Amsterdam, 9 April 2020 EMA/CHMP/199869/2020 Rev 2 Committee for Medicinal Products for Human Use (CHMP) Assessment report Zeposia International non-proprietary name: ozanimod Procedure No. EMEA/H/C/004835/0000 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 .............................................. 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. Problem statement ............................................................................................. 12 2.1.1. Disease or condition ......................................................................................... 12 2.1.2. Epidemiology .................................................................................................. 12 2.1.3. Aetiology and pathogenesis .............................................................................. 12 2.1.4. Clinical presentation, diagnosis .......................................................................... 13 2.1.5. Management ................................................................................................... 13 2.2. About the product .............................................................................................. 15 2.3. Quality aspects .................................................................................................. 15 2.3.1. Introduction .................................................................................................... 15 2.3.2. Active Substance ............................................................................................. 16 2.3.3. Finished Medicinal Product ................................................................................ 19 2.3.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 23 2.3.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 23 2.3.6. Recommendation for future quality development ................................................. 23 2.4. Non-clinical aspects ............................................................................................ 24 2.4.1. Introduction .................................................................................................... 24 2.4.2. Pharmacology ................................................................................................. 24 2.4.3. Pharmacokinetics............................................................................................. 26 2.4.4. Toxicology ...................................................................................................... 27 2.4.5. Ecotoxicity/environmental risk assessment ......................................................... 32 2.4.6. Discussion on non-clinical aspects...................................................................... 32 2.4.7. Conclusion on the non-clinical aspects ................................................................ 35 2.5. Clinical aspects .................................................................................................. 35 2.5.1. Introduction .................................................................................................... 35 2.5.2. Pharmacokinetics............................................................................................. 44 2.5.3. Pharmacodynamics .......................................................................................... 56 2.5.4. Discussion on clinical pharmacology ................................................................... 62 2.5.5. Conclusions on clinical pharmacology ................................................................. 63 2.6. Clinical efficacy .................................................................................................. 64 2.6.1. Dose response study ........................................................................................ 66 2.6.2. Main studies ................................................................................................... 68 2.6.3. Discussion on clinical efficacy .......................................................................... 105 2.6.4. Conclusions on the clinical efficacy ................................................................... 112 2.7. Clinical safety .................................................................................................. 113 2.7.1. Discussion on clinical safety ............................................................................ 151 2.7.2. Conclusions on the clinical safety ..................................................................... 159 2.8. Risk Management Plan ...................................................................................... 160 2.9. Pharmacovigilance ............................................................................................ 165 2.10. New Active Substance ..................................................................................... 165 Assessment report EMA/CHMP/199869/2020 Page 2/188 2.11. Product information ........................................................................................ 165 2.11.1. User consultation ......................................................................................... 165 2.11.2. Labelling exemptions .................................................................................... 165 2.11.3. Quick Response (QR) code ............................................................................ 166 2.11.4. Additional monitoring ................................................................................... 166 3. Benefit-Risk Balance............................................................................ 166 3.1. Therapeutic Context ......................................................................................... 166 3.1.1. Disease or condition ....................................................................................... 166 3.1.2. Available therapies and unmet medical need ..................................................... 166 3.1.3. Main clinical studies ....................................................................................... 167 3.2. Favourable effects ............................................................................................ 167 3.3. Uncertainties and limitations about favourable effects ........................................... 169 3.4. Unfavourable effects ......................................................................................... 171 3.5. Uncertainties and limitations about unfavourable effects ....................................... 173 3.6. Effects Table .................................................................................................... 176 3.7. Benefit-risk assessment and discussion ............................................................... 178 3.7.1. Importance of favourable and unfavourable effects ............................................ 178 3.7.2. Balance of benefits and risks ........................................................................... 181 3.7.3. Additional considerations on the benefit-risk balance ......................................... 182 3.8. Conclusions ..................................................................................................... 182 4. Recommendations ............................................................................... 183 Assessment report EMA/CHMP/199869/2020 Page 3/188 List of abbreviations 4MSU 4-months safety update 9HPT 9-hole peg test AE Adverse event ADH Alcohol dehydrogenase ADME Absorption, distribution, metabolism, and excretion ADRs Adverse Drug Reactions AESI Adverse event of special interest AKR Aldo-keto reductase ALC Absolute lymphocyte count ALDH Aldehyde dehydrogenase ALT Alanine aminotransferase ANCOVA Analysis of covariance ARR Annualized relapse rate AST Aspartate aminotransferase AUC Area under the concentration-time curve AUC0-24 Area under the plasma concentration time curve over 24 hours AV Atrioventricular BCRP Breast cancer resistance protein BMI Body mass index CD Crohn’s disease CDP Confirmed disability progression CDP-3M Confirmed disability progression at 3 months CDP-6M Confirmed disability progression at 6 months CFU Colony Forming Unit CHMP Committee for Medicinal Products for Human Use CI Confidence interval Cmax Maximum plasma concentration CL/F Apparent oral clearance CNS Central nervous system COPD Chronic obstructive pulmonary disease CQAs Critical Quality Attributes CR Copy-reference CSR Clinical study report CTD Common technical document CYP Cytochrome P450 DBP Diastolic blood pressure DDI Drug-drug interaction DLCO Diffusing capacity for carbon monoxide DMT Disease-modifying treatment Assessment report EMA/CHMP/199869/2020 Page 4/188 DoE Design of