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numbered

CONFIDENTIAL 2015N265172_00The GlaxoSmithKline group of companies 201223

1

Division: Worldwide DevelopmentRetention Category: GRS019Information Type: Meta-Analysis Results Report

Title: Results Report for 201223, a Pooled Analysis of BEL112233 and BEL112234, Two Long-term, Extension Studies of BEL110751 and BEL110752, to Investigate Long-term Safety and Organ Damage Accrual with Belimumab Treatment in Systemic Lupus Erythematosus.

Compound Number: GSK1550188

Effective Date: 4-NOV-2015

Description: Pooled analyses of belimumab patients who participated in BEL112233 or BEL112234.

Subject: Systemic lupus erythematosus (SLE), Belimumab, SLICC/ACR Damage Index (SDI), Pooled analysis, Safety, Long-term, Transition analysis

Authors: MBBS

Director, Clinical DevelopmentApproved via email

Date

1/11/2015

PhDDirector, Clinical StatisticsApproved via email

Date

4/11/2015

Contributors:

MEdUS Medical Affairs Scientific Director

Date

Director, SERMDate

Approved by:

MD, MSCEDirector, Global R&D, Immuno-Inflammation Therapeutic AreaApproved via email

Date

28/10/2015

Acknowledgments:Medical writing assistance was provided by PhD of Fishawack Indicia Ltd.

Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited.

1

Table of Contents Page TITLE PAGE .......................................................................................................... 1. INTRODUCTION ................................................................................................ 2. OBJECTIVES .....................................................................................................

2.1. Safety Objective .............................................................................................. 2.2. Primary Analysis .............................................................................................. 2.3. Key Secondary Analyses ................................................................................. 2.4. Other Secondary Analyses ..............................................................................

3. INVESTIGATIONAL PLAN ................................................................................ 3.1. Design .............................................................................................................

3.1.1. BEL112233 .................................................................................................. 3.1.2. BEL112234 .................................................................................................. 3.1.3. Key Differences Between BEL112233 and BEL112234 Protocols ..............

3.2. Selection of Populations .................................................................................. 3.3. Treatments ...................................................................................................... 3.4. Study Assessments .........................................................................................

3.4.1. SDI Total Score ........................................................................................... 3.4.2. BILAG Scores .............................................................................................. 3.4.3. Daily Prednisone Dose Equivalent .............................................................. 3.4.4. SELENA SLEDAI ........................................................................................ 3.4.5. Medical History/Medical Classification ......................................................... 3.4.6. Clinical Laboratory Evaluations ...................................................................

3.5. Statistical Analyses .......................................................................................... 3.5.1. Data Quality Issues ..................................................................................... 3.5.2. Analysis Populations ................................................................................... 3.5.3. Demographic and Baseline Characteristics ................................................. 3.5.4. Safety Analyses ........................................................................................... 3.5.5. Primary Analysis .......................................................................................... 3.5.6. Secondary Analyses .................................................................................... 3.5.7. Post Hoc Analyses ......................................................................................

4. RESULTS ........................................................................................................... 4.1. Summary of Population ................................................................................... 4.2. Patient Demographics .....................................................................................

4.2.1. Baseline Disease Characteristics ................................................................ 4.2.2. Concomitant Medications ............................................................................ 4.2.3. Study Withdrawals .......................................................................................

4.3. Safety Analyses ............................................................................................... 4.3.1. Study Drug Exposure .................................................................................. 4.3.2. Adverse Events ........................................................................................... 4.3.3. Serious Adverse Events .............................................................................. 4.3.4. AEs of Special Interest ................................................................................ 4.3.5. Clinical Laboratory Evaluations ...................................................................

4.4. Primary Analysis .............................................................................................. 4.5. Key Secondary Analyses .................................................................................

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CONFIDENTIAL 2015N265172_00201223

4.5.1. Time to First SDI Worsening ....................................................................... 4.5.2. Transition Analysis ......................................................................................

4.6. Other Secondary Analyses .............................................................................. 4.6.1. SDI Sensitivity Analysis (Post Hoc) ............................................................. 4.6.2. Change From Baseline in SDI by Year, Subgroup Analyses ....................... 4.6.3. Secondary Transition Modeling ................................................................... 4.6.4. Total SDI Score by Year Interval ................................................................. 4.6.5. Change from Baseline in SDI among Patients with a Fatal AE ................... 4.6.6. Change from Baseline in SDI Organ Damage System ................................

5. DISCUSSION ..................................................................................................... 6. CONCLUSIONS ................................................................................................. 7. REFERENCES ................................................................................................... 8. TABLES ............................................................................................................. 9. FIGURES ............................................................................................................ 10. APPENDICES .................................................................................................. Appendix 1 RAP errata: Summary of deviations from planned analyses ........ Appendix 2 Adverse Event Severity Grading Tables......................................... Appendix 3 Adverse events of special interest ................................................. Appendix 4 Summary of multi-state modeling in changes in SLICC/ACR damage index (SDI) .............................................................................................. Appendix 5 MITT and MITT Five Year Completer populations data tables ......

Table 1.01 Demographic and Baseline Characteristics .......................................... Table 1.02 Demographic and Baseline Characteristics .......................................... Table 1.03 Demographic and Baseline Characteristics, by SDI Baseline Category Table 1.04 Demographic and Baseline Characteristics, by baseline Proteinuria

(0.5g/24hr) ......................................................................... Table 1.05 Medical History ..................................................................................... Table 1.06 Race and Racial Combination Details .................................................. Table 1.07 Number of Subjects in each Subgroup ................................................. Table 1.08 Baseline Disease Activity ...................................................................... Table 1.09 Baseline Disease Activity ...................................................................... Table 1.10 Baseline Disease Activity, by SDI Baseline Category ........................... Table 1.11 Baseline Disease Activity, by Proteinuria (0.5g/24hr) .... Table 1.12 SLE Disease Duration and ACR Classification Criteria at Baseline ...... Table 1.13 SLE Disease Duration and ACR Classification Criteria at Baseline ...... Table 1.14 SELENA SLEDAI Organ and Item Involvement at Baseline ................. Table 1.15 BILAG Grade by Organ Domain at Baseline......................................... Table 1.16 Autoantibody Levels at Baseline ........................................................... Table 1.17 Baseline Immunoglobulin Levels .......................................................... Table 1.18 Baseline Levels of Complement and Other Biomarkers ....................... Table 1.18 Baseline Levels of Complement and Other Biomarkers*old* ................ Table 1.19 Subject Enrolment ................................................................................ Table 1.20 Enrolment by Site ................................................................................. Table 1.21 Subject Disposition ............................................................................... Table 1.22 Subject Completion Status by Study Year ............................................ Table 1.23 Summary of Vital Signs at Baseline ......................................................

586060606168687070717374767676778391

102134134137140

146152153155156161166176186189192195198201203207211212223225226

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CONFIDENTIAL 2015N265172_00201223

Table 1.24 Time to Withdrawal ............................................................................... Table 2.01 SLE Medication Use ............................................................................. Table 2.02 Corticosteroid, Anti-malarial and Immunosuppressant Use at Baseline Table 2.03 SLE Medication Change ....................................................................... Table 2.04 Study Drug Exposure ............................................................................ Table 2.05 Study Drug Exposure ............................................................................ Table 3.01 Total SDI Score by Year Interval .......................................................... Table 3.02 Total SDI Score by Year Interval .......................................................... Table 3.03 Total SDI Score by Year Interval .......................................................... Table 3.04 Change from Baseline in Total SDI Score by Year Interval .................. Table 3.05 Change from Baseline in Total SDI Score by Year Interval .................. Table 3.06 Change from Baseline in Total SDI Score, Baseline SDI Score=0 ....... Table 3.06 Change from Baseline in Total SDI Score, Baseline SDI Score>=1 ..... Table 3.07 Change from Baseline in Total SDI Score, Baseline

Proteinuria0.5g/24hr .............................................................................. Table 3.08 Change from baseline in Total SDI score by baseline Hypertension-

Yes........................................................................................................... Table 3.08 Change from baseline in Total SDI score by baseline Hypertension-No

................................................................................................................. Table 3.09 Change from baseline in Total SDI score by baseline Diabetes-Yes .... Table 3.09 Change from baseline in Total SDI score by baseline Diabetes-No ..... Table 3.10 Change from Baseline in Total SDI Score by Race-Asian .................... Table 3.10 Change from Baseline in Total SDI Score by Race-American Indian or

Alaska Native ........................................................................................... Table 3.10 Change from Baseline in Total SDI Score by Race-White .................... Table 3.10 Change from Baseline in Total SDI Score by Race-Black or African

American .................................................................................................. Table 3.11 Change from Baseline in Total SDI Score by Ethnicity-Hispanic or

Latino Origin ............................................................................................ Table 3.11 Change from Baseline in Total SDI Score by Ethnicity-Not Hispanic or

Latino Origin ............................................................................................ Table 3.12 Change from Baseline in Total SDI Score by Age Group =65 years .. Table 3.13 Change from Baseline in Total SDI Score by Gender - Female ............ Table 3.13 Change from Baseline in Total SDI Score by Gender - Male ................ Table 3.14 Change from Baseline in Total SDI Score, Baseline SELENA-SLEDAI

Score=10 ............................................................................................... Table 3.16 Change from Baseline in Total SDI Score by Baseline SLE Medication

Usage, Immunosuppressants: Yes .......................................................... Table 3.16 Change from Baseline in Total SDI Score by Baseline SLE Medication

Usage, Immunosuppressants: No ............................................................

227228232233235237238240242244246248250

252

254

256

258260262264

266268

270

272

274276278280282

284

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CONFIDENTIAL 2015N265172_00201223

Table 3.16 Change from Baseline in Total SDI Score by Baseline SLE Medication Usage, Anti-malarial: Yes ........................................................................

Table 3.16 Change from Baseline in Total SDI Score by Baseline SLE Medication Usage, Anti-malarial: No ..........................................................................

Table 3.16 Change from Baseline in Total SDI Score by Baseline SLE Medication Usage, Prednisone Dose Category: 0 ......................................................

Table 3.17 Predicted Probability of SDI/Death State in 5 Years Time by Current SDI State .................................................................................................

Table 3.18 Time to First SDI Worsening by Year Interval ....................................... Table 3.19 Multistate Transition Modelling: Covariate/ Factor Modelling

Progression from SDI=0 to SDI=1 ........................................................... Table 3.20 Multi-State Transition Modelling: Covariate/ Factor Modelling

Progression from SDI=1 to SDI>=2 ......................................................... Table 3.21 Summary of Change from Baseline in SDI Organ System SubScore

by Year .................................................................................................... Table 3.22 Summary of Change from Baseline in SDI Organ System SubScore

by Year .................................................................................................... Table 3.23 Total SDI Score by Year Interval - WOCF Analysis .............................. Table 3.24 Total SDI Score by Year Interval - WOCF Analysis .............................. Table 3.25 Change from Baseline in Total SDI Score by Year Interval - WOCF

Analysis ................................................................................................... Table 3.26 Change from Baseline in Total SDI Score by Year Interval - WOCF

Analysis ................................................................................................... Table 3.27 Change from Baseline in Total SDI Score by Baseline SLE Medication

Usage, Immunosuppressants: Yes .......................................................... Table 3.27 Change from Baseline in Total SDI Score by Baseline SLE Medication

Usage, Immunosuppressants: No ............................................................ Table 3.27 Change from Baseline in Total SDI Score by Baseline SLE Medication

Usage, Anti-malarial: Yes ........................................................................ Table 3.27 Changefrom Baseline in Total SDI Score by Baseline SLE Medication

Usage, Anti-malarial: No .......................................................................... Table 3.27 Change from Baseline in Total SDI Score by Baseline SLE Medication

Usage, Prednisone Dose Category: 0 ...................................................... Table 3.27 Change from Baseline in Total SDI Score by Baseline SLE Medication

Usage,Prednisone Dose Category: >0 to 7.5 to =1 ........ Table 3.30 Time to SDI Worsening by Year Interval and Baseline Disease

Duration ................................................................................................... Table 3.31 Change from Baseline (Observed Case) in SDI Total Score for

BEL110751 (BLISS-76) and BEL110752 (BLISS-52 ............................... Table 3.32 Change from Baseline in Total SDI Score to Withdrawal Visit .............. Table 4.01 Adverse Events Summary ....................................................................

292

294

296

302303

304

306

308

332356358

360

362

364

366

368

370

372

374

376378380381

382

384385386

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CONFIDENTIAL 2015N265172_00201223

Table 4.02 Adverse Events by SOC ....................................................................... Table 4.03 Serious Adverse Events, by SOC ......................................................... Table 4.04 Study Agent Related Adverse Events, by SOC .................................... Table 4.05 Adverse Events Resulting in Study Agent Discontinuation, by SOC ..... Table 4.06 Adverse Events Rates by SOC ............................................................. Table 4.07 Serious Adverse Event Rate, by SOC .................................................. Table 4.08 Study Agent Related Adverse Event Rate, by SOC .............................. Table 4.09 Adverse Events Resulting in Study Agent Discontinuation Rate, by

SOC ......................................................................................................... Table 4.10 Adverse Events by SOC and PT ........................................................... Table 4.11 Serious Adverse Events by SOC and PT ............................................. Table 4.12 Study Agent Related Adverse Events by SOC and PT ......................... Table 4.13 Adverse Events Resulting in Study Agent Discontinuation by SOC and

PT ............................................................................................................ Table 4.14 Deaths by SOC and PT ........................................................................ Table 4.15 Adverse Events by PT .......................................................................... Table 4.16 Serious Adverse Events by PT ............................................................. Table 4.17 Study Agent Related Adverse Events by PT ........................................ Table 4.18 Adverse Events Resulting in Study Agent Discontinuation by PT ......... Table 4.19 Adverse Events by SOC and Severity .................................................. Table 4.20 Relationship between System Organ Class and Verbatim Text ............ Table 4.21 Adverse Events of Special Interest by Category ................................... Table 4.22 Adverse Events of Special Interest Rate by Category .......................... Table 4.23 Malignant Neoplasm Adverse Events of Special Interest by Category

and PT ..................................................................................................... Table 4.24 Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events of

Special Interest by Category and PT ....................................................... Table 4.25 Serious Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse

Events of Special Interest by Category and PT ....................................... Table 4.26 Infection Adverse Events of Special Interest by Category and PT ........ Table 4.27 Serious Infection Adverse Events of Special Interest by Category and

PT ............................................................................................................ Table 4.28 Severe Infection Adverse Events of Special Interest by Category and

PT ............................................................................................................ Table 4.29 Serious/Severe Infection Adverse Events of Special Interest by

Category and PT ...................................................................................... Table 4.30 Infection Adverse Events of Special Interest Leading to

Discontinuation by Category and PT ....................................................... Table 4.31 Depression/Suicide/Self-injury Adverse Events of Special Interest by

Category and PT ...................................................................................... Table 4.32 Malignant Neoplasm Adverse Events of Special Interest Rate by

Category and PT ...................................................................................... Table 4.33 infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events of

Special Interest Rate by Category and PT ............................................... Table 4.34 Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events of

Special Interest Rate by Category and PT ...............................................

388392396400404408412

416420542576

612624628748776806812828

11211127

1131

1139

11451147

1153

1157

1159

1163

1165

1167

1179

1187

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CONFIDENTIAL 2015N265172_00201223

Table 4.35 Infection Adverse Events of Special Interest Rate by Category and PT Table 4.36 Serious Infection Adverse Events of Special Interest Rate by Category

and PT ..................................................................................................... Table 4.37 Severe Infection Adverse Events of Special Interest Rate by Category

and PT ..................................................................................................... Table 4.38 Serious/Severe Infection Adverse Events of Special Interest Rate by

Category and PT ...................................................................................... Table 4.39 Serious/Severe Infection Adverse Events of Special Interest Rate

Leading to Discontinuation by Category and PT ...................................... Table 4.40 Depression/Suicide/Self-injury Adverse Events of Special Interest

Rate by Category and PT ........................................................................ Table 4.41 Infection Adverse Events of Special Interest by Category .................... Table 4.42 Infection Adverse Events of Special Interest Rate by Category ............ Table 4.47 Worst Laboratory Toxicity Grade by Year Interval: Hematology ........... Table 4.48 Worst Laboratory Toxicity Grade by Year Interval: Liver Function ........ Table 4.49 Worst Laboratory Toxicity Grade by Year Interval: Electrolytes ............ Table 4.50 Worst Laboratory Toxicity Grade by Year Interval: Other Chemistries . Table 4.51 Worst Laboratory Toxicity Grade by Year Interval: Urinalysis ............... Table 4.52 Worst Laboratory Toxicity Grade by Year Interval: IgG ........................ Table 4.53 Laboratory Toxicity Grade Worsening of at Least 2 Grades from

Baseline: Hematology .............................................................................. Table 4.54 Laboratory Toxicity Grade Worsening of at Least 2 Grades from

Baseline: Liver Function ........................................................................... Table 4.55 Laboratory Toxicity Grade Worsening of at Least 2 Grades from

Baseline: Electrolytes ............................................................................... Table 4.56 Laboratory Toxicity Grade Worsening of at Least 2 Grades from

Baseline: Other Chemistries .................................................................... Table 4.57 Laboratory Toxicity Grade Worsening of at Least 2 Grades from

Baseline: Urinalysis.................................................................................. Table 4.58 Laboratory Toxicity Grade Worsening of at Least 2 Grades from

Baseline: IgG ........................................................................................... Table 4.59 IgG below the Lower Limit of Normal (LLN) during each Year Interval . Table 4.60 IgG below the Lower Limit of Normal (LLN) during each Year Interval

among Subjects with IgG>=LLN at Baseline ............................................ Table 4.61 Percentage Change [2] from Baseline in Proteinuria (P/C Ratio) ......... Table 4.62 Percentage Change [2] from Baseline in Proteinuria (P/C Ratio), ........ Table 4.62 Percentage Change [2] from Baseline in Proteinuria (P/C

Ratio),Baseline Proteinuria>0.5g/24hr ..................................................... Table 4.63 GSK Adjudicated Opportunistic Infections/Herpes Zoster Adverse

Events ...................................................................................................... Table 4.64 GSK Adjudicated Opportunistic Infections/Herpes Zoster Adverse

Events Rate ............................................................................................. Listing 1.01 Listing of All Fatal Adverse Events ...................................................... Listing 1.02 Listing of Subjects who did not take Study Drug ................................. Listing 1.03 Listing of Serious GSK Adjudicated Opportunistic Infections Adverse

Events ......................................................................................................

1189

1195

1199

1203

1207

120912111213121512191223122912331237

1239

1242

1244

1247

1249

12501251

125212531254

1254

1256

125812601263

1264

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CONFIDENTIAL 2015N265172_00201223

Figure 1.01 Time to First SDI Worsening ................................................................ Figure 1.02 Time to withdrawal ............................................................................... Figure 1.03 Time to First SDI Worsening by Baseline SDI Score ........................... Figure 1.04 Time to First SDI Worsening by Baseline Disease Duration ................

Appendix 6 High Disease Activity and High Disease Activity Five Year Completer subpopulations data tables ...............................................................

Table 1.101 Demographic and Baseline Characteristics ........................................ Table 1.102 Demographic and Baseline Characteristics ........................................ Table 1.103 Demographic and Baseline Characteristics, by SDI Baseline

Category: =0 ............................................................................................ Table 1.103 Demographic and Baseline Characteristics, by SDI Baseline

Category: >=1 .......................................................................................... Table 1.104 Demographic and Baseline Characteristics, by Baseline Proteinuria:

0.5g/24hr ............................................................................................... Table 1.105 Medical History ................................................................................... Table 1.106 Race and Racial Combination Details ................................................ Table 1.107 Number of Subjects in each Subgroup ............................................... Table 1.108 Baseline Disease Activity .................................................................... Table 1.109 Baseline Disease Activity .................................................................... Table 1.110 Baseline Disease Activity, by SDI Baseline Category: =0 ................... Table 1.110 Baseline Disease Activity, by SDI Baseline Category: >=1 ................. Table 1.111 Baseline Disease Activity, by Proteinuria: 0.5g/24hr ......................... Table 1.112 SLE Disease Duration and ACR Classification Criteria at Baseline .... Table 1.113 SLE Disease Duration and ACR Classification Criteria at Baseline .... Table 1.114 SELENA SLEDAI Organ and Item Involvement at Baseline ............... Table 1.115 BILAG Grade by Organ Domain at Baseline ....................................... Table 1.116 Autoantibody Levels at Baseline ......................................................... Table 1.117 Baseline Immunoglobulin Levels ........................................................ Table 1.118 Baseline Levels of Complement and Other Biomarkers ..................... Table 1.119 Subject Enrolment .............................................................................. Table 1.120 Enrolment by Site ............................................................................... Table 1.121 Subject Disposition ............................................................................. Table 1.122 Subject Completion Status by Study Year .......................................... Table 1.123 Summary of Vital Signs at Baseline .................................................... Table 1.124 Time to Withdrawal ............................................................................. Table 2.101 SLE Medication Use ........................................................................... Table 2.102 Corticosteroid, Anti-malarial and Immunosuppressant Use at

Baseline ................................................................................................... Table 2.103 SLE Medication Change ..................................................................... Table 2.104 Study Drug Exposure .......................................................................... Table 2.105 Study Drug Exposure .......................................................................... Table 3.101 Total SDI Score by Year Interval ........................................................ Table 3.102 Total SDI Score by Year Interval ........................................................

1266126712681269

127012701273

1276

1279

1282

128512881289129112921296130013041308131213161319132213261329133213341338133913481349135013511352

135813591361136313641366

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CONFIDENTIAL 2015N265172_00201223

Table 3.103 Total SDI Score by Year Interval ........................................................ Table 3.104 Change from Baseline in Total SDI Score by Year Interval ................ Table 3.105 Change from Baseline in Total SDI Score by Year Interval ................ Table 3.106 Change from Baseline in Total SDI Score, Baseline SDI Score=0 ..... Table 3.106 Change from Baseline in Total SDI Score, Baseline SDI Score>=1 ... Table 3.107 Change from Baseline in Total SDI Score, Baseline Proteinuria

0.5g/24hr ............................................................................................... Table 3.108 Change from baseline in Total SDI score by baseline Hypertension-

Yes........................................................................................................... Table 3.108 Change from baseline in Total SDI score by baseline Hypertension-

No ............................................................................................................ Table 3.109 Change from baseline in Total SDI score by baseline Diabetes - Yes Table 3.109 Change from baseline in Total SDI score by baseline Diabetes - No . Table 3.110 Change from Baseline in Total SDI Score by Race-BLACK OR

AFRICAN AMERICAN ............................................................................. Table 3.110 Change from baseline in Total SDI score by Race-AMERICAN

INDIAN OR ALASKA NATIVE ................................................................. Table 3.110 Change from Baseline in Total SDI Score by Race-ASIAN ................ Table 3.110 Change from Baseline in Total SDI Score by Race-WHITE................ Table 3.111 Change from Baseline in Total SDI Score by Ethnicity-Hispanic or

Latino Origin ............................................................................................ Table 3.111 Change from Baseline in Total SDI Score by Ethnicity-Not Hispanic

or Latino Origin ........................................................................................ Table 3.112 Change from Baseline in Total SDI Score by Age Group =65 Years Table 3.113 Change from Baseline in Total SDI Score by Gender - Female .......... Table 3.113 Change from Baseline in Total SDI Score by Gender - Male .............. Table 3.114 Change from Baseline in Total SDI Score, Baseline SELENA-

SLEDAI Score>=10.................................................................................. Table 3.114 Change from Baseline in Total SDI Score, Baseline SELENA-

SLEDAI Score

Table 3.119 Multi-State Transition Modelling: Covariate/ Factor Modelling Progression from SDI=0 to SDI=1 ...........................................................

Table 3.120ate Transition Modelling: Covariate/ Factor Modelling Progression from SDI=1 to SDI >=2 ............................................................................

Table 3.121 Summary of Change from Baseline in SDI Organ System SubScore by Year ....................................................................................................

Table 3.122 Summary of Change from Baseline in SDI Organ System SubScore by Year ....................................................................................................

Table 3.123 Total SDI Score by Year Interval - WOCF Analysis ............................ Table 3.124 Total SDI Score by Year Interval - WOCF Analysis ............................ Table 3.125 Change from Baseline in Total SDI Score by Year Interval - WOCF

Analysis ................................................................................................... Table 3.126 Change from Baseline in Total SDI Score by Year Interval - WOCF

Analysis ................................................................................................... Table 3.127 Time to SDI Worsening by Year Interval - WOCF Analysis ................ Table 3.128 Summary of Change from Baseline in SDI Organ System SubScore

by Year - WOCF Analysis ........................................................................ Table 3.129 Time to SDI Worsening by Year Interval, Baseline SDI Score=0 ........ Table 3.129 Time to SDI Worsening by Year Interval, Baseline SDI Score>=1 ...... Table 4.101 Adverse Events Summary .................................................................. Table 4.102 Adverse Events by SOC ..................................................................... Table 4.103 Serious Adverse Events, by SOC ....................................................... Table 4.104 Study Agent Related Adverse Events, by SOC .................................. Table 4.105 Adverse Events Resulting in Study Agent Discontinuation, by SOC ... Table 4.106 Adverse Events Rates by SOC ........................................................... Table 4.107 Serious Adverse Event Rate, by SOC ................................................ Table 4.108 Study Agent Related Adverse Event Rate, by SOC ............................ Table 4.109 Adverse Events Resulting in Study Agent Discontinuation Rate, by

SOC ......................................................................................................... Table 4.110 Adverse Events by SOC and PT ......................................................... Table 4.111 Serious Adverse Events by SOC and PT ........................................... Table 4.112 Study Agent Related Adverse Events by SOC and PT ....................... Table 4.113 Adverse Events Resulting in Study Agent Discontinuation by SOC

and PT ..................................................................................................... Table 4.114 Deaths by SOC and PT ...................................................................... Table 4.115 Adverse Events by PT ........................................................................ Table 4.116 Serious Adverse Events by PT ........................................................... Table 4.117 Study Agent Related Adverse Events by PT ....................................... Table 4.118 Adverse Events Resulting in Study Agent Discontinuation by PT ....... Table 4.119 Adverse Events by SOC and Severity ................................................ Table 4.120 Relationship between System Organ Class and Verbatim Text .......... Table 4.121 Adverse Events of Special Interest by Category ................................. Table 4.122 Adverse Events of Special Interest Rate by Category ........................ Table 4.123 Malignant Neoplasm Adverse Events of Special Interest by Category

and PT .....................................................................................................

1430

1432

1434

145814821484

1486

14881490

14911515151615171519152315251527152815321536

1540154416011623

1636164016441694170217131715172918731879

1883

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CONFIDENTIAL 2015N265172_00201223

Table 4.124 Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events of Special Interest by Category and PT .......................................................

Table 4.125 Serious Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events of Special Interest by Category and PT .......................................

Table 4.126 Infection Adverse Events of Special Interest by Category and PT ...... Table 4.127 Serious Infection Adverse Events of Special Interest by Category and

PT ............................................................................................................ Table 4.128 Severe Infection Adverse Events of Special Interest by Category and

PT ............................................................................................................ Table 4.129 Serious/Severe Infection Adverse Events of Special Interest by

Category and PT ...................................................................................... Table 4.130 Infection Adverse Events of Special Interest Leading to

Discontinuation by Category and PT ....................................................... Table 4.131 Depression/Suicide/Self-injury Adverse Events of Special Interest by

Category and PT ...................................................................................... Table 4.132 Malignant Neoplasm Adverse Events of Special Interest Rate by

Category and PT ...................................................................................... Table 4.133 Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events of

Special Interest Rate................................................................................ Table 4.134 Infusion/Anaphylaxis/Hypersensitivity Reaction Adverse Events of

Special Interest Rate by Category and PT ............................................... Table 4.135 Infection Adverse Events of Special Interest Rate by Category and

PT ............................................................................................................ Table 4.136 Serious Infection Adverse Events of Special Interest Rate by

Category and PT ...................................................................................... Table 4.137 Severe Infection Adverse Events of Special Interest Rate by

Category and PT ...................................................................................... Table 4.138 Serious/Severe Infection Adverse Events of Special Interest Rate by

Category and PT ...................................................................................... Table 4.139 Infection Adverse Events of Special Interest Rate Leading to

Discontinuation by Category and PT ....................................................... Table 4.140 Depression/Suicide/Self-injury Adverse Events of Special Interest

Rate by Category and PT ........................................................................ Table 4.141 Infection Adverse Events of Special Interest by Category .................. Table 4.142 Infection Adverse Events of Special Interest Rate by Category .......... Table 4.147 Worst Laboratory Toxicity Grade by Year Interval: Hematology ......... Table 4.148 Worst Laboratory Toxicity Grade by Year Interval: Liver Function ...... Table 4.149 Worst Laboratory Toxicity Grade by Year Interval: Electrolytes .......... Table 4.150 Worst Laboratory Toxicity Grade by Year Interval: Other Chemistries Table 4.151 Worst Laboratory Toxicity Grade by Year Interval: Urinalysis ............. Table 4.152 Worst Laboratory Toxicity Grade by Year Interval: IgG ...................... Table 4.153 Laboratory Toxicity Grade Worsening of at Least 2 Grades from

Baseline: Hematology .............................................................................. Table 4.154 Laboratory Toxicity Grade Worsening of at Least 2 Grades from

Baseline: Liver Function ...........................................................................

1887

18911893

1899

1903

1905

1909

1911

1913

1917

1923

1925

1931

1935

1939

1943

194519471949195119551959196519691973

1975

1978

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CONFIDENTIAL 2015N265172_00201223

Table 4.155 Laboratory Toxicity Grade Worsening of at Least 2 Grades from Baseline: Electrolytes ...............................................................................

Table 4.156 Laboratory Toxicity Grade Worsening of at Least 2 Grades from Baseline: Other Chemistries ....................................................................

Table 4.157 Laboratory Toxicity Grade Worsening of at Least 2 Grades from Baseline: Urinalysis..................................................................................

Table 4.158 Laboratory Toxicity Grade Worsening of at Least 2 Grades from Baseline: IgG ...........................................................................................

Table 4.159 IgG below the Lower Limit of Normal (LLN) during each Year Interval Table 4.160 IgG below the Lower Limit of Normal (LLN) during each Year Interval

among Subjects with IgG>=LLN at Baseline ............................................ Table 4.161 Percentage Change [2] from Baseline in Proteinuria (P/C Ratio) ....... Table 4.162 Percentage Change [2] from Baseline in Proteinuria (P/C Ratio)by

Baseline Proteinuria:

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ABBREVIATIONS

ACR American College of RheumatologyAE Adverse eventALT Alanine transaminaseANA Anti-nuclear antibodyAST Aspartate transaminaseaCL Anti-cardiolipinBILAGBLySBMIBP

British Isles Lupus Assessment GroupB lymphocyte Stimulation factorBody mass indexBlood pressure

C Complement CRP C-reactive proteinCIdsDNA

Confidence intervaldouble-stranded DNA

eCRF Electronic case report formEUGI

European UnionGastrointestinal

GCSP Global Clinical Safety & PharmacovigilanceGGT Gamma-glutamyl transferaseGSKHDhpf

GlaxoSmithKlineHigh diseasehigh power field

IgG Immunoglobulin GIQR Inter quartile rangeIV intravenousLLNLLOQ

Lower limit of normalLower limit of quantitation

MedDRA Medical Dictionary for Regulatory ActivitiesMITT Modified intent-to-treatMSM Multi-State Modelmsm Multi-state modeling procedure in RNMSC Non-Malignant Skin CancerPGAPT

Physician’s Global AssessmentProthrombin time

RAPRBC

Reporting and Analysis PlanRed blood cell

SAESC

Serious adverse eventSubcutaneous

SD Standard deviationSDI SLICC/ACR Damage IndexSELENA Safety of Estrogen in Lupus National AssessmentSLE Systemic Lupus ErythematosusSLEDAI Systemic Lupus Erythematosus Disease Activity IndexSLICC Systemic Lupus International Collaborating ClinicsSMQ Standardized MedDRA Query

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SoC Standard lupus careULNWOCF

Upper limit of normalWorst observation carried forward

Trademark Information

Trademarks of the GlaxoSmithKline group of companies

Trademarks not owned by the GlaxoSmithKline group of companies

BENLYSTA SAS

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1. INTRODUCTION

The efficacy and safety of belimumab in systemic lupus erythematosus (SLE) was demonstrated in two large, multicenter, Phase 3 trials, BLISS-76 (BEL110751,formerly HSG1006-C1056; NCT00410384) [Furie R et al. 2011] and BLISS-52 (BEL110752, formerly HGS1006-C1057; NCT00424476) [Navarra SV et al. 2011], which spanned 76 and 52 weeks, respectively. Organ damage, a predictor of future mortality, occurs over a longer time period in most patients with SLE compared with the period studied in the BLISS trials [Sutton EJ et al. 2013, Rahman P et al. 2001]. Therefore, we conducted a pooled analysis of long-term data from continuation trials of the BLISS-76 and BLISS-52 trials to examine long-term safety and organ damage following 5 years of belimumab exposure (201223).

BEL112233 (formerly HGS1006-C1066; NCT00724867) is a continuation trial of belimumab plus standard lupus care (SoC) in patients with SLE who completed BEL110751 in the USA; patients were randomized (1:1:1 ratio) to receive belimumab 1 mg/kg, belimumab 10 mg/kg or placebo (SoC) for 76 weeks.

BEL112234 (formerly HGS1006-C1074; NCT00712933) is an ongoing continuation trial of belimumab plus SoC in patients with SLE who completed BEL110751 or BEL110752 protocols in countries other than the USA. It also includes five patients from a single site in Mexico who completed BEL112232 (NCT00732940), an open-label Phase 2 study. BEL110752 patients were randomized (1:1:1 ratio) to intravenous (IV) infusion belimumab 1 mg/kg, belimumab 10 kg/mg or placebo for 52 weeks. BEL112232 patients were randomized to receive 100 mg of belimumab (one subcutaneous [SC] injection) on Days 0, 7, 14, and then every 2 weeks thereafter or 200 mg of belimumab (two SCinjections of 100 mg each) on Days 0, 2, and 4 and then 100 mg (one SC injection) three times per week thereafter.

BEL112233 and BEL112234 have similar study designs; patients received open-label belimumab plus SoC every 4 weeks. However, because the dosing regimen in BEL112232 was different to the 4-weekly IV mg/kg regimens in BEL117051, BEL117052, BEL112233 and BEL112234, and because no Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) assessments were performed, the five patients in BEL112234 whose parent study was BEL112232 were excluded from the 201223 pooled analysis.

The purpose of this interim report is to pool the BEL110751, BEL110752, BEL112233 and BEL112234 data over 5 years, using a data cut-off point of February 14, 2014, to examine the changes in SDI score and assess the long-term safety of belimumab in patients with SLE.

2. OBJECTIVES

2.1. Safety Objective

Safety data from BEL110751, BEL110752, BEL112233 and BEL112234 were pooled toassess the safety of long-term belimumab exposure.

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2.2. Primary Analysis

The primary analysis was change in SDI from baseline (defined as the visit prior to first dose of belimumab) at the 5–6-year interval of belimumab treatment.

2.3. Key Secondary Analyses

The key secondary analyses were time to first SDI worsening and SDI transition analysis.

2.4. Other Secondary Analyses

Other secondary analyses included change from baseline in SDI score for subgroups, secondary transition modeling, total SDI score, and change from baseline in SDI organ damage system.

3. INVESTIGATIONAL PLAN

3.1. Design

This was an interim analysis of pooled data from two ongoing, open-label, long-term, continuation studies, BEL112233 and BEL112234 (Figure 1).

3.1.1. BEL112233

BEL112233 is a multicenter, long-term continuation study of belimumab plus SoC in patients with SLE who completed BEL110751 in the US. In the study, BEL110751, adult patients were randomized (1:1:1 ratio) to receive belimumab 1 mg/kg, belimumab 10 mg/kg or placebo at Weeks 0, 2, and 4, then every 4 weeks for 76 weeks. On entering BEL112233, patients who had received placebo were switched to receive belimumab 10 mg/kg and, following a protocol amendment, those who had received belimumab 1 mg/kg went on to receive the 10 mg/kg dose.

3.1.2. BEL112234

BEL112234 is a multicenter, long-term continuation study of belimumab plus SoC in patients with SLE who completed BEL110751, or BEL110752, in countries other than the US (and five patients from a single site in Mexico who completed BEL112232, an open-label Phase 2 study, but who were excluded from this analysis due to an incomparable dosing regimen). BEL110752 patients were randomized (1:1:1 ratio) to receive belimumab 1 mg/kg, belimumab 10 mg/kg or placebo at Weeks 0, 2, and 4, then every 4 weeks for 52 weeks. On entering BEL112234, patients who had received placebo were switched to belimumab 10 mg/kg and, following a protocol amendment, those who had received belimumab 1 mg/kg received the 10 mg/kg dose.

3.1.3. Key Differences Between BEL112233 and BEL112234 Protocols

BEL112233 enrolled US patients; BEL112234 enrolled non-US patients.

A larger number of assessments were conducted in BEL112233; only SDI and safety were assessed in BEL112234.

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Concomitant medications were recorded in BEL112233, with detailed dosing information. In BEL112234 the investigator was required to indicate if a patient was taking selected medications but did not collect dosing information. The exception was patients who were taking prednisone or other corticosteroids, for whom the investigator was asked to indicate if the patient was taking ≤ 7.5 mg, >7.5 mg to ≤40 mg, or >40 mg prednisone equivalent.

Figure 1 Study Schematic for Parent and Long-Term Extension Studies

3.2. Selection of Populations

All patients who enrolled in BEL112233 or BEL112234 (with the exception of the five BEL112232 patients), were included in this analysis. The inclusion and exclusion criteria were the same in both BEL112233 and BEL112234 and are described in the study protocols (Clinical Protocol HGS1006-C1066 and Clinical Protocol HGS1006-C1074). Patients who successfully completed the parent studies were invited to take part in an extension study.

3.3. Treatments

On entering BEL112233 or BEL112234, patients who had received placebo in the parent studies were switched to receive open-label belimumab 10 mg/kg plus SoC. The protocols initially included patients receiving belimumab 1 mg/kg and 10 mg/kg but following a protocol amendment (Dated: March 09, 2011 in BEL112233 and July 29, 2011 in BEL112234) all patients were prescribed belimumab 10 mg/kg. Patients who initially received belimumab 1 mg/kg were pooled with patients who received belimumab 10 mg/kg for the purpose of the GSK 201223 analysis.

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3.4. Study Assessments

Following finalization of the Reporting and Analysis Plan (RAP) (7 April 2014) and the RAP errata (13 May 2014) some deviations were identified in the study analyses. These are summarized in Appendix 1.

Baseline for patients who were randomized to placebo in the parent study was the last assessment prior to receiving belimumab in either study BEL112233 or BEL112234. For most assessments, this was the data collected at the start of the extension study, but for those assessments that are missing at the extension baseline or were only collected in the parent study, these values were the final assessment in the parent study. For patients who were randomized to belimumab in the parent study, the baseline values were the last assessment prior to receiving belimumab in the parent study. For most assessments this was the assessment conducted at the baseline visit, but it may be the screening visit if the baseline assessment was missing (or if the assessment was only scheduled to be performed at screening).

Patients who did not continue into an extension study were not included in this analysis.

Visit intervals were defined using the patient’s actual visit dates. The intervals were based on the 52-week SDI assessment in the parent studies and the 48-week protocol years in BEL112233/BEL112234. SDI, adverse events (AEs) and laboratory assessments are reported using the same intervals. As the intervals are patient-specific they do not align perfectly to calendar years, and there is some overlap in the range of study days in each interval. For example, an AE starting on Day 363 may be assigned to Year 0–1 or Year 1–2; depending upon whether the patient’s end of year visit (as shown in Figure 2) occurred before or after Day 363 (target date for end of year visit was Day 365, but it may have occurred a few days earlier of later).

Last study visit was at data cut off for ongoing patients and defined in the following hierarchical order for other patients: (1) exit visit, (2) death date, (3) later of discontinuation date and treatment end date and (4) date of baseline visit (for non-modified intent-to-treat [MITT] patients who withdrew without an exit visit).

3.4.1. SDI Total Score

SDI total score is the sum of the individual items on the SDI questionnaire [American College of Rheumatology, 2015a].

SDI assessments were conducted yearly (every 48 weeks) in studies BEL112233 and BEL112234. SDI assessments in the parent studies were conducted at baseline, Day 364 and Day 532/study exit in BEL110751, and at baseline, Day 364/study exit in BEL110752. In the continuation studies BEL112233 and BEL112234, annual SDIassessments were conducted every 48 weeks, therefore, there is a small discrepancy between calendar years and true years of belimumab exposure. As such, visit intervals were defined using the patient’s actual visit dates. The intervals were based on the 52-week SDI assessment in the parent studies and the 48-week protocol years in BEL112233 and BEL112234. SDI, adverse events (AEs) and laboratory assessments are reported using the same intervals (Figure 2 and RAP Table 1).

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3.4.2. BILAG Scores

British Isles Lupus Assessment Group (BILAG) domain involvement score was defined as previously described [Isenberg and Gordon, 2000]. The BILAG [Yee, 2008] was programmed to be consistent with the algorithm used in the parent studies BEL110751 and BEL110752 (see BEL110751 and BEL110752 Clinical Study Reports). BILAG scores were collected in BEL112233, BEL110751 and BEL110752 but not in BEL112234.

3.4.3. Daily Prednisone Dose Equivalent

All corticosteroid dosages were converted to a prednisone equivalent in milligrams according to the conversion factors described in the parent studies.

Figure 2 Mapping of SDI Study Assessments to Visit Intervals

3.4.4. SELENA SLEDAI

Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is a weighted index in which signs and symptoms, laboratory tests, and physician’s assessment for nine organ systems are given a weighted score and summed if present at the time of the visit or in the preceding 10 days [American College of Rheumatology, 2015b]. To ensure consistency with the parent studies, a modified version of the SELENA-SLEDAI score was used (Appendix 1). Safety of Estrogen in Lupus National Assessment (SELENA) SLEDAI was collected in BEL112233, BEL110751 and BEL110752 but not in BEL112234.

In a deviation from the RAP, SLEDAI-2K was not reported (Appendix 1).

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3.4.5. Medical History/Medical Classification

All unique medical history terms from BEL110751, BEL110752, BEL112233, and BEL112234 were reviewed by a GSK medical reviewer to identify the terms used to classify patients as having a history of hypertension or diabetes. AE data from BEL110751 and BEL110752 were reviewed to identify placebo-treated patients with a diagnosis of diabetes or hypertension prior to commencing belimumab treatment. Prior and concomitant terms from BEL112233 and BEL112234 were reviewed by a GSK medical reviewer to identify terms that were classified as corticosteroids, anti-malarial, or immunosuppressant medications. The classification of prior and concomitant terms into corticosteroids, anti-malarial, or immunosuppressant medications had previously been completed for BEL110751 and BEL110752 (Appendix 1).

3.4.6. Clinical Laboratory Evaluations

Appendix 7 and Appendix 8 of BEL112233 Protocol and Appendix 2 of BEL112234 Protocol describe the laboratory parameters tested and define the toxicity grades used.

Laboratory toxicity was graded using Adverse Event Severity Grading Tables (Appendix 2) when possible. The worst laboratory toxicity grades during each treatment year and during the ‘anytime post-baseline’ period for each laboratory parameter within each laboratory category (hematology, liver function, electrolytes, other chemistries, urinalysis, and immunoglobulins [Ig]) are presented.

3.5. Statistical Analyses

All data summaries were performed using the latest available version of SAS software. The Multi-State Modeling (MSM) was performed using the multi-state modeling procedure (msm) in R v3.1.0.

Unless otherwise stated, continuous variables were summarized with the statistics mean, median, standard deviation (SD), 25th and 75th percentiles, minimum and maximum. Categorical variables were summarized with frequency counts and percentages. A ‘missing’ category was added to frequency counts if there was at least one missing record. Percentages were calculated using the number of non-missing observations as the denominator.

As this is an interim analysis pre-specified data listings were restricted to listings of deaths and patients who did not receive a dose of study medication.

3.5.1. Data Quality Issues

Data Management endeavored to clean all data required in this reporting effort but some queries remained open at the time of database release; these included a small number ofSDI-related queries. Forty AEs were uncoded at database release; all were subsequently coded by the dictionaries group.

During the reporting of this study several data issues were identified. Where appropriate the statistical analysis was adjusted or extended to minimize their impact. For example,

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according to the inclusion criteria, patients were eligible for inclusion in the continuationstudy if they were able to receive their first dose of belimumab in the continuation studywithin 4 weeks of their last dose in the parent study; as a number of patients had a longer than expected interval between studies, the exposure associated with the gap was removed from the AE patient-year calculation. Worst observation carried forward (WOCF) analyses were performed to assess the impact of decreases in SDI item level scores. Amendments to the planned analyses are documented in Appendix 1.

Some inconsistencies in AEs leading to withdrawal were noted: Table 4.01 (Adverse events summary; Appendix 5) shows 88 patients had an AE leading to discontinuation while Table 1.22 (Completion status, Appendix 5) shows 85 patients had a withdrawal due to an AE. Three patients recorded their reason for withdrawal as other (on the withdrawals page) but on the AE page had recorded an AE that led to withdrawal. Further investigation by data management indicated that these three patients had a dose interruption due to an AE not a withdrawal due to an AE. There were two further compensating mismatches: one patient had an AE leading to withdrawal recorded on the AE dataset but withdrew due to investigator decision.

As detailed in Section 4.2.3 three patients who died during the study were recorded as having withdrawn due to ‘other’ reasons on the electronic case report form (eCRF). These patients are included in Table 1.22 (Appendix 5) as having withdrawn due to ‘other’ reasons and are not included in Table 4.01 (Appendix 5) as having an AE leading to withdrawal.

Six patients had an SDI assessment after their last on study visit; these are not included in the SDI analysis.

Where possible these anomalies will be queried for final reporting.

3.5.2. Analysis Populations

3.5.2.1. Modified Intent-to-Treat Population

The modified intent-to-treat (MITT) population was defined as all patients (except those from BEL112232) who were enrolled in BEL112233 or BEL112234 and received at least one dose of belimumab in either of these studies.

3.5.2.2. MITT Five Year Completer Population

The MITT Five Year Completer population was defined as those patients who were in the MITT population and had also completed a SDI assessment after 5 calendar years (1825 days) of belimumab exposure.

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3.5.2.3. High Disease Activity Population

The High Disease Activity (seriologically active) population was defined as all patients in the MITT population with low complement (C)3 (

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3.5.4.1. Extent of Exposure

Summary statistics (n, mean, median, 25th, 75th percentiles, minimum and maximum) were analyzed for the duration of exposure to belimumab and the total number of infusions.

3.5.4.2. Adverse Events

AE incidences are summarized by the number and percent of patients with at least one AE, treatment-related AE, serious AE (SAE), severe AE, serious and/or severe AE, AE resulting in study agent discontinuation, and deaths. AE rate was calculated as the number of events per 100 patient years.

AEs are presented by Medical Dictionary for Regulatory Activities (MedDRA v16.1) system organ classes in descending order from the system organ class with the highest ‘any time post-baseline’ incidence/rate for any AE within the class, to the system organ class with the lowest ‘any time post-baseline’ incidence/rate. AEs adjudicated by GSK (Appendix 3) were adjudicated at GSK at the time of reporting and may change as further information becomes available.

AEs that occurred on the same day as the first infusion were considered to be on treatment. AEs spanning more than one study year interval were recorded in the year in which they began. In a change from the RAP, the time period between parent and extension studies was not included in the patient years calculation for AEs, to ensure the reporting period for AEs was not overestimated (Appendix 1).

3.5.4.3. Adverse Events/Outcomes of Special Interest

AEs/outcomes of special interest (malignant neoplasms, infusion/anaphylaxis/hypersensitivity reactions, all infections, depression/suicide/self-injury, and death) were defined as described in Appendix 3. The number and percentage of patients with at least one occurrence of an AE/outcome of special interest is provided.

3.5.4.4. Serious/Severe Infections

The number and percentage of patients with Investigator-identified serious/severe infections are presented.

3.5.4.5. Clinical Laboratory Evaluations

Worst laboratory toxicity since baseline within the following laboratory categories is presented: hematology, liver function, electrolytes, other chemistries, urinalysis and Ig(graded using Adverse Event Severity Grading Tables when possible).

Toxicity grade shifts from baseline of ≥2 grades during each treatment year interval and during the entire post-baseline period for each laboratory parameter within each laboratory category (hematology, liver function, electrolytes, other chemistries, urinalysis and Ig) are summarized.

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The number and percentage of patients with IgG values below the lower limit of normal (LLN) at any time during each year interval is presented for all patients and for patients above LLN at baseline.

Summary statistics are presented for the percentage change from baseline in proteinuria for all patients, for patients whose baseline proteinuria was ≤0.5 g/24 h and those whose baseline proteinuria was >0.5 g/24 h. Proteinuria was not collected in BEL112234 therefore these summaries only include BEL12233 patients.

3.5.5. Primary Analysis

The primary measure was change in SDI from baseline to the 5–6-year interval of belimumab treatment for the MITT population. This analysis was also performed for the MITT Five Year Completer, High Disease Activity and High Disease Activity Five Year Completer populations.

SDI scores increase over time; once a patient meets the criteria for positive scoring an item that item should always be marked as present, even if the patient subsequently recovered. Due to incorrect scoring, the locked study databases contain 35 patients with a decrease in SDI score since baseline. These patients were excluded from all SDI analyses. A post hoc sensitivity analysis was performed in which all patients were included and the highest item level SDI score was carried forward to subsequent assessments (WOCF).

3.5.6. Secondary Analyses

3.5.6.1. Time to First SDI Worsening

Time to first SDI worsening was summarized in a Kaplan–Meier plot. The number at riskat the start of each year interval was the number of non-censored patients who had not reported a worsening by the end of the previous year interval. The number censored was the number of patients censored by the end of the study year interval.

Patients who withdrew/completed prior to their first SDI worsening were censored at their final SDI assessment date prior to study exit/data cut-off. As a deviation from theRAP, patients who were ongoing in the study were censored at their last SDI assessment date (Appendix 1). Patients who withdrew prior to having a post-baseline SDI assessment were censored at treatment start date. Patients who had a decrease in SDI or who did not have a baseline SDI value were not included in the analysis.

3.5.6.2. Transition Analysis

Transition analyses are described in detail in Appendix 4.

Review of the SDI changes indicated that approximately 90% of patients had a baseline SDI score of 0, 1, or 2 and that the majority of patients reported a transition of

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The MSM included MITT patients who did not have a SDI decrease and who had at least two SDI assessments, or one SDI assessment and died. A MSM was fitted to total SDI score or death category at each visit and predicted probabilities of SDI or death category in 5 years’ time were estimated. The MSM was fitted using the msm procedure in R [Jackson C 2011, Bruce R et al. 2014].

3.5.6.3. Change from Baseline in SDI Score Subgroup Analyses

Change from baseline in SDI total score was summarized by year interval (MITT and High Disease Activity populations) for the following subgroups: baseline SDI score (0, ≥1), baseline proteinuria (≤0.5 g/24 h, >0.5 g/24 h), baseline hypertension, baseline diabetes, race, ethnicity, age group (7.5 mg to ≤40 mg prednisone equivalent, >40 mg prednisone equivalent).

3.5.6.4. Secondary Transition Modeling

Transition analyses are described in detail in Appendix 4. A MSM was fitted to total SDI score at each visit adjusted for the following covariates/factors of interest: gender, age, age at diagnosis (added post RAP), race, Hispanic, number of ACR criteria fulfilled at baseline, SELENA-SLEDAI at baseline (added post RAP), corticosteroid use at baseline, anti-malarial use at baseline, immunosuppressant use at baseline, anti-malarial and immunosuppressant use at baseline, baseline diabetes, baseline hypertension, anti dsDNA ≥30 IU/m at baseline, low C3/C4 at baseline, and aCL baseline. Covariates/factors were fitted into the model individually and then evaluated together. Any covariate/factor that failed to converge was removed from the model.

3.5.6.5. Total SDI Score

Total SDI score was summarized by year interval for the MITT, MITT Five Year Completer, High Disease Activity and High Disease Activity Five Year Completer populations. Additionally, total SDI score at withdrawal was summarized for patients who withdrew from the study prior to Year 5.

3.5.6.6. SDI Organ Damage

Change from baseline in SDI organ damage system (ocular, neuropsychiatric, renal, pulmonary, cardiovascular, peripheral vascular, gastrointestinal [GI], musculoskeletal, skin, premature gonadal failure, diabetes and malignancy) was summarized by year interval for the MITT, MITT Five Year Completer, High Disease Activity and High Disease Activity Completer populations.

3.5.7. Post Hoc Analyses

Post hoc analyses included:

Time to first SDI worsening by baseline SDI Time to first SDI worsening by baseline disease duration

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WOCF sensitivity analysis of patients excluded from SDI analyses due to a reported decrease in SDI

A sensitivity analysis of change in SDI from baseline among patients who withdrew and had an SDI assessment on day of withdrawal

A sensitivity analysis of change in SDI from baseline in patients who had a fatal AE

Number (%) of patients with a >50% decrease from baseline in protein:creatinine ratio

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4. RESULTS

4.1. Summary of Population

The number of patients recruited from each of the parent studies and enrolled in each of the continuation studies is shown in Figure 3. Three patients entered study BEL112234 but received no study medication, so were excluded from the MITT population. Therefore, a total of 998 patients were included in this interim analysis.

Figure 3 Summary of Patients Recruited to 201223 Analysis

aPatient numbers at data cut-off; bincludes 3 patients who died; cincludes 11 patients who had an exit visit but whose completion status was unknown at data cut-off. Ten of these patients were subsequently recorded as completing the study; one withdrew due to investigator decision.

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AE, adverse event; MITT, modified intent-to-treat; SDI, Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index

4.2. Patient Demographics

Of the 998 patients included in the MITT population, 392 patients were included in the MITT Five Year Completer population and 493 were included in the High Disease population. The demographic characteristics of these populations are shown in Table 1and the demographics of the High Disease Activity Five Year Completer (N=185) population are shown in Appendix 6 (Data Table 1.102). The majority of patients in the MITT and MITT Five Year Completer populations were female (94.2% and 93.1%, respectively) and had a mean age of 38.7 years and 39.6 years, respectively. The MITT and High Disease Activity populations were generally similar; however, patients in the High Disease Activity subpopulation were slightly younger, mean age (SD) 35.4 (10.54) years compared with 38.7 (11.49) years for the MITT population and had a slightly lower mean weight (SD), 63.38 (14.578) kg compared with 67.08 (17.534) kg for the MITT population.

Table 1 Baseline Demographic Characteristics of the MITT, MITT Five Year Completer and High Disease Activity Populations

MITT (N=998)

MITT Five Year Completer (N=392)

High Disease Activity (N=493)

Sex, n (%)Female

Male940 (94.2)

58 (5.8)365 (93.1)27 (6.9)

469 (95.1)24 (4.9)

Hispanic or Latino origin, n (%)No

Yes636 (63.7)362 (36.3)

223 (56.9)169 (43.1)

316 (64.1)177 (35.9)

Age, mean (SD) years 38.7 (11.49) 39.6 (10.50) 35.4 (10.54)Height, mean (SD) cm 161.45 (8.012) 160.88 (7.922) 161.46 (7.617)Weight, mean (SD) kg 67.08 (17.534) 67.28 (17.945) 63.38 (14.578)BMI, mean (SD) kg/m2 25.65 (5.970) 25.93 (6.269) 24.26 (5.069)Systolic BP, mean (SD) mmHg 118.6 (15.45) N/A 117.5 (14.79)Diastolic BP, mean (SD) mmHg 75.6 (10.24) N/A 75.6 (10.69)Medical history, n (%)

HypertensionProteinuria >0.5 g/24 h

Diabetes

291 (29.2)169 (16.9)

40 (4.0)

N/A 124 (25.2)103 (20.9)

7 (1.4)Source: Data Table 1.01, Table 1.02, Table 1.05, Table 1.23 (Appendix 5) and Table 1.101, Table 1.105, Table 1.123(Appendix 6)BMI, body mass index; BP, blood pressure; MITT, modified intent-to-treat; N/A, not available;SD, standard deviation

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4.2.1. Baseline Disease Characteristics

The baseline disease characteristics of the MITT, MITT Five Year Completer and High Disease populations are shown in Table 2 and Table 3. The MITT and MITT Five Year Completer populations had a mean (SD) baseline SDI of 0.7 (1.19) and 0.7 (1.13), respectively, and approximately 40% of patients in both populations had organ damage (SDI ≥1) at baseline. Mean SELENA-SLEDAI was 8.2 (4.18) (MITT population) and 9.2 (3.75) (MITT Five Year Completer population). At baseline, 169 patients (16.9%) in the MITT population and 68 patients (17.3%) in the MITT Five Year Completer population had proteinuria, defined as >0.5 g/24 h.

With the exception of higher anti-dsDNA antibody levels and lower C3 and C4 levels (which define the High Disease Activity population), the baseline characteristics of the High Disease Activity population were similar to those of the MITT population. The mean (SD) anti-dsDNA antibody level was 149.9 (59.66) IU/mL for the High Disease Activity population compared with 103.7 (73.62) IU/mL for the MITT population. The percentage of the High Disease Activity population with low baseline C3 and low C4 levels was 75.7% and 87.8%, respectively. This compares with 44.3% and 52.3% of the MITT population with low baseline C3 and C4 levels, respectively. SELENA SLEDAI was also higher in the High Disease Activity population with 47.9% scoring ≥10, 52.1% ≥9 and a mean (SD) of 9.4 (3.94) compared with mean (SD) of 8.2 (4.18) for the MITT population.

Baseline disease characteristics of the High Disease Activity Five Year Completer population are shown in Appendix 6 (Data Table 1.109, Table 1.113).

ACR classification, SELENA-SLEDAI by organ domain and BILAG grade by organ domain (MITT and High Disease populations) are shown in Appendix 5 (Data Table 1.12, Table 1.13, Table 1.14, Table 1.15) and Appendix 6 (Data Table 1.112, Table 1.113, Table 1.114, Table 1.115).

Baseline characteristics described by baseline SDI category and proteinuria (MITT and High Disease Activity populations) are presented in Appendix 5 (Data Table 1.03, Table 1.04) and Appendix 6 (Data Table 1.103, Table 1.104).

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Table 2 Baseline Patient Characteristics, MITT, MITT Five Year Completer and High Disease Activity Populations

MITT (N=998) MITT Five Year Completer (N=392)

High Disease Activity (N=493)

SLE disease duration, years mean (SD)

median25th percentile75th percentile

MinimumMaximum

6.69 (6.239)4.701.929.570.0

36.8

6.30 (6.152)4.401.639.380.0

36.4

6.81 (6.266)5.032.209.540.1

36.8SELENA SLEDAI score, mean (SD) 8.2 (4.18) 9.2 (3.75) 9.4 (3.94)SELENA SLEDAI category, n (%)

≤9≥10

634 (63.5)364 (36.5)

217 (55.4)175 (44.6)

257 (52.1)236 (47.9)

PGA score, mean (SD) 1.189 (0.5997) 1.359 (0.4786) 1.227 (0.6060)PGA category, n (%)

0–1>1–2.5

>2.5

312 (31.3)680 (68.1)

6 (0.6)

65 (16.6)326 (83.2)

1 (0.3)

146 (29.6)341 (69.2)

6 (1.2)SDI category, n (%)a

01

≥2Missing

585 (58.6)235 (23.5)176 (17.6)

2 (0.2)

229 (58.4)94 (24.0)69 (17.6)

0

310 (62.9)114 (23.1)67 (13.6)

2 (0.4)SDI damage index scorea, mean (SD) 0.7 (1.19) 0.7 (1.13) 0.6 (1.01)SLE flare index, n (%)

At least 1 flareAt least 1 severe flare

186 (18.6)8 (0.8)

86 (21.9)1 (0.3)

93 (18.9)6 (1.2)

Proteinuria, g/24 h, mean (SD) 0.4155 (0.8622) 0.4141 (0.8112) 0.5396 (1.0439)Proteinuria categoryb, n (%)

≤0.5 g/24 h>0.5–

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Table 3 Baseline Complement and Autoantibody Levels, MITT and High Disease Activity Populations

MITT (N=998) High Disease Activity (N=493)Complement 3, mg/L

Low: 1800 mg/L, n (%)mean (SD)

442 (44.3)552 (55.3)

4 (0.4)967.1 (301.23)

373 (75.7)120 (24.3)

0777.3 (214.78)

Complement 4, mg/dLLow: 47 mg/dL, n (%)

mean (SD)

552 (52.3)469 (47.0)

7 (0.7)16.8 (9.62)

433 (87.8)60 (12.2)

010.9 (5.39)

Anti-dsDNA, IU/mLNegative

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slightly higher percentage of the High Disease Activity population were receiving a combination of corticosteroids, anti-malarials and immunosuppressants (31% vs 25%),respectively.

Until data cut-off, the majority of patients received a maximum prednisone equivalent dose of >7.5 to ≤ 40 mg/day (57.5% of the MITT population and 63.7% of the High Disease Activity population) (Appendix 5, Data Table 2.01 and Appendix 6, Data Table 2.101).

Table 4 Use of Concomitant Medications at Baseline, MITT Population at Baseline

MITT (N=998)Use of allowable SLE medication, n (%)

Corticosteroids aloneAnti-malarials alone

Immunosuppressants aloneCorticosteroids and anti-malarials

Corticosteroids and immunosuppressantsAnti-malarials and immunosuppressants

Corticosteroids, anti-malarials and immunosuppressants

138 (13.8)66 (6.6)22 (2.2)

311 (31.2)158 (15.8)35 (3.5)

252 (25.3)Prednisone equivalent use of corticosteroids (mg/day)

mean (SD) 10.02 (8.129)

Source: Data Table 2.02 (Appendix 5)MITT, modified intent-to-treat; SD, standard deviation; SLE, systemic lupus erythematosus

4.2.3. Study Withdrawals

Prior to data cut-off, there were 427 withdrawals (MITT population); among these patients median time to withdrawal was 939 days (Appendix 5, Data Table 1.24). Reasons for withdrawal were recorded as patient request (168 patients), AEs (85 patients), and Other (70 patients). Where additional information was provided for the ‘Patient request’ or ‘other’categories of withdrawals, the most common reason, as adjudicated by GSK, was a desire to become pregnant (n=68); other reasons included logistical issues (n=37), desire to start a different treatment, and perceived lack of efficacy (n=12). AEs leading to study withdrawal are shown in Appendix 5 (Data Table 4.05). The number of patients completing each study year and the number of patients that withdrew from the study (along with reasons) are shown in Table 5 (MITT population).

Of 493 patients in the High Disease Activity population, 231 withdrew, with a median time to withdrawal of 947 days (Appendix 6, Data Table 1.124). The reasons for study withdrawal were similar to that of the MITT population (Appendix 6, Data Table 1.122, Table 4.105)

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Table 5 Study Withdrawals and Reason, By Year, MITT Population

Overall(N=998)

Year 0–1(N=998)

Year 1–2(N=955)

Year 2–3(N=861)

Year 3–4(N=734)

Year 4–5(N=655)

Year 5–6(N=531)

Year 6a+(N=354)

n (%) 427 (42.8) 43 (4.3) 94 (9.8) 115 (13.4) 62 (8.4) 48 (7.3) 37 (7.0) 28 (7.9)

AEsb, n (%) 88 (8.8) 15 (1.5) 15 (1.6) 20 (2.3) 18 (2.5) 13 (2.0) 2 (0.4) 2 (0.6)

Investigator decisionc, n (%)

48 (4.8) 4 (0.4) 6 (0.6) 10 (1.2) 4 (0.5) 2 (0.3) 11 (2.1) 11 (3.1)

Lack ofcompliance, n (%)

12 (1.2) 1 (0.1) 1 (0.1) 5 (0.6) 1 (0.1) 2 (0.3) 2 (0.4) 0

Lack of efficacy, n (%)

16 (1.6) 2 (0.2) 5 (0.5) 5 (0.6) 1 (0.1) 1 (0.2) 2 (0.4) 0

Lost to follow-up, n (%)

25 (2.5) 1 (0.1) 6 (0.6) 7 (0.8) 5 (0.7) 2 (0.3) 1 (0.2) 3 (0.8)

Otherd, n (%) 70 (7.0) 4 (0.4) 15 (1.6) 14 (1.6) 14 (1.9) 8 (1.2) 6 (1.1) 9 (2.5)

Protocol violation, n (%)

3 (0.3) 0 2 (0.2) 0 0 1 (0.2) 0 0

Patient request, n (%)

168 (16.8) 16 (1.6) 44 (4.6) 54 (6.3) 19 (2.6) 19 (2.9) 13 (2.4) 3 (0.8)

Source: Data Table 1.22 (Appendix 5)aAt data cut-off; bincludes 3 patients who were incorrectly recorded as experiencing an AE that resulted in drug discontinuation; however, although they had a dose interruption, they did not withdraw from the study; cincludes one patient who reported an AE leading to discontinuation but the investigator recoded reason for withdrawal as ‘investigator decision’; dincludes three patients who died during the study and investigator recorded reason for withdrawal as ‘Other’.AE, adverse event; MITT, modified intent-to-treat; N, patients who were in the study at the start of the interval.

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4.3. Safety Analyses

4.3.1. Study Drug Exposure

The mean (SD) study drug exposure time (from first dose of belimumab in the parent or extension study) was 1579.5 (661.28) days and the mean (SD) number of study drug infusions was 55.1 (23.42) (MITT population). The mean (SD) study drug exposure time for the MITT Five Year Completer population was 2201.1 (136.87) days and the mean (SD) number of study drug infusions was 77.2 (6.08). The total number of belimumab infusions that patients received until data cut-off is shown in Figure 4. Study drug exposures for the High Disease Activity and High Disease Activity Five Year Completer populations are shown in Appendix 6 (Data Table 2.104, Table 2.105). For the High Disease Activity population, the mean (SD) study drug exposure time was 1548.7 (674.99) days and the mean (SD) number of study drug infusions was 54.1 (23.87). There was also little difference between the MITT Five Year Completer and High Disease Activity Five Year Completer populations (Appendix 5, Data Table 2.05 and Appendix 6, Data Table 2.105).

Figure 4 Total Number of Belimumab Infusions Until Data Cut-Off

Source: Data Table 2.04, Table 2.05 (Appendix 5)MITT, modified intent-to-treat

4.3.2. Adverse Events

4.3.2.1. Incidence of Adverse Events

The majority (96.5%) of patients in the MITT population experienced an AE with 43.4% determined as drug-related (possible, probable, or definite) by the investigator (Table 6). The incidence of AEs in the High Disease Activity population was similar to that of the

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MITT population, with 97% of patients reporting at least 1 AE, and 43% considered to be drug-related (Appendix 6, Data Table 4.101).

There were 88 AEs that resulted in study discontinuation, the most common (by system organ class) were immune system disorders (21) and infections and infestations (18) (Appendix 5, Data Table 4.05).

The incidence of AEs, summarized by system organ class, reported during each year interval of the study is summarized in Table 7 (MITT population) and Appendix 6 (Data Table 4.102; High Disease Activity population). For both the MITT and High Disease Activity populations, the most common AEs were infections and infestations, which were reported by 83% and 82% of patients in each population, respectively (Table 7 and Appendix 6, Data Table 4.102).

4.3.2.2. Rate of Adverse Events

The rate of AEs in the MITT population was 247/100 patient years at study year interval 5–6 (402 patient years) and 391/100 patient years any time post-baseline (4320 patient years) (Appendix 5, Data Table 4.06). In study year interval 5–6 there were 20.6 drug-related AEs per 100 patient years, with the most common being infections and infestations (13.7/100 patient years) and GI disorders (1.7/100 patient years) (Appendix 4, Data Table 4.08). Any time post-baseline there were 43.1 drug-related AEs per 100 patient-years, and the most common were infections and infestations (19.5/100 patient-years) and GI disorders (6.9/100 patient-years) (Appendix 5, Data Table 4.08).

The rates of AEs in the High Disease Activity population were similar to the MITT population. The number of drug-related AEs any time post-baseline (2090 patient-years) was 978 (46.8/100 patient-years); the most common were infections and infestations (18.1/100 patient-years) and GI disorders (7.5/100 patient-years) (Appendix 6, Data Table 4.106, Table 4.108).

4.3.3. Serious Adverse Events

The incidence of SAEs summarized by system organ class, is shown in Table 8 (MITT population). Th