22 November 2016 EMA/853812/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report Zinplava International non-proprietary name: bezlotoxumab Procedure No. EMEA/H/C/004136/0000 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, 2017. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Problem statement ............................................................................................... 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 11 General information .................................................................................................. 11 2.2.3. Finished Medicinal Product ................................................................................ 13 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 15 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 15 2.2.6. Recommendations for future quality development ............................................... 16 2.3. Non-clinical aspects ............................................................................................ 16 2.3.1. Introduction .................................................................................................... 16 2.3.2. Pharmacology ................................................................................................. 16 2.3.3. Pharmacokinetics............................................................................................. 18 2.3.4. Toxicology ...................................................................................................... 19 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 19 2.3.6. Discussion on non-clinical aspects...................................................................... 19 2.3.7. Conclusion on the non-clinical aspects ................................................................ 20 2.4. Clinical aspects .................................................................................................. 20 2.4.1. Introduction .................................................................................................... 20 2.4.2. Pharmacokinetics............................................................................................. 21 2.4.3. Pharmacodynamics .......................................................................................... 24 2.4.4. Discussion on clinical pharmacology ................................................................... 26 2.4.5. Conclusions on clinical pharmacology ................................................................. 26 2.5. Clinical efficacy .................................................................................................. 27 2.5.1. Dose response studies...................................................................................... 27 2.5.2. Main studies ................................................................................................... 27 2.5.3. Discussion on clinical efficacy ............................................................................ 81 2.5.4. Conclusions on the clinical efficacy ..................................................................... 88 2.6. Clinical safety .................................................................................................... 88 Immunological events ........................................................................................... 93 Adverse events of special interest ......................................................................... 94 2.6.1. Discussion on clinical safety .............................................................................. 94 2.6.2. Conclusions on the clinical safety ....................................................................... 95 2.7. Risk Management Plan ........................................................................................ 96 2.8. Pharmacovigilance ............................................................................................ 101 2.9. New Active Substance ....................................................................................... 101 2.9.1. User consultation ........................................................................................... 102 2.9.2. Labelling exemptions ..................................................................................... 102 Assessment report EMA/853812/2016 Page 2/110 2.9.3. Additional monitoring ..................................................................................... 102 3. Benefit-Risk Balance............................................................................ 103 3.1. Therapeutic Context ......................................................................................... 103 3.1.1. Disease or condition ....................................................................................... 103 3.1.2. Available therapies and unmet medical need ..................................................... 103 3.2 Main clinical studies ........................................................................................ 104 3.2.1 Favourable effects ....................................................................................... 104 3.2.2 Uncertainties and limitations about favourable effects ....................................... 105 3.2.3 Unfavourable effects ..................................................................................... 106 3.2.4 Uncertainties and limitations about unfavourable effects ................................... 106 3.2.5 Effects Table ................................................................................................ 106 3.3 Benefit-risk assessment and discussion .............................................................. 108 3.3.1 Importance of favourable and unfavourable effects ........................................... 108 3.3.2 Balance of benefits and risks .......................................................................... 108 3.4 Conclusions .................................................................................................... 109 4. Recommendations ............................................................................... 109 Assessment report EMA/853812/2016 Page 3/110 List of abbreviations Abbreviation/Term Definition ACV Arithmetic coefficient of variation ADA Anti-drug antibody AE Adverse event ALP Alkaline phosphatase ALT Alanine aminotransferase ANOVA Analysis of variance ANCOVA Analysis of covariance APaT All patients as treated AST Aspartate aminotransferase AUC Area under the concentration-time curve BBA` Brucella blood agar BBB Blood-brain barrier BILI Bilirubin BLQ Below limit of quantification BMI Body mass index BP Blood pressure BUN Blood urea nitrogen °C Degree(s) Celsius C. difficile Clostridium difficile CDI Clostridium difficile infection CDS Clinical Development Scientist CFR Food and Drug Administration Code of Federal Regulations CI Confidence interval Cmax Maximum concentration CMV Cytomegalovirus CMV IgG Cytomegalovirus immunoglobulin G CQM Clinical Quality Management CRF Case report form CSR Clinical Study Report CT Computed tomography CV Coefficient of variation DHEA Dehydroepiandrosterone DHEA-S Dehydroepiandrosterone sulfated conjugate DILI Drug induced liver injury DNA Deoxyribonucleic acid DTL Drug tolerance level ECG Electrocardiogram ECI Event of clinical interest ECL Electrochemiluminescence eCRF Electronic case report form eDMC External Data Monitoring Committee Assessment report EMA/853812/2016 Page 4/110 Abbreviation/Term Definition EIA Enzyme Immunoassay ERC Ethical Review Committee EUB Emergency Unblinding Call Center °F Degree(s) Fahrenheit FAS Full analysis set FBR Future Biomedical Research FDA U.S. Food and Drug Administration FSE First subject enrolled FSG Fasting serum glucose FSH Follicle stimulating hormone GBRC Genetic and Other Biomedical Research GCC Global Clinical Compliance GC & PVC Global Clinical and Pharmacovigilance Compliance GCP Good Pharmacovigilance Practices GDH Glutamate dehydrogenase GI Gastrointestinal GM Geometric mean GMR Geometric mean ratio GPvP Good Pharmacovigilance Practice H Hour HA Hospital acquired HIV Human immunodeficiency virus HR Heart rate ICF Informed consent form ICH International Conference on Harmonisation IEC Independent Ethics Committee IgG Immunoglobulin G IM Intramuscular IND Investigational