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Praluent, INN-Alirocumab 23 July 2015 EMA/CHMP/392430/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Praluent International non-proprietary name: alirocumab Procedure No. EMEA/H/C/003882/0000 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, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure ............................................ 14 1.1. Submission of the dossier .................................................................................... 14 1.2. Steps taken for the assessment of the product ....................................................... 15 2. Scientific discussion .............................................................................. 16 2.1. Introduction....................................................................................................... 16 2.2. Quality aspects .................................................................................................. 17 2.2.1. Introduction .................................................................................................... 17 2.2.2. Active Substance ............................................................................................. 17 2.2.3. Finished Medicinal Product ................................................................................ 20 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 23 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 24 2.2.6. Recommendation(s) 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 ...................................................................................................... 27 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 28 2.3.6. Discussion on non-clinical aspects...................................................................... 28 2.3.7. Conclusion on the non-clinical aspects ................................................................ 29 2.4. Clinical aspects .................................................................................................. 29 2.4.1. Introduction .................................................................................................... 29 2.4.2. Pharmacokinetics............................................................................................. 33 2.4.3. Pharmacodynamics .......................................................................................... 45 2.4.4. Discussion on clinical pharmacology ................................................................... 50 2.4.5. Conclusions on clinical pharmacology ................................................................. 53 2.5. Clinical efficacy .................................................................................................. 53 2.5.1. Dose response studies...................................................................................... 53 2.5.2. Main studies ................................................................................................... 55 2.5.3. Discussion on clinical efficacy ............................................................................ 79 2.5.4. Conclusions on the clinical efficacy ..................................................................... 82 2.6. Clinical safety .................................................................................................... 82 2.6.1. Discussion on clinical safety ............................................................................ 117 2.6.2. Conclusions on the clinical safety ..................................................................... 121 2.7. Risk Management Plan ...................................................................................... 122 2.8. Pharmacovigilance ............................................................................................ 125 2.9. Product information .......................................................................................... 126 2.9.1. User consultation ........................................................................................... 126 2.9.2. Additional monitoring ..................................................................................... 126 3. Benefit-Risk Balance............................................................................ 126 4. Recommendations ............................................................................... 133 Assessment report EMA/CHMP/392430/2015 Page 2/134 List of abbreviations µg Microgram µM Micrometer A Absorbance A280 UV Absorbance at 280 nm AAV Adeno-associated Virus ACS Acute coronary syndrome ACTH Adrenocorticotropic hormone ADA Anti-drug antibodies ADCC Antibody-dependent cell-mediated cytotoxicity ADH Autosomal dominant hypercholesterolemia ADI Acceptable daily intake AE Adverse event AEX Anion exchange chromatography ALT Alanine aminotransferase AMD Automated mini doser (formerly referred to as LVI [larger volume injector] and 3.5 mL personal injector) ANOVA Analysis of variance Apo A-1: Apolipoprotein A-1 ApoB Apolipoprotein B ApoE Apolipoprotein E ApoE-/- Apolipoprotein E-deficient AQL Acceptance quality level AST Aspartate aminotransferase ATP Adult treatment panel AUC Area under the curve (systemic exposures) AUCinf Area under the concentration-time curve from time 0 to infinity AUClast Area under the concentration time curve from time 0 to the last quantifiable concentration AUCx-y Area under the concentration-time curve from time x to time y AUECx-y Area under the effect curve from time x to time y BA Bioavailability BAV Bovine adenovirus Assessment report EMA/CHMP/392430/2015 Page 3/134 BBB Blood Brain Barrier BD Birth day BE Bioequivalence BLA Biologics license application BMI Body mass index BP Bubble point bpm Beats per minute BSA Bovine serum albumin BSE Bovine spongiform encephalopathy BUN Blood urea nitrogen C1q Complement component 1, q subcomponent CAD Coronary artery disease CAS Completer analysis set CAS Chemical Abstracts Service CCI Container closure integrity CD Circular dichroism CD81 Cluster of differentiation 81, a major component of the hepatitis C virus entry complex CDC Complement-dependent cytotoxicity cDNA Complimentary deoxyribonucleic acid CDR Complimentary determining region CE-HPLC Cation exchange high performance liquid chromatography CE-SDS Capillary electrophoresis - sodium dodecyl sulfate CETP Cholesteryl ester transfer protein CFU Colony forming units cGMP Current Good Manufacturing Practices CH Constant domain of the heavy chain CHD Coronary heart disease CHMP Committee for Medicinal Products for Human Use CHO Chinese hamster ovary CHO-K1 Epithilioid cell line originally isolated from the Chinese hamster ovaries CI Confidence interval cIEF Capillary isoelectric focusing Assessment report EMA/CHMP/392430/2015 Page 4/134 CK Creatine kinase CL Clearance CL Constant domain of the light chain CL/F Estimated mean apparent clearance Cmax Maximum concentration CMC Chemistry, Manufacturing, and Controls CMQ Company MedDRA Query CNS Central nervous system CO2 Carbon dioxide CoA Certificate of Analysis CPP Critical process parameter CQA Critical quality attribute CrCL Creatinine clearance CSR Clinical study report CTCAE Common Terminology Criteria for Adverse Events CTD Common Technical Document CV Coefficient of variation CV Column volume CV Cardiovascular CVD Cardiovascular disease Da Dalton DBP: Diastolic blood pressure DDI Drug-drug-interactions DF Diafiltration DM: Diabetes mellitus DMC Data monitoring committee DNA Deoxyribonucleic acid DO Dissolved oxygen DOE Design of experiment DP Drug product DS Drug substance EC50 Area under the concentration-time curve from week 8 to week 12 required to achieve half-maximal response Assessment report EMA/CHMP/392430/2015 Page 5/134 ECG Electrocardiogram Eff Effect magnitude EGF Epidermal Growth Factor eGFR Estimated glomerular filtration rate ELISA Enzyme linked immunosorbent assay EPC End of production cells EPD Embryo-foetal and Postnatal Development ePPND Enhanced pre- and post-natal development ESI-TOF Electrospray ionization - time of flight EU Endotoxin units F Bioavailability FAS Full analysis set FBS Foetal bovine serum FcRn Neonatal Fc receptor FDA Food and Drug Administration FDS Formulated drug substance FH Familial hypercholesterolemia FTIR Fourier transform infrared spectroscopy G0F,G1F, G2F Fucosylated glycans with zero (G0F), one (G1F) or two (G2F) galactose residues GCP Good Clinical Practice GD Gestation day GLP Good Laboratory Practice GMP Good Manufacturing Practices GOF Gain of Function GOFm Gain-of function
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