25 January 2018 EMA/88475/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Hemlibra International non-proprietary name: emicizumab Procedure No. EMEA/H/C/004406/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2018. Reproduction is authorised provided the source is acknowledged. Table of contents Background information on the procedure .................................................. 8 1.1. Submission of the dossier ..................................................................................... 8 1.2. Steps taken for the assessment of the product ........................................................ 9 2. Scientific discussion .............................................................................. 10 2.1. Problem statement ............................................................................................. 10 2.1.1. Disease or condition ........................................................................................ 10 2.1.2. Epidemiology .................................................................................................. 10 2.1.3. Clinical presentation, diagnosis and prognosis ..................................................... 11 2.1.4. Management .................................................................................................. 11 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction ................................................................................................... 13 2.2.2. Active Substance ............................................................................................. 13 2.2.3. Finished Medicinal Product ................................................................................ 18 2.2.4. Discussion on chemical, pharmaceutical and biological aspects ............................. 22 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 22 2.3. Non-clinical aspects ............................................................................................ 23 2.3.1. Introduction ................................................................................................... 23 2.3.2. Pharmacology ................................................................................................. 23 2.3.3. Pharmacokinetics ............................................................................................ 30 2.3.4. Toxicology ...................................................................................................... 31 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 36 2.3.6. Discussion on non-clinical aspects ..................................................................... 36 2.3.7. Conclusion on the non-clinical aspects ............................................................... 37 2.4. Clinical aspects .................................................................................................. 38 2.4.1. Introduction ................................................................................................... 38 2.4.2. Pharmacokinetics ............................................................................................ 40 2.4.3. Pharmacodynamics .......................................................................................... 48 2.4.4. Discussion on clinical pharmacology .................................................................. 53 2.4.5. Conclusions on clinical pharmacology ................................................................. 54 2.5. Clinical efficacy .................................................................................................. 55 2.5.1. Dose response studies ..................................................................................... 55 2.5.2. Main studies ................................................................................................... 56 2.5.3. Discussion on clinical efficacy............................................................................ 86 2.5.4. Conclusions on the clinical efficacy .................................................................... 91 2.6. Clinical safety .................................................................................................... 91 2.6.1. Discussion on clinical safety ............................................................................ 105 2.6.2. Conclusions on the clinical safety .................................................................... 109 2.7. Risk Management Plan ...................................................................................... 111 2.8. Pharmacovigilance ........................................................................................... 114 2.9. New Active Substance ...................................................................................... 114 2.10. Product information ........................................................................................ 114 2.10.1. User consultation......................................................................................... 114 Assessment report EMA/88475/2018 Page 2/126 2.10.2. Additional monitoring ................................................................................... 114 3. Benefit-Risk Balance ........................................................................... 116 3.1. Therapeutic Context ......................................................................................... 116 3.1.1. Disease or condition ...................................................................................... 116 3.1.2. Available therapies and unmet medical need .................................................... 116 3.1.3. Main clinical studies ....................................................................................... 116 3.2. Favourable effects ............................................................................................ 116 3.3. Uncertainties and limitations about favourable effects .......................................... 117 3.4. Unfavourable effects......................................................................................... 117 3.5. Uncertainties and limitations about unfavourable effects ....................................... 118 3.6. Effects Table ................................................................................................... 118 3.7. Benefit-risk assessment and discussion............................................................... 121 3.7.1. Importance of favourable and unfavourable effects ........................................... 121 3.7.2. Balance of benefits and risks .......................................................................... 121 3.7.3. Additional considerations on the benefit-risk balance ......................................... 122 3.8. Conclusions ..................................................................................................... 122 4. Recommendations ............................................................................... 122 Assessment report EMA/88475/2018 Page 3/126 List of abbreviations 95/99 TI 95% confidence/99% probability tolerance interval A280 absorbance at 280 nanometres AC acceptance criterion ADA anti-drug antibody ADCC antibody-dependent cell-mediated cytotoxicity ADE acceptable daily exposure ADI acceptable daily intake AE adverse event AGE advanced glycation end-products aPCC activated prothrombin complex concentrates APTT activated partial thromboplastin time AR annual report ATA anti-therapeutic antibody ATCC American Type Culture Collection ATS attribute testing strategy AU absorbance unit AUC area under the curve BI bioindicator bp base pair BSA bovine serum albumin CDR complementarity-determining region CH constant domain of the heavy chain CHO Chinese hamster ovary CI confidence interval CIP clean-in-place CL constant domain of the light chain CMV cytomegalovirus CoA certificate of analysis CPE cytopathic effect CPP critical process parameter CQA critical quality attribute Assessment report EMA/88475/2018 Page 4/126 CV coefficient of variation DF diafiltration DL detection limit DoE design of experiment DP Drug Product DS Drug Substance ESMO equivalent in sample mean only F/T freeze/thaw Fab antigen-binding portion of immunoglobulin molecule Fc effector portion of the immunoglobulin molecule FcRn neonatal Fc receptor HC heavy chain HCCF harvested cell culture fluid HCP host cell proteins IgG immunoglobulin G IgG1(κ) immunoglobulin G1(κ) IPC in-process control IV intravenous IVPCV integrated viable packed cell volume KPI key performance indicator LC light chain mAb monoclonal antibody MCB master cell bank MHC major histocompatibility complex MoA mechanism of action MPN most probable number MSV murine sarcoma virus MTV mouse thymic virus NA not applicable N.D. not detected NE no excursion NEM N-ethylmaleimide NF National Formulary Assessment report EMA/88475/2018 Page 5/126 NIR near infrared NT not tested OD optical density OQ operational qualification P p-value (overall analysis of variance) pCPP potential critical process parameter