London, 21 March 2013 EMA/305826/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Kynamro Solution for injection 189mg International non-proprietary name: mipomersen Procedure No. EMEA/H/C/002429/0000 Assessment report as adopted by the CHMP with all information of a commercially confidential nature 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 ..................................... 5 2. SCIENTIFIC DISCUSSION ............................................................................. 8 2.1 Introduction ............................................................................................... 8 2.2. Quality aspects ......................................................................................... 9 2.2.1. Introduction .......................................................................................... 9 2.2.2. Active Substance .................................................................................... 9 2.2.3. Finished Medicinal Product ......................................................................12 2.2.4. Discussion on chemical, pharmaceutical and biological aspects ...................15 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ............16 2.3. Non-clinical aspects ..................................................................................16 2.3.1. Introduction .........................................................................................16 2.3.2. Pharmacology .......................................................................................17 2.3.3. Pharmacokinetics ..................................................................................19 2.3.4. Toxicology ............................................................................................21 2.3.5. Discussion on non-clinical aspects ...........................................................28 2.3.6. Conclusion on the non-clinical aspects .....................................................29 2.4. Clinical aspects ........................................................................................30 2.4.1. Introduction .........................................................................................30 2.4.2. Pharmacokinetics ..................................................................................32 2.4.3. Pharmacodynamics ................................................................................35 2.4.4. Discussion on clinical pharmacology ........................................................36 2.4.5. Conclusions on clinical pharmacology .......................................................38 2.5. Clinical efficacy ........................................................................................39 2.5.1. Dose response studies ...........................................................................40 2.5.2. Main studies .........................................................................................42 2.5.3. Discussion on clinical efficacy ..................................................................58 2.5.4. Conclusions on the clinical efficacy ..........................................................61 2.6. Clinical safety ..........................................................................................61 2.6.1. Discussion on clinical safety ....................................................................72 2.6.2. Conclusions on the clinical safety ............................................................78 2.7. Pharmacovigilance ...................................................................................79 2.8. User consultation .....................................................................................81 3. BENEFIT-RISK BALANCE ............................................................................ 82 4. RECOMMENDATIONS .................................................................................. 88 5. APPENDIX ................................................................................................ 113 Kynamro Page 2/114 List of abbreviations ACE angiotensin-converting enzyme ADR adverse drug reaction AE adverse event ALT alanine aminotransferase Amu atomic mass unit Apo A apolipoprotein A Apo B apolipoprotein B ApoB-100 Apoliloproptein B-100 ASO antisense oligonucleotide AST aspartate aminotransferase AUC area under the concentration-time curve AUC(INF) area under the concentration-time curve to infinity BID twice daily BMI body-mass index BRB bilirubin C cholesterol CDP clinical development plan CGE-UV capillary gel electrophoresis with ultraviolet detection CHD coronary heart disease CHMP Committee for Medicinal Products for Human Use CI confidence interval CL plasma clearance Cmax maximum plasma concentration CNS central nervous system CQAs Critical Quality Attributes CrCl creatinine clearance CRP C-reactive protein CSR clinical study report CT computed tomography CV(S) cardiovascular CWL Cool white fluorescent light CYP cytochrome P450 DNA deoxyribonucleic acid ELISA enzyme-linked immunosorbent assay EMA European Medicines Agency E-R exposure-response EU European Union FDA Food and Drug Administration (US) FH familial hypercholesterolaemia FLS flu like symptom FTIR Fourier transform infrared spectroscopy GC Gas chromatography GLP Good Laboratory Practices HA health authority HDL-C high density lipoprotein cholesterol HeFH heterozygous familial hypercholesterolaemia HMG-CoA hydroxyl-methyl-glutaryl-Coenzyme A HoFH homozygous familial hypercholesterolaemia HPLC High Performance Liquid Chromatography HsCRP High sensitivity C-reactive protein ICAC independent central adjudication committee ICH International Conference on Harmonisation ICH International Conference on Harmonization Kynamro Page 3/114 IDL intermediate density lipoprotein IRMPD-FT-ICR-MS infrared multi-photon decomposition-Fourier transform-ion cyclotron resonance-mass spectrometry ISR injection site reaction IV intravenous(ly) i.v. intravenous(ly) KF Karl Fischer LC-MS/MS Liquid chromatography with tandem mass spectrometry LDL low density lipoprotein LDL-C low-density lipoprotein cholesterol LDPE Low Density Polyethylene LFT liver function test Lp[a] lipoprotein A LSC Liquid scintillation counting MAA Marketing Authorisation Application MedDRA Medical Dictionary of Regulatory Activities mg milligram ml milliliter MOE 2′- methoxyethyl mRNA messenger RNA MTD maximum tolerated dose MTP microsomal triglyceride transfer protein NADPH nicotinamide adenine dinucleotide phosphate NMR Nuclear Magnetic Resonance NOAEL no-observed-adverse-effect-level OLE open-label extension PD pharmacodynamic(s) PET primary efficacy timepoint PFS Pre-filled syringes Ph. Eur.European Pharmacopoeia PK pharmacokinetic(s) PO oral(ly) Pop-PK population pharmacokinetics QD once daily QOW every other week QW once weekly QWBA quantitative whole-body autoradiography RBC red blood parameters RMP Risk Management Plan RNA ribonucleic acid ROW rest of world SA Scientific Advice SAE serious adverse event SC subcutaneous(ly) s.c. subcutaneous(ly) SCE Summary of Clinical Efficacy SOP Standard Operating Procedures SPC Summary of Product Characteristics TC total cholesterol ULN upper limit of normal US United States Vc/F apparent volume of distribution of the central compartment VLDL very low density lipoprotein WFI Water for injection Kynamro Page 4/114 1. Background information on the procedure 1.1. Submission of the dossier The applicant Genzyme Europe BV submitted on 28 July 2011 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Kynamro, through the centralised procedure under Article 3(2)(a) of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 23 September 2010. The applicant applied for the following indication: Kynamro is an apolipoprotein B (apo B) synthesis inhibitor indicated as an adjunct to maximally tolerated lipid-lowering medications and diet to reduce low density lipoprotein-cholesterol (LDL-C), apo B, total cholesterol (TC), non-high density lipoprotein-cholesterol (non-HDL-C) and lipoprotein (a) [Lp(a)] in patients with homozygous familial hypercholesterolaemia (HoFH) and in patients with severe heterozygous familial hypercholesterolaemia (severe HeFH). The legal basis for this application refers to: Article 8.3 of Directive 2001/83/EC, as amended - complete and independent application. The application submitted is composed of administrative information, complete quality data, non-clinical and clinical data based on applicants’ own tests and studies and/or bibliographic literature substituting/supporting certain tests or studies. Information on Paediatric requirements Pursuant to Article 7 of Regulation (EC) No 1901/2006, the application included an EMA Decision(s) P/139/2011 on the agreement of a paediatric investigation plan (PIP). At the time of submission of the application, the PIP P/139/2011 was not yet completed as some measures were deferred. Information relating to orphan market exclusivity Similarity Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised orphan medicinal products because there