22 May 2014 EMA/CHMP/231450/2014 Committee for Medicinal Products for Human Use (CHMP) CHMP assessment report Gazyvaro International non-proprietary name: OBINUTUZUMAB Procedure No.: EMEA/H/C/002799/0000 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, 2014. Reproduction is authorised provided the source is acknowledged. Product information Name of the medicinal product: Gazyvaro Applicant: Roche Registration Ltd 6 Falcon Way Shire Park Welwyn Garden City AL7 1TW UNITED KINGDOM Active substance: OBINUTUZUMAB International Nonproprietary Name/Common Name: OBINUTUZUMAB Pharmaco-therapeutic group (ATC Code): (L01) Therapeutic indication: Gazyvaro in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) and with comorbidities making them unsuitable for full-dose fludarabine based therapy (see section 5.1). Pharmaceutical form: Concentrate for solution for infusion Strength: 1000 mg Route of administration: Intravenous use Packaging: vial (glass) Package size: 1 vial CHMP assessment report EMA/CHMP/231450/2014 Page 2/123 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Manufacturers ...................................................................................................... 8 1.3. Steps taken for the assessment of the product ......................................................... 8 2. Scientific discussion ................................................................................ 9 2.1. Introduction......................................................................................................... 9 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction .................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 14 2.2.3. Finished Medicinal Product ................................................................................ 16 2.2.4. Overview of the Quality by Design approach ....................................................... 17 2.2.5. Discussion on chemical, pharmaceutical and biological aspects .............................. 23 2.2.6. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 26 2.2.7. Recommendations for future quality development................................................ 27 2.3. Non-clinical aspects ............................................................................................ 27 2.3.1. Introduction .................................................................................................... 27 2.3.2. Pharmacology ................................................................................................. 27 2.3.3. Pharmacokinetics............................................................................................. 31 2.3.4. Toxicology ...................................................................................................... 33 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 36 2.3.6. Discussion on non-clinical aspects...................................................................... 37 2.3.7. Conclusion on the non-clinical aspects ................................................................ 39 2.4. Clinical aspects .................................................................................................. 40 2.4.1. Introduction .................................................................................................... 40 2.4.2. Pharmacokinetics............................................................................................. 41 2.4.3. Pharmacodynamics .......................................................................................... 44 2.4.4. Discussion on clinical pharmacology ................................................................... 44 2.4.5. Conclusions on clinical pharmacology ................................................................. 46 2.5. Clinical efficacy .................................................................................................. 46 2.5.1. Dose response study(ies) ................................................................................. 46 2.5.2. Main study(ies) ............................................................................................... 47 2.5.3. Discussion on clinical efficacy ............................................................................ 86 2.5.4. Conclusions on the clinical efficacy ..................................................................... 89 2.6. Clinical safety .................................................................................................... 89 2.6.1. Discussion on clinical safety ............................................................................ 106 2.6.2. Conclusions on the clinical safety ..................................................................... 113 2.7. Pharmacovigilance ............................................................................................ 113 2.8. Risk Management Plan ...................................................................................... 114 2.9. User consultation ............................................................................................. 118 3. Benefit-Risk Balance............................................................................ 119 4. Recommendations ............................................................................... 121 CHMP assessment report EMA/CHMP/231450/2014 Page 3/123 List of abbreviations ADCC antibody-dependent cellular cytotoxicity ADCP antibody-dependent cellular phagocytosis ASO RQ-PCR allelic-specific oligonucleotide real-time quantitative polymerase chain reaction AUC area under the plasma concentration-time curve BMI Body Mass Index CDC complement-dependent cytotoxicity CHMP Committee for Medicinal Products for Human Use CHOP cyclophosphamide, doxorubicin, vincristine, and prednisone CI confidence interval CIRS Cumulative Illness Rating Scale Clb chlorambucil CLL chronic lymphocytic leukemia Cmax maximum plasma concentration CR complete response CrCl creatinine clearance CRi complete response with incomplete marrow recovery CSR clinical study report CT computed tomography CYP cytochrome P450 DDI drug-drug interaction DFS disease-free survival DLBCL diffuse large B cell lymphoma DLT dose limiting toxicity DS drug substance DSMB Data Safety Monitoring Board EFS event-free survival ELISA enzyme-linked immunosorbent assay EMA European Medicines Agency EORTC QLQ European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire ESMO European Society for Medical Oncology FC fludarabine, cyclophosphamide CHMP assessment report EMA/CHMP/231450/2014 Page 4/123 FCR fludarabine, cyclophosphamide and rituximab FDA Food and Drug Administration GA101 obinutuzumab (RO5072759) GClb obinutuzumab plus chlorambucil GCLLSG German CLL Study Group GCP Good Clinical Practice G-CSF granulocyte-colony stimulating factor HAHA human anti-human antibody HIV human immunodeficiency virus HR hazard ratio HRQoL health-related quality of life iDCC independent Data Coordinating Center IgG immunoglobulin G IgHV immunoglobulin heavy chain variable region iNHL indolent non-Hodgkin’s lymphoma IRC Independent Review Committee IRR infusion related reaction ITT intent-to-treat IWCLL International Workshop on Chronic Lymphocytic Leukemia MAA Marketing Authorization Application mAb monoclonal antibody MedDRA Medical Dictionary for Regulatory Activities MRD minimal residual disease NCI National Cancer Institute NHL non-Hodgkin’s lymphoma nPR nodular partial response ORR overall response rate OS overall survival PCR pentostatin, cyclophosphamide, rituximab PD progressive disease PFS progression free survival PK pharmacokinetic popPK population pharmacokinetics CHMP assessment report EMA/CHMP/231450/2014 Page 5/123 PR partial response QoL quality of life RClb rituximab plus chlorambucil SAE serious adverse event SAP Statistical Analysis Plan SD stable disease SOC system organ class TLS tumor lysis syndrome ZAP70 zeta-chain-associated protein kinase 70 CHMP assessment report EMA/CHMP/231450/2014 Page 6/123 1. Background information on the procedure 1.1. Submission of the dossier The applicant Roche Registration Ltd submitted on 25 April 2013 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Gazyvaro, through the centralised procedure falling within the Article 3(1) and point 1 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 20 September 2012. Gazyvaro was designated as an orphan medicinal product EU/3/12/1054 on 10 October 2012. Gazyvaro was designated as an orphan medicinal product in the following indication: Treatment of chronic lymphocytic