15 September 2016 EMA/CHMP/594718/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report NINLARO International non-proprietary name: ixazomib Procedure No. EMEA/H/C/003844/0000 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, 2016. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier ...................................................................................... 6 1.2. Steps taken for the assessment of the product ......................................................... 7 1.3. Steps taken for the re-examination procedure ......................................................... 8 2. Scientific discussion ................................................................................ 8 2.1. Introduction......................................................................................................... 8 2.2. Quality aspects .................................................................................................. 10 2.2.1. Introduction .................................................................................................... 10 2.2.2. Active Substance ............................................................................................. 10 2.2.3. Finished Medicinal Product ................................................................................ 13 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17 2.2.6. Recommendation(s) for future quality development ............................................. 17 2.3. Non-clinical aspects ............................................................................................ 17 2.3.1. Introduction .................................................................................................... 17 2.3.2. Pharmacology ................................................................................................. 17 2.3.3. Pharmacokinetics............................................................................................. 26 2.3.4. Toxicology ...................................................................................................... 33 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 48 2.3.6. Discussion on non-clinical aspects...................................................................... 48 2.3.7. Conclusion on the non-clinical aspects ................................................................ 50 2.4. Clinical aspects .................................................................................................. 50 2.4.1. Introduction .................................................................................................... 50 2.4.2. Pharmacokinetics............................................................................................. 52 2.4.3. Pharmacodynamics .......................................................................................... 63 2.4.4. Discussion on clinical pharmacology ................................................................... 65 2.4.5. Conclusions on clinical pharmacology ................................................................. 67 2.5. Clinical efficacy .................................................................................................. 68 2.5.1. Dose response studies...................................................................................... 68 2.5.2. Main study ...................................................................................................... 71 2.5.3. Discussion on clinical efficacy ............................................................................ 99 2.5.4. Conclusions on the clinical efficacy ................................................................... 102 2.6. Clinical safety .................................................................................................. 102 2.6.1. Discussion on clinical safety ............................................................................ 115 2.6.2. Conclusions on the clinical safety ..................................................................... 117 2.7. Risk Management Plan ...................................................................................... 118 2.8. Pharmacovigilance ............................................................................................ 123 2.9. Product information .......................................................................................... 123 2.9.1. User consultation ........................................................................................... 123 2.9.2. Additional monitoring ..................................................................................... 123 Assessment report EMA/654545/2016 Page 2/153 3. Benefit-Risk Balance............................................................................ 123 4. Recommendations ............................................................................... 128 5. Re-examination of the CHMP opinion of 26 May 2016 ......................... 128 5.1. Risk Management Plan ...................................................................................... 134 5.2. Pharmacovigilance ............................................................................................ 141 5.3. Product information .......................................................................................... 141 5.3.1. User consultation ........................................................................................... 141 5.3.2. Additional monitoring ..................................................................................... 141 6. Benefit-risk balance ............................................................................ 141 7. Recommendations following re-examination ....................................... 147 Assessment report EMA/654545/2016 Page 3/153 List of abbreviations Abbreviation Term ADME absorption, distribution, metabolism, excretion ADR adverse drug reactions AE adverse event ALT alanine aminotransferase API Active pharmaceutical ingredient AS active substance ASCT autologous stem cell transplant AST aspartate aminotransferase AUC area under the plasma concentration versus time curve AUC0-last area under the plasma concentration versus time curve from time zero to the time of the last quantifiable concentration AUC0-216 area under the plasma concentration versus time curve from time zero to 216 hours postdose AUC0-264 area under the plasma concentration versus time curve from time zero to 264 hours postdose BCRP breast cancer resistance protein BCS Biopharmaceutics Classification System BPI-SF Brief Pain Inventory – Short-form BSA body surface area CHMP Committee for medicinal products for human use CI confidence interval Cmax maximum observed plasma concentration CR complete response CrCL creatinine clearance CQA Critical quality attribute CSR clinical study report DDI drug-drug interaction DLT dose-limiting toxicity DOR duration of response DOS Design of experiments ECOG Eastern Cooperative Oncology Group Emax maximum inhibition EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire ESRD end-stage renal disease EU European Union FDA Food and Drug Administration FLC free light chain FTIR Fourier transform infrared spectroscopy GC Gas chromatography GC-MS Gas chromatography mass spectrometry GMP Good manufacturing practice HDT high dose therapy HLT High-Level Term HPLC High performance liquid chromatography HR hazard ratio ICH International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use ICP-MS Inductively coupled plasma mass spectrometry IDMC independent data monitoring committee IMiD immunomodulatory drug IMWG International Myeloma Working Group IR Infrared IRC independent review committee IRT interdisciplinary review team ISS Integrated Summary of Safety KF Karl Fisher titration Assessment report EMA/654545/2016 Page 4/153 Abbreviation Term LenDex lenalidomide plus dexamethasone LiHMDS Lithium hexamethyldisilazane LOD Loss on drying LS least squares MCC Microcrystalline cellulose MedDRA Medical Dictionary for Regulatory Activities Millennium Millennium Pharmaceuticals, Inc., and its affiliates MM multiple myeloma MMVAR/IFM Multiple Myeloma Velcade at Relapse/Intergroupe Francophone du Myélome MR minimal response MRP2 multidrug resistance protein 2 MS Mass spectrometry MTD maximum tolerated dose NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events NDMM newly diagnosed multiple myeloma NEC not elsewhere classified NMR Nuclear magnetic resonance NP-HPLC Normal-phase HPLC NSCLC non-small cell lung carcinoma OAT organic anion transporter OATP organic anion transporting polypeptide OCT organic cation transporter ORR overall response rate PAR Proven acceptable range PBPK physiologically based pharmacokinetic PD progressive disease PFS progression-free survival