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Nerventra Laquinimod 22 May 2014 EMA/451905/2014 Committee for Medicinal Products for Human Use (CHMP) Nerventra laquinimod Procedure No. EMEA/H/C/002546 Applicant: Teva Pharma GmbH Assessment report as adopted by the CHMP with all commercially confidential information 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 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 ........................................................ 9 1.3. Steps taken for the re-examination procedure ....................................................... 10 2. Scientific Discussion .............................................................................. 11 2.1. Introduction ...................................................................................................... 11 2.2. Quality aspects .................................................................................................. 12 2.2.1. Introduction ................................................................................................... 12 2.2.2. Active Substance ............................................................................................. 12 2.2.3. Finished Medicinal Product ................................................................................ 14 2.2.4. Discussion on chemical, pharmaceutical and biological aspects ............................. 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 16 2.2.6. Recommendation(s) for future quality development ............................................. 16 2.3. Non-clinical aspects ............................................................................................ 17 2.3.1. Introduction ................................................................................................... 17 2.3.2. Pharmacology ................................................................................................. 17 2.3.3. Pharmacokinetics ............................................................................................ 19 2.3.4. Toxicology ...................................................................................................... 20 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 26 2.3.6. Discussion on non-clinical aspects ..................................................................... 27 2.3.7. Conclusion on the non-clinical aspects ............................................................... 34 2.4. Clinical aspects .................................................................................................. 34 2.4.1. Introduction ................................................................................................... 34 2.4.2. Pharmacokinetics ............................................................................................ 36 2.4.3. Pharmacodynamics .......................................................................................... 39 2.4.4. Discussion on clinical pharmacology .................................................................. 40 2.4.5. Conclusions on clinical pharmacology ................................................................. 41 2.5. Clinical efficacy .................................................................................................. 42 2.5.1. Dose response studies ..................................................................................... 42 2.5.2. Main studies ................................................................................................... 43 2.5.3. Discussion on clinical efficacy............................................................................ 77 2.5.4. Conclusions on the clinical efficacy .................................................................... 84 2.6. Clinical safety .................................................................................................... 84 2.6.1. Patient exposure ............................................................................................. 84 2.6.2. Adverse events ............................................................................................... 85 2.6.3. Serious adverse event/deaths/other significant events ......................................... 87 2.6.4. Laboratory, ECG findings, Vital signs ................................................................. 93 2.6.5. Safety in special populations ............................................................................. 96 2.6.6. Safety related to drug-drug interactions and other interactions ............................. 96 2.6.7. Discontinuation due to adverse events ............................................................... 96 2.6.8. Post marketing experience ............................................................................... 97 2.6.9. Additional analyses .......................................................................................... 97 2.6.10. Discussion on clinical safety ............................................................................ 98 2.6.11. Conclusions on the clinical safety ................................................................... 101 Nerventra EMA/451905/2014 Page 2/138 2.7. Pharmacovigilance ........................................................................................... 101 2.8. Risk Management Plan ...................................................................................... 101 2.9. User consultation ............................................................................................. 106 3. Benefit-Risk Balance ........................................................................... 106 4. Recommendations ............................................................................... 111 5. Re-examination of the CHMP opinion of 23 January 2014 ................... 111 5.1. Detailed grounds for re-examination submitted by the applicant ............................ 112 5.2. Additional expert consultation ............................................................................ 122 5.3. Overall conclusion on grounds for re-examination ................................................ 127 5.4. Updated Benefit-Risk Balance ............................................................................ 132 5.5. Recommendations following re-examination ........................................................ 137 Nerventra EMA/451905/2014 Page 3/138 List of abbreviations 9-HPT 9-Hole Peg Test ACTH Adrenocorticotropic Hormone AE Adverse Event AhR Aryl hydrocarbon receptor ALT Alanine transaminase/Alanine Aminotransferase ANCOVA Analysis of Covariance AST Aspartate transaminase/Aspartate Aminotransferase AUC Area Under Curve AV Atrioventricular BCS Biopharmaceutical Classification System CALUX Chemically-Activated Luciferase Expression CDP Confirmed Disability Progression CEP Certificate of Suitability to the monographs of the European Pharmacopoeia CGR Country and Geographical Region CHMP Committee for Medicinal Products for Human Use CI Confidence Interval Cmax Maximum Plasma Concentration Cmin Minimum Plasma Concentration CNS Central Nervous System CO Completers (cohort) CPRD Clinical Practice Research DataLink CQA Critical Quality Attribute CRP C-Reactive Protein CTCAE Common Terminology Criteria for Adverse Events CYPs Cytochromes DELAQ N-deethylated metabolite DLC Dioxin-like compounds DMSO Dimethyl sulfoxide DMT Disease Modifying Therapy DOE Design of Experiments DVT Deep Venous Thrombosis EAE Experimental Autoimmune Encephalomyelitis EC European Commission EC20 Effective concentration at 20% ECG Electrocardiogram ED50 Effective dose at 50% (Median Effective Dose) ED90 Effective dose at 90% EDSS Expanded Disability Status Scale EMA European Medicines Agency EQ-5D European Quality of Life-5 Dimensions Health Survey Nerventra EMA/451905/2014 Page 4/138 ER Estrogen Receptor ERA Environmental Risk Assessment ESR Erythrocyte Sedimentation Rate EU European Union EV Evaluable (cohort) FMEA Failure Mode Effect Analysis GA Glatiramer Acetate GC Gas Chromatography GCP Good Clinical Practices GD Gestation Day Gd Gadolinium GdE Gadolinium Enhancing GGT Gamma Glutamyl Transferase GI Gastrointestinal GLP Good Laboratory Practices GPRD General Practice Research Database HCT Hematocrit hERG human ether-a-go-go-related gene HIV Human Immunodeficiency Virus HPLC High Performance Liquid Chromatography HR Hazard Ratio I3C Indol-3-Carbinol ICH International Conference On Harmonization IFN Interferon Ig Immunoglobulin IHD Ischaemic Heart Disease IM or i.m Intramuscular IR Infrared ITT Intention to Treat IV or i.v Intravenous IVRS Centralised Interactive Voice Response System IWRS Interactive Web Response System KF Karl Fisher KLH Keyhole Limpet Hemocyanin Kow Octanol/water partition coefficient LAQ Laquinimod LC-MS/MS Liquid Chromatography Tandem Mass Spectrometry LDPE Low density polyethylene LOAEL Lowest Observed Adverse Effect Level MCQME methyl 5-chloro-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylate MCV Mean Cell Volume MFIS Modified Fatigue Impact Scale MNAR Missing Not At Random MNBN Micronucleated Binucleated (cell) Nerventra EMA/451905/2014
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