components required for computing the DAS28 (CRP) value is missing, the DAS 28 (CRP) score was set to missing. DAS28 (CRP) remission is defined as a DAS28 (CRP) value of ≤ 2.6 at a visit.

Data from all randomized patients, i.e., Efficacy Full Analysis Set (Placebo Controlled Period), was included and analyzed according to the randomized treatment groups. A CMH test stratified by the use of MTX at baseline (0 mg/week, >  t  .5 mg/week, or ≥ 12.5 mg/week) was used to test treatment difference between a sirukumab group (50 mg q4w or 100 mg q2w) and the placebo group on proportion of patients with DAS28 (CRP) remission at Week 24. The 95% CIs for the treatment differences were calculated based on the Wald statistics. Imputation rules:  Patients who met TF criteria prior to Week 24 or who met EE criteria at Week 18 were considered as non-responders.  Patients who had missing data at Week 24 were considered non-responders. 161 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Proportion of patients who achieve a major clinical response by Week 52 A patient was considered to have achieved a major clinical response (MCR) if the patient achieves an ACR 70 response for 6 continuous months (24 weeks) in the study period (i.e., through Week 52). MCR status was determined based on ACR 70 response status at scheduled visits over any 6-month (24-week) period. Data for ACR assessment were to be collected every 2 weeks from Week 0 to Week 8 (inclusive) and every 4 weeks from Week 12 to Week 52 (inclusive). In addition, the data are also to be collected at Week 18. Single intermittent missing ACR 70 responses over a 6-month (24-week) period may be ignored for the determination of MCR status over the period; otherwise, missing ACR 70 response will result in a missing value for MCR over the period. Analysis Methods Data from all randomized patients, i.e., Efficacy Full Analysis Set (Placebo Controlled Period), were included and analyzed according to the randomized treatment groups. A CMH test stratified by the use of MTX at baseline (0 mg/week, >  t  .5 mg/week, or ≥ 12.5 mg/week) was used to test treatment difference between a sirukumab group (50 mg q4w or 100 mg q2w) and the placebo group on proportion of patients who achieve a major clinical response by week 52. The 95% CIs for the treatment differences were calculated based on the Wald statistics. Imputation rules:  Patients who met TF criteria prior to Week 52 or who met EE criteria at Week 18 or LE criteria at Week 40 were considered as not having achieved a MCR by Week 52.  Patients with missing MCR were considered as not having achieved a MCR by Week 52.

5. TESTING PROCEDURE TO CONTROL FOR MULTIPLICITY

ARA3002 Since the first three tests in the testing sequence were significant at p<0.05, a truncated Hochberg method was applied to the 2 hypotheses for comparing (1) 100 mg q2 week group to placebo group for change from baseline in HAQ-DI score at Week 24 and (2) comparing 50 mg q4 week group to the placebo group in change from baseline in vdH-S score at Week 52. Since both of them were significant at p<0.04, testing continued at the α=0.05 level.

162 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

ARA3003 In this fixed sequential testing order, each of the hypotheses was tested at a 2-sided α-level of 0.05 given that significance was achieved for the preceding hypothesis in the specified order.

163 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 10: Analysis of the number of Patients who Achieved ACR 20, ACR 50 and DAS28 Responses by Age; Study ARA3003

165 Status: Approved , Date: 28 June 2017

PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 1 shows scatter plot of unadjusted data points for change in DAS28 (CRP) at Week 24 against age (1 data point per patient); fitted lines are linear regression lines by treatment with 95% CI. The improvements in DAS28 were consistently greater with sirukumab compared with placebo.

Figure 1: Scatter Plot of Change of baseline in DAS28 (CRP) at Week 24

Note: The youngest patient was 18 years of age and the eldest 84 years (across all 3 studies) and so the linear regression lines extend beyond the collected age range.

168 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 11: Week 18 Measures of Inflammation in Patients Randomized to Placebo in ARA3002 and ARA3003

Early Escaped Did Not Early Escape Patients Randomized to Placebo ARA3002 and ARA3003 281 569

Tender joint counts N 281 484 Mean (SD) 30.08 (14.141) 13.00 (12.898) Median 28.00 10.00 Range (5.0; 68.0) (0.0; 68.0) IQ range (19.00; 39.00) (3.00; 19.00)

Swollen Joint Counts N 281 484 Mean (SD) 18.11 (9.474) 7.05 (6.999) Median 16.00 5.00 Range (4.0; 62.0) (0.0; 41.0) IQ range (12.00; 22.00) (2.00; 10.00)

Percent improvement from baseline in Tender joint counts N 281 484 Mean (SD) -29.73 (55.355) 50.44 (41.119) Median -11.90 55.68 Range (-433.3; 35.0) (-200.0; 100.0) IQ range (-40.00; 0.00) (27.89; 81.82)

Percent improvement from baseline in Swollen Joint Counts N 281 484 Mean (SD) -27.08 (49.970) 52.92 (38.642) Median -12.50 55.56 Range (-280.0; 69.2) (-200.0; 100.0) IQ range (-39.29; 6.67) (29.22; 83.33)

DAS28 (CRP) score N 279 476 Mean (SD) 6.13 (0.841) 4.32 (1.330) Median 6.11 4.38 Range (4.0; 8.0) (1.2; 7.3) IQ range (5.59; 6.71) (3.30; 5.27)

169 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 11: Week 18 Measures of Inflammation in Patients Randomized to Placebo in ARA3002 and ARA3003

Early Escaped Did Not Early Escape CRP N 279 476 Mean (SD) 2.49 (2.513) 1.75 (2.251) Median 1.66 0.96 Range (0.0; 17.0) (0.0; 21.6) IQ range (0.71; 3.54) (0.45; 2.23)

HAQ DI score N 281 484 Mean (SD) 1.59 (0.600) 1.20 (0.657) Median 1.63 1.25 Range (0.0; 3.0) (0.0; 2.9) IQ range (1.25; 2.00) (0.75; 1.75)

CDAI score N 280 484 Mean (SD) 42.73 (11.627) 20.78 (13.568) Median 42.10 18.20 Range (16.6; 71.9) (0.1; 67.5) IQ range (34.30; 50.50) (10.00; 29.25)

SDAI score N 278 476 Mean (SD) 45.22 (12.420) 22.40 (13.988) Median 44.19 20.43 Range (18.7; 82.4) (0.8; 68.4) IQ range (36.61; 53.66) (11.11; 30.82)

Adapted from [BB_INFLAMMATION.RTF] [CNTO136\Z_ADCOM\DBR_ADCOM\RE_ADCOM\PROD\BB_INFLAMMATION.SAS] 25JUN2017, 01:07

170 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 12: Additional Modeling Results for Death The analyses below provide estimates of the difference of incidence rates (95% CI) for deaths through 52 weeks of exposure comparing the following treatment arms against placebo: patients randomized to sirukumab 50 mg q4w and 100 mg q2w (Start 50 mg q4w and Start 100 mg q2w, respectively) and the combination of each of these 2 groups with patients randomized to placebo who later switched to sirukumab 50 mg q4w or 100 mg q2w (Combined 50 mg q4w and Combined 100 mg q2w, respectively). All analyses presented were done using data from Study CNTO136ISS (combination of ARA3002 and ARA3003) up to 52 weeks of exposure.

Limitations: It should be noted, due to the early escape in the study design, the composition of the placebo group is altered and the initial randomization properties are no longer preserved after Week 18. In addition, duration of observation of placebo patients is reduced relative to the sirukumab treatment groups, and unless hazards are constant over time, this creates additional bias. Therefore, any comparisons to placebo after Week 18 must be interpreted with caution. Furthermore, as a result of the addition of the early and late escape patients to the combined sirukumab arms, the combined sirukumab arms include a mixture of 2 distinct populations: (1) patients who were randomized to sirukumab, and (2) early/late escape patients with greater disease burden at the time of escape/conversion to sirukumab compared with patients who were randomized to sirukumab (while those same patients are censored from the placebo arm). Since disease burden has been identified as an important covariate affecting the risk of death (see below), the combined sirukumab arms constitute a heterogeneous patient population with respect to the risk of death. Therefore, comparisons between the combined sirukumab arms and placebo are biased and should be interpreted with caution.

A modeling exercise utilizing baseline risk factors and/or disease burden (post-baseline) covariates to attempt to mitigate this bias in treatment comparisons to placebo was conducted and is presented below.

Three different types of covariate-based bias mitigation approaches are considered: No covariates (ie, no bias mitigation), baseline risk factors only, and baseline risk factors and disease burden covariates. The approaches are applied to both the combined and start sirukumab arms comparisons to placebo. The baseline risk factors were selected first, out of a large set of candidate variables, using a statistical significance criterion (p-value <0.001, to account for multiplicity) applied to a Poisson regression model. The baseline risk factors that were chosen were age and baseline HAQ. The disease burden covariates were selected, out of a large set of candidate variables, by assessing their statistical significance (p-value <0.001) when added to the Poisson model including age and baseline HAQ as covariates. The variables selected were average CRP and average HAQ over the entire time in study (up to 52 weeks).

A Poisson regression model with log link and dispersion fixed at 1 (fitted using iteratively reweighted least squares as implemented in the glm function in R) was used to estimate the incidence rates of death by treatment arm. All estimated incidence rates are represented per 100 patient years. The analyses were stratified by study, through the inclusion of a study effect term in the models. Approximate standard errors for the differences in incidence rates were obtained 171 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document via the Delta method and were used to derive asymptotic confidence intervals based on a normal approximation.

As previously discussed, additional baseline risk factors and disease burden covariates were incorporated in the models to allow estimation of risk-adjusted incidence rates, potentially mitigating bias concerns associated with the switching of non-responder placebo patients to sirukumab. Estimated incidence rates for models with covariates were calculated with covariates set at their median values (calculated across all patients, irrespective of treatment).

Table 1 below provides the estimated difference in death incidence rates between the Start and Combined sirukumab arms and placebo, with associated 95% C.I., utilizing the 3 different bias mitigation model-based approaches described.

Table 1: Estimated differences in death incidence rates (per 100 patient-years) between Start and Combined sirukumab arms and placebo, with associated 95% C.I., based on Poisson regression fit with different covariates included for potential bias mitigation Covariates Start 50 mg Start 100 mg Comb. 50 mg Comb. 100 mg None 0.299 (-0.279,0.876) 0.538 (-0.135,1.211) 0.668 (0.029,1.307) 0.836 (0.148,1.524) Basel. Only 0.118 (-0.112,0.349) 0.217 (-0.077,0.510) 0.264 (-0.034,0.563) 0.353 (0.004,0.702) Basel. & Post. 0.094 (-0.057,0.245) 0.181 (-0.044,0.405) 0.154 (-0.017,0.324) 0.238 (0.011,0.465)

The estimated differences in death incidence rates obtained from the Poisson regression model without any covariates (but treatment and study) are substantially reduced when baseline risk factors (age and baseline HAQ) are included in the model, most noticeably for the Combined sirukumab arms. Further reductions in the estimated differences in death incidence rates are observed when the disease burden covariates (average CRP and HAQ) are incorporated into the model, suggesting that the uncorrected estimated differences are biased toward larger treatment effects, especially for the Combined sirukumab arms comparisons. The length of the 95% C.I. decreases with the magnitude of the estimated difference in incidence rates, indicating greater estimation precision with the inclusion of covariates. A graphical view of the results in Table 1 is displayed in the top row of Figure 1 below. The impact of the different covariate adjustment strategies on the estimated differences can be clearly visualized.

172 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Figure 1: Estimated differences in incidence rates between Start and Combined sirukumab arms and placebo, with associated 95% C.I., based on Poisson regression fit with different covariates included for bias mitigation.

Note that thirty patients who discontinued the study prior to Week 18 had missing values for the two post-baseline covariates used in the models. Imputed values for these post-baseline covariates were used to allow the inclusion of all patients in the models utilizing those variables (third bias mitigation approach). Missing average CRP for placebo patients and missing average HAQ for all patients were imputed with the corresponding baseline values. Missing average CRP values for sirukumab patients were imputed with the mean of the non-missing average CRP values of the respective sirukumab regimen. Results based on non-imputed data (ie, removing patients with missing post-baseline covariate values from the model fits including those variables) are nearly identical to the ones using the imputed data.

173 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

Appendix 13: Definition of Subgroups in Studies ARA3002 and ARA3003

Definition of Subgroups -ARA3002 To evaluate the consistency in the primary efficacy endpoints (proportion of patients who achieve ACR 20 at Week 16 and change from baseline in vdH-S score at Week 52) over demographics, baseline characteristics, prior and baseline medication use, subgroup analyses will be performed. The subgroups for subgroup analyses include, but are not limited to, the following:

1. Subgroups defined by demographics:

 Gender (male, female)  Race (White, Black or African American, Asian, Other)  Geographic Location [North America, Europe, Latin America, Asia Pacific (Asia/Australia/ New Zealand), South Africa]  Age (< 45 years, ≥ 45 years to < 65 years, ≥ 65 years)  Weight (quartiles) 2. Subgroups defined by baseline characteristics:

 Disease duration (< 1 year, ≥1 year to < 3 years, ≥3 years)  Rheumatoid factor (positive, negative)  Anti-CCP (positive, negative)  Rheumatoid factor and anti-CCP (positive for both, otherwise)  Number of swollen joints (<10, ≥ 10)  Number of tender joints (<10, ≥ 10)  HAQ (< 1, ≥1 to <2, ≥ 2)  CRP (< 15 mg/L, ≥ 15 mg/L at Week 0)  Previous joint surgery (yes, no) 3. Subgroups defined by medication use:

 Prior DMARDs (1, 2, ≥ 3)  Prior NSAIDs (yes, no)  Prior MTX (yes, no)  Baseline oral corticosteroids (yes, no)  Baseline MTX (0 mg/week, > 0 to < 12.5 mg/week, ≥ 12.5 mg/week)

174 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

 Baseline DMARDs (yes, no)  Prior MTX > 15 mg/week for ≥ 4 weeks  Prior MTX > 15 mg/week for ≥ 4 weeks and CRP ≥ 15 mg/L at Screening

Definition of Subgroups - ARA3003 To evaluate the consistency in the primary efficacy endpoints (proportion of patients who achieve ACR 20 response at Week 16) over demographics, baseline characteristics, prior and baseline medication use, subgroup analyses will be performed. The following is a list of subgroups for subgroup analyses:

Subgroups defined by demographics:

 Gender: Male, Female  Race: White, Black or African American, Asian, Other  Geographic Location: North America, Europe, Latin America, Asia Pacific (Asia/Australia/ New Zealand)  Age: < 45 years, ≥ 45 years to < 65 years, ≥ 65 years  Weight: quartiles Subgroups defined by baseline characteristics:

 Disease duration (< 1 year, ≥1 year to < 3 years, ≥3 years)  Rheumatoid factor (Positive, Negative)  Anti-CCP (positive, negative)  Rheumatoid factor and anti-CCP (positive for both, otherwise)  Number of swollen joints (<10, ≥ 10)  Number of tender joints (<10, ≥ 10)  HAQ (< 1, ≥1 to <2, ≥ 2)  CRP (< 15 mg/L, ≥ 15 mg/L at Week 0)  Previous joint surgery (yes, no) Subgroups defined by prior and baseline medicine use:

 Prior DMARDs (1, 2, ≥ 3)  Prior NSAIDS (yes,no)  Prior MTX (yes,no)  Baseline oral corticosteroids (yes,no)

175 Status: Approved , Date: 28 June 2017 PLIVENSIA™ (sirukumab) Rheumatoid arthritis Briefing Document

 Baseline MTX (0 mg/week, > 0 to < 12.5 mg/week, ≥ 12.5 mg/week)  Baseline DMARDs including MTX (yes, no)  Number of anti TNF α medications used prior to study entry (1, ≥2)  Failed (due to Lack of Efficacy) any prior anti TNF therapy (yes, no) Intolerant to any prior anti TNF therapy (yes, no).

176 Status: Approved , Date: 28 June 2017