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Assessment Report 28 January 2021 EMA/CHMP/95252/2021 Committee for Medicinal Products for Human Use (CHMP) Assessment report Nexpovio International non-proprietary name: selinexor Procedure No. EMEA/H/C/005127/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ...................................................................................... 8 1.2. Steps taken for the assessment of the product ....................................................... 10 2. Scientific discussion .............................................................................. 12 2.1. Problem statement .......................................................................................... 12 2.1.1. Disease or condition ......................................................................................... 12 2.1.2. Epidemiology .................................................................................................. 12 2.1.3. Biologic features .............................................................................................. 12 2.1.4. Clinical presentation, diagnosis and stage/prognosis ............................................ 12 2.1.5. Management ................................................................................................... 13 2.2. Quality aspects ............................................................................................... 15 2.2.1. Introduction .................................................................................................... 15 2.2.2. Active Substance ............................................................................................. 15 2.2.3. Finished Medicinal Product ................................................................................ 19 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 23 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 23 2.2.6. Recommendations for future quality development................................................ 24 2.3. Non-clinical aspects ......................................................................................... 24 2.3.1. Introduction .................................................................................................... 24 2.3.2. Pharmacology ................................................................................................. 24 2.3.3. Pharmacokinetics............................................................................................. 26 2.3.4. Toxicology ...................................................................................................... 28 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 32 2.3.6. Discussion on non-clinical aspects...................................................................... 32 2.3.7. Conclusion on the non-clinical aspects ................................................................ 33 2.4. Clinical aspects ............................................................................................... 34 2.4.1. Introduction .................................................................................................... 34 2.4.2. Pharmacokinetics............................................................................................. 35 2.4.3. Pharmacodynamics .......................................................................................... 41 2.4.4. Discussion on clinical pharmacology ................................................................... 47 2.4.5. Conclusions on clinical pharmacology ................................................................. 50 2.5. Clinical efficacy ............................................................................................... 50 2.5.1. Dose response study ........................................................................................ 50 2.5.2. Main study ...................................................................................................... 56 2.5.3. Discussion on clinical efficacy ............................................................................ 92 2.5.4. Conclusions on the clinical efficacy ..................................................................... 98 2.6. Clinical safety ................................................................................................. 99 2.6.1. Discussion on clinical safety ............................................................................ 118 2.6.2. Conclusions on the clinical safety ..................................................................... 123 2.7. Risk Management Plan ................................................................................... 124 2.8. Pharmacovigilance ......................................................................................... 128 2.9. New Active Substance .................................................................................... 128 2.10. Product information ...................................................................................... 128 Assessment report EMA/CHMP/95252/2021 Page 2/138 2.10.1. User consultation ......................................................................................... 128 2.10.2. Additional monitoring ................................................................................... 128 3. Benefit-Risk Balance............................................................................ 129 3.1. Therapeutic Context ....................................................................................... 129 3.1.1. Disease or condition ....................................................................................... 129 3.1.2. Available therapies and unmet medical need ..................................................... 129 3.1.3. Main clinical studies ....................................................................................... 129 3.2. Favourable effects ......................................................................................... 130 3.3. Uncertainties and limitations about favourable effects ........................................ 130 3.4. Unfavourable effects ...................................................................................... 131 3.5. Uncertainties and limitations about unfavourable effects .................................... 132 3.6. Effects Table ................................................................................................. 132 3.7. Benefit-risk assessment and discussion ............................................................ 134 3.7.1. Importance of favourable and unfavourable effects ............................................ 134 3.7.2. Balance of benefits and risks ........................................................................... 134 3.7.3. Additional considerations on the benefit-risk balance ......................................... 135 3.8. Conclusions .................................................................................................. 136 4. Recommendations ............................................................................... 136 Assessment report EMA/CHMP/95252/2021 Page 3/138 List of abbreviations Abbreviation Definition ACN acetonitrile AE adverse event ALT alanine aminotransferase ANC absolute neutrophil count ASCT autologous stem cell transplant AST aspartate aminotransferase BCLPD bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab BCPD bortezomib, carfilzomib, pomalidomide, and daratumumab C1D1 Cycle 1 Day 1 CAR-T chimeric antigen receptor-T cell therapy CBR clinical benefit rate CHMP Committee for Medicinal Products for Human use CI confidence interval CLPD carfilzomib, lenalidomide, pomalidomide, and daratumumab CPD carfilzomib, pomalidomide, and daratumumab CQA Critical Quality Attribute CR complete response CSR clinical study report CT computed tomography DCB duration of clinical benefit DCR disease control rate DIPEA N,N-Diisopropylethylamine DoE Design of experiments DOR duration of response Double-class refractory refractory to at least 1 proteasome inhibitor and at least 1 immunomodulatory drug (including glucocorticoids) DSC Differential Scanning Calorimetry DVS Dynamic Vapor Sorption ECOG Eastern Cooperative Oncology Group EU European Union FACT-MM Functional Assessment of Cancer Therapy–Multiple Myeloma FDA Food and Drug Administration; FHAD Flatiron Health Analytic Database FLC free light chain FMEA Failure mode effects analysis Assessment report EMA/CHMP/95252/2021 Page 4/138 Abbreviation Definition FT-IR Fourier transform infrared spectroscopy GC glucocorticoid GC gas chromatography GR glucocorticoid receptor GTI Genotoxic Impurities HDPE High density polyethylene HPLC High performance liquid chromatography HR hazard ratio HRMS High resolution mass spectrometry ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for
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