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Mylotarg, INN-Gemtuzumab Ozogamicin 22 February 2018 EMA/155284/2018 Committee for Medicinal Products for Human Use (CHMP) Assessment report Mylotarg International non-proprietary name: gemtuzumab ozogamicin Procedure No. EMEA/H/C/004204/0000 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 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 2.1.1. Disease or condition ........................................................................................... 9 2.1.2. Epidemiology and risk factors, screening tools/prevention ...................................... 9 2.1.3. Biologic features ................................................................................................ 9 2.1.4. Clinical presentation, diagnosis and stage/prognosis .............................................. 9 2.1.5. Management ..................................................................................................... 9 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 18 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 19 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 20 2.2.6. Recommendation(s) for future quality development ............................................. 21 2.3. Non-clinical aspects ............................................................................................ 21 2.3.1. Introduction .................................................................................................... 21 2.3.2. Pharmacology ................................................................................................. 21 2.3.3. Pharmacokinetics............................................................................................. 28 2.3.4. Toxicology ...................................................................................................... 31 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 47 2.3.6. Discussion on non-clinical aspects...................................................................... 49 2.3.7. Conclusion on the non-clinical aspects ................................................................ 51 2.4. Clinical aspects .................................................................................................. 51 2.4.1. Introduction .................................................................................................... 51 2.4.2. Pharmacokinetics............................................................................................. 55 2.4.3. Pharmacodynamics .......................................................................................... 60 2.4.4. Discussion on clinical pharmacology ................................................................... 63 2.4.5. Conclusions on clinical pharmacology ................................................................. 65 2.5. Clinical efficacy .................................................................................................. 65 2.5.1. Dose response studies...................................................................................... 65 2.6. Main study – ALFA0701 ....................................................................................... 66 2.6.1. Discussion on clinical efficacy .......................................................................... 101 2.6.2. Conclusions on the clinical efficacy ................................................................... 104 2.7. Clinical safety .................................................................................................. 104 2.7.1. Discussion on clinical safety ............................................................................ 124 2.7.2. Conclusions on the clinical safety ..................................................................... 128 2.8. Risk Management Plan ...................................................................................... 128 2.9. New Active Substance ....................................................................................... 130 2.10. Product information ........................................................................................ 131 Assessment report EMA/155284/2018 Page 2/138 2.10.1. User consultation ......................................................................................... 131 2.10.2. Additional monitoring ................................................................................... 131 3. Benefit-Risk Balance............................................................................ 131 3.1. Therapeutic Context ......................................................................................... 131 3.1.1. Disease or condition ....................................................................................... 131 3.1.2. Available therapies and unmet medical need ..................................................... 131 3.1.3. Main clinical studies ....................................................................................... 131 3.2. Favourable effects ............................................................................................ 131 3.3. Uncertainties and limitations about favourable effects ........................................... 132 3.4. Unfavourable effects ......................................................................................... 132 3.5. Uncertainties and limitations about unfavourable effects ....................................... 132 3.6. Effects Table .................................................................................................... 133 3.7. Benefit-risk assessment and discussion ............................................................... 133 3.7.1. Importance of favourable and unfavourable effects ............................................ 133 3.7.2. Balance of benefits and risks ........................................................................... 134 3.7.3. Additional considerations on the benefit-risk balance ......................................... 134 3.8. Conclusions ..................................................................................................... 135 4. Recommendations ............................................................................... 135 Assessment report EMA/155284/2018 Page 3/138 List of abbreviations Term Definition AAS Amino Acid Substitution AcBut (4-(4'acetylphenoxy)butanoic acid) ADA anti-drug antibody ADC antibody-drug conjugate ADE AraC/DNR/etoposide ADR adverse drug reaction AE adverse event ALFA Acute Leukemia French Association ALP alkaline phosphatase ALT alanine aminotransferase AML acute myeloid leukaemia ANC absolute neutrophil count APL acute promyelocytic leukaemia AraC cytarabine AST aspartate aminotransferase AT As Treated AUC area under the plasma concentration-time curve BCRP breast cancer resistance protein BMA bone marrow aspirate BSA bovine serum albumin CD Cluster of Differentiation CDR Complementarity determining region CFU Colony Forming Units CHMP Committee for Medicinal Products for Human Use CI confidence interval CL Clearance CLL1 C-type lectin-like molecule-1 Cmax Maximum Serum Concentration CNS central nervous system COG Children's Oncology Group COSY correlation spectroscopy CQA critical quality attribute CR complete remission CR1 first CR CRF case report form CRp complete remission with incomplete platelet recovery CSR clinical study report CTCAE Common Terminology Criteria for Adverse Events CV coefficient of variation CYP Cytochrome P450 DClo daunorubicin and clofarabine DL dose level DMH dimethylhydrazide DNA deoxyribonucleic acid DNR daunorubicin DS drug substance EC European Community ECG electrocardiogram ECOG Eastern Cooperative Oncology Group ED50, ED90, ED95 dose that produces 50%/90%/95% of maximum response EFS event-free survival ELISA enzyme-linked immunosorbent assay ELN European Leukemia Network EMA European Medicines Agency Emax maximum achievable response EOP end of production Assessment report EMA/155284/2018 Page 4/138 EU European Union EU Endotoxin Units FDA Food and Drug Administration FLAG-Ida fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin FLT3 FMS-like tyrosine
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