19 July 2012 EMA/702390/2012 Committee for Medicinal Products for Human Use (CHMP) Assessment report Adcetris International non-proprietary name: brentuximab vedotin Procedure No. EMEA/H/C/002455 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union Product information Name of the medicinal product: Adcetris Applicant: Takeda Global Research and Development Centre (Europe) Ltd. 61 Aldwych London WC2B 4AE United Kingdom Active substance: brentuximab vedotin International Nonproprietary Name/Common Name: brentuximab vedotin Pharmaco-therapeutic group Monoclonal antibodies (ATC Code): (L01XC12) ADCETRIS is indicated for the treatment of adult Therapeutic indication(s): patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL): 1. following autologous stem cell transplant (ASCT) or 2. following at least two prior therapies when ASCT or multi-agent chemotherpay are not a treatment option ADCETRIS is indicated for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). Pharmaceutical form(s): Powder for concentrate for solution for infusion Strength(s): 50 mg Route(s) of administration: Intravenous use Packaging: vial (glass) Package size(s): 1 vial Adcetris CHMP assessment report Page 2/102 Rev10.11 Table of contents 1. Background information on the procedure .............................................. 9 1.1. Submission of the dossier ...................................................................................... 9 1.2. Steps taken for the assessment of the product ....................................................... 10 2. Scientific discussion .............................................................................. 12 2.1. Introduction....................................................................................................... 12 2.2. Quality aspects .................................................................................................. 14 2.2.1. Introduction .................................................................................................... 14 2.2.2. Active Substance ............................................................................................. 14 2.2.3. Finished Medicinal Product ................................................................................ 20 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 22 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 22 2.2.6. Recommendations for future quality development................................................ 22 2.3. Non-clinical aspects ............................................................................................ 23 2.3.1. Introduction .................................................................................................... 23 2.3.2. Pharmacology ................................................................................................. 23 2.3.3. Pharmacokinetics............................................................................................. 25 2.3.4. Toxicology ...................................................................................................... 28 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 33 2.3.6. Discussion on non-clinical aspects...................................................................... 34 2.3.7. Conclusion on the non-clinical aspects ................................................................ 40 2.4. Clinical aspects .................................................................................................. 40 2.4.1. Introduction .................................................................................................... 40 2.4.2. Pharmacokinetics............................................................................................. 41 2.4.3. Pharmacodynamics .......................................................................................... 45 2.4.4. Discussion on clinical pharmacology ................................................................... 45 2.4.5. Conclusions on clinical pharmacology ................................................................. 46 2.5. Clinical efficacy .................................................................................................. 46 2.5.1. Dose response studies...................................................................................... 46 2.5.2. Main studies ................................................................................................... 47 Supportive studies .................................................................................................... 65 2.5.3. Discussion on clinical efficacy ............................................................................ 68 2.5.4. Conclusions on the clinical efficacy ..................................................................... 71 2.6. Clinical safety .................................................................................................... 72 2.6.1. Discussion on clinical safety .............................................................................. 80 2.6.2. Conclusions on the clinical safety ....................................................................... 84 2.7. Pharmacovigilance .............................................................................................. 84 2.8. User consultation ............................................................................................... 91 3. Benefit-Risk Balance.............................................................................. 92 4. Recommendations ................................................................................. 99 Adcetris CHMP assessment report Page 3/102 Rev10.11 List of abbreviations A280 Absorbance at 280 nm ABVD doxorubicin, bleomycin, vinblastine, dacarbazine ADC Antibody-Drug Conjugate ADCC antibody-dependent cell-mediated cytotoxicity AE adverse event ALCL anaplastic large cell lymphoma ALT/SGTP alanine transaminase alloSCT allogeneic stem cell transplant ALK anaplastic lymphoma kinase ASCT autologous stem cell transplant ASM-free Animal Source Material-Free AST Aspartate Aminotransferase ATA antitherapeutic antibodies AUC area under the concentration-versus-time curve BDS Bulk Drug Substance BCNU carmustine BCRP breast cancer resistance protein BEACOPP bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone BSA body surface area BSC best supportive care cAC10 Anti-CD30 Antibody CALGB Cancer and Leukemia Group B CD Circular Dichroism CDC complement-dependent cytotoxicity CE-SDS Capillary Electrophoresis-SDS CEX Cation Exchange Chromatography CFU Colony Forming Unit cGMP Current Good Manufacturing Practice CE-LIF Capillary Electrophoresis with Laser-Induce Fluorescence CHEF Chinese Hamster Elongation Factor CHO Chinese Hamster Ovary CHOP cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin®), prednisone CI confidence interval CL clearance Cmax maximum concentration CMPI 2-Chloro-1-Methyl Pyridinium Iodide CMV cytomegalovirus CNS central nervous system CR complete remission CRu unconfirmed complete remission CSR clinical study report CT computed tomography CTCAE Common terminology criteria for adverse events CTCL cutaneous T cell lymphoma CV coefficient of variance CYP cytochrome P450 Da Dalton DCHA Dicyclohexylamine DDI Drug drug interaction DHAOx dexamethasone, high-dose cytarabine, and oxaliplatin DHFR Dihydrofolate Reductase DIPEA N,N-Diisopropylethylamine DLT Dose limiting toxicity DMSO Dimethyl Sulphoxide DO Dissolved Oxygen Adcetris CHMP assessment report Page 4/102 Rev10.11 DoR duration of response DP Drug Product DS drug substance DSC Differential Scanning Calorimetry dSEC Denaturing Size Exclusion Chromatography DTNB 5,5‟-dithiobis-(2-nitrobenzoic acid) DTT Dithiothreitol EBV Epstein-Barr virus ECG electrocardiogram ECL electro-chemiluminescent ECOG Eastern Cooperative Oncology Group EdU 5-ethynyl-2′-deoxyuridine EDTA Ethylenediaminetetraacetic Acid EFS event free survival ELISA Enzyme Linked Immunoadsorbent Assay EOT end of treatment EPOCH etoposide, vincristine, and doxorubicin ESHAP etoposide, cisplatin, cytarabine, prednisone ESMO European Society for Medical Oncology EtOAc Ethyl Acetate Et2O Ethyl Ether Refined (Diethyl Ether) EU Endotoxin Units Fab antigen-binding fragment Fc heavy chain constant FDA Food and Drug Administration FDG fluorodeoxyglucose FIO For Information Only FMOC-MeVal-OH Nα-(9-Fluorenylmethyloxycarbonyl)-N-Methyl-L-Valine FTIR Fourier Transform Infra Red Spectroscopy GGT Gamma Glutamyltransferase GI gastrointestinal GLP Good Laboratory Practice GM-CSF granulocyte macrophages colony stimulating factory GMP Good Manufacturing Practice GMR geometric mean ratio GVD gemcitabine, vinorelbine, and pegylated liposomal doxorubicin HAP Hamster Antibody Production HC Heavy Chain HCl Hydrochloric Acid HDPE High Density Polyethylene HEK human embryonic kidney HEPA High Efficiency Particulate Absorbing hERG human ether à-go-go related gene HIC Hydrophobic Interaction Chromotography HL Hodgkin lymphoma HMW High Molecular Weight HNST / HNSTD Highest Non-Severely