Janssen Research & Development Briefing Document Arthritis Advisory Committee PLIVENSIA™ (sirukumab) Status: Approved Date: 28 June 2017 Prepared by: Janssen Research & Development, LLC EDMSnumber: 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 OFTERMS.....................................................................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 CLINICALDEVELOPMENT 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 Table1: 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 Table25: 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 1or 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<LLN through 18 Weeks of Exposure in the DMARD-IR and TNFα-Failure Studies.........................................................106 Table 31: Malignancies in Phase 3 sirukumab studies compared with the expected number in the general population according to the SEER database.......................................................111 Table 32: Aminotransferase Abnormalities in Sirukumab Phase 3 Studies...........................................112 Table33: Number of patients with post-baseline values by maximum toxicity grade for hematology lab parameters through 18 weeks of exposure...................................................114 Table 34: Shift in LDL and triglycerides from baseline to highest post-baseline value through 18 weeks (Studies 3002 and 3003 pooled).................................................................................116 Table 35: Hypersensitivity reactions excluding injection site reactions..................................................118 Table36: 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.......................................................................................................120 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 PartB)..............................................................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 (StudyC1377T04 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 Figure21: 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 Figure22: 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 Figure32: 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 Figure34: 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 50mg (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/ RAdevelopment programs......................................................121 Figure39: 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 ImmunoglobulinG1 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.52,59Patients 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 withactive RA.  Two global pivotal Phase 3 studies were designed to evaluate sirukumab 50 mg q4w and 100mg 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 investigatedby:  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