Benlysta, INN- belimumab

1 7 Westferry Circus Canary Wharf London E14 4HB United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E-mail Website An agency of the European Union Assessment report Benlysta International Non proprietary Name: belimumab Procedure No. EMEA/H/C/002015 Assessment Report as adopted by the CHMP with all information of a commercially confidential nature deleted Product information Name of the medicinal product: Benlysta Marketing Authorisation Holder: Glaxo Group Limited Glaxo Wellcome House Berkeley Avenue Greenford, Middlesex UB6 0NN United Kingdom Active substance: belimumab International Non-proprietary Name: belimumab Pharmaco-therapeutic group (ATC Code): Selective immunosuppressants (L04AA26) Therapeutic indication.

2 Add-on therapy in adult patients with active autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity ( positive anti-dsDNA and low complement) despite standard therapy. Pharmaceutical form: Powder for concentrate for solution for infusion Strengths: 120 mg and 400 mg Route of administration: Intravenous use Packaging: vial (glass) Package size: 1 vial Assessment report Benlysta Page 2/94 Table of contents 1. Background information on the 6 Submission of the 6 Steps taken for the assessment of the 6 2. Scientific 7 7 Quality 9 9 Active 9 Finished Medicinal 11 Discussion on chemical, pharmaceutical and biological 12 Conclusions on the chemical.

3 Pharmaceutical and biological 13 Non-clinical 14 14 14 16 17 Ecotoxicity/environmental risk 23 Discussion on non-clinical 23 Conclusion on the non-clinical 24 Clinical 24 24 26 31 Discussion and conslusion clinical 32 Clinical 33 Dose response 33 Main 34 Discussion on clinical 59 Conclusions on the clinical 64 Clinical 65 Discussion on clinical 81 Conclusions on the clinical 81 82 Benefit-risk 88 Discussion on the benefit-risk 93 Risk management 94 Similarity with authorised orphan medicinal 94 Market 94 Significance of paediatric 94 Conformity with agreed Paediatric Investigation 94 94 Assessment report Benlysta Page 3/94 List of abbreviations aCl anticardiolipin (antibody)

4 ACR American College of Rheumatology ADA anti-drug antibodies ADME absorption, distribution, metabolism, excretion AE adverse event ALT alanine transaminase ANA antinuclear antibody ANC absolute neutrophil count ANOVA analysis of variance APTT

5 Activated partial thromboplastin time ARISg Adverse Reaction Information System Global (HGS safety database) AST aspartate transaminase ATC Anatomical Therapeutic Chemical classification system BILAG British Isles Lupus Assessment Group BLyS B lymphocyte stimulator protein BLA Biologics Licensing Application BMI body mass index Bpm beats per minute BUN blood urea nitrogen CBER Center for Biologics Evaluation and Research CCP cyclic citrullinated peptide CDIR cytokine-dependent infusion reaction CI confidence

6 Interval CL total body clearance of drug CMV Cytomegalovirus CNS central nervous system COPD chronic obstructive pulmonary disease CRD controlled repeat dose CRP C-reactive protein CSR clinical study report CT computed tomography dL Deciliter DMARD disease-modifying anti-rheumatic drug DMC data monitoring committee DMID Division of Microbiology and Infectious Disease dsDNA double-stranded deoxyribonucleic acid ECG Electrocardiogram ECL Electrochemiluminescence

7 ELISA enzyme-linked immunosorbent assay EMA European Medicines Agency EOP2 End of Phase 2 ER emergency room FDA Food and Drug Administration G Gram GGT gamma-glutamyl transferase GLP Good Laboratory Practice hERG human ether-a-go-go related-gene HGS Human Genome Sciences HLGT high level group term HLT high level term HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A HSR hypersensitivity reaction ICH International Conference on Harmonization Assessment report Benlysta Page 4/94 Ig Immunoglobulin INN International Nonproprietary Name IS Immunosuppressant ITT

8 Intention-to-treat IU international units IV Intravenous Kg Kilogram LDH lactic dehydrogenase LLN lower limit of normal LLOQ lower limit of quantification LOD limit of detection LRTI lower respiratory tract infection Mcg Microgram MedDRA Medical Dictionary for Regulatory Activities Mg Milligram MITT modified intent-to treat mL Milliliter

9 MMF mycophenolate mofetil mmHg millimeters of mercury MRT mean residence time following intravenous dosing MTX Methotrexate NMSC non-melanoma skin cancer NSAID non-steroidal anti-inflammatory drug NSCLC non-small cell lung cancer PGA Physician Global Assessment PK Pharmacokinetics PT prothrombin time PTT partial thromboplastin time RA rheumatoid arthritis RBC red blood cell (count)

10 RF rheumatoid factor RR relative risk SAE serious adverse event SC Subcutaneous SELENA Safety of Estrogen in Lupus National Assessment SLE systemi