19 July 2012 EMA/882900/2011 Committee for Medicinal Products for Human Use (CHMP) Assessment Report Glybera authorised International Nonproprietary Name: Alipogene tiparvovec longer Procedure No. EMEA/H/C/002145 no Note Assessment Report as adopted byproduct the CHMP with all information of a commercially confidential nature deleted. Medicinal 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union Table of contents (The CHMP report includes the CAT and CHMP assessment of the initial application, the re-examination procedure and the assessment following the European Commission request dated 30 January 2012) 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier.................................................................................... 6 1.2. The Steps taken for the assessment of the product ................................................. 7 1.3. Steps taken for the re-examination procedure ........................................................ 8 1.5 Steps taken following the EC request for assessment of the benefit risk in patients with severe or multiple pancreatitis attacks......................................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction .................................................................................................... 10 2.2. Quality aspects ................................................................................................ 12 2.2.1. Introduction .................................................................................................authorised 12 2.2.2. Active Substance........................................................................................... 12 2.2.3. Finished Medicinal Product .............................................................................. 16 2.2.4. Discussion on chemical, pharmaceutical and biological aspects............................. 19 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ..................... 22 2.2.6. Recommendation(s) for future quality developmenlongert............................................ 23 2.3. Non-clinical aspects .......................................................................................... 23 2.3.1. Introduction ................................................................................................. 23 2.3.2. Pharmacology ...............................................................................................no 23 2.3.3. Pharmacokinetics .......................................................................................... 26 2.3.4. Toxicology.................................................................................................... 27 2.3.5. Discussion on non-clinical aspects.................................................................... 31 2.3.6. Conclusion on the non-clinical aspects .............................................................. 32 2.4. Clinical aspects ................................................................................................ 33 2.4.1. Introduction .................................................................................................product 33 2.4.2. Pharmacokinetics .......................................................................................... 34 2.4.3. Pharmacodynamics........................................................................................ 36 2.4.4. Discussion on clinical pharmacology ................................................................. 37 2.4.5. Conclusions on clinical pharmacology ............................................................... 38 2.5. Clinical efficacy ................................................................................................ 38 2.5.1. Preparation-01 study (supportive study for CT-AMT-010-01) ............................... 39 2.5.2. MedicinalCT-AMT-010-01 study .................................................................................... 42 2.5.3. Preparation-02 study (supportive study for CT-AMT-011-01) ............................... 45 2.5.4. CT-AMT-011-01 study .................................................................................... 47 2.5.5. CT-AMT-011-02 study .................................................................................... 53 2.5.6. CT-AMT-011-03 study (Pooled analysis of all pancreatitis data further to CAT request)57 2.5.7. Discussion on clinical efficacy .......................................................................... 61 2.5.8. Conclusions on the clinical efficacy................................................................... 69 Assessment report EMA/882900/2011 Page 2/147 2.6. Clinical safety .................................................................................................. 70 2.6.1. Discussion and conclusions on clinical safety ..................................................... 72 2.7. Pharmacovigilance............................................................................................ 73 2.8. Significance Non-Conformity of paediatric studies ................................................. 73 2.9. User consultation ............................................................................................. 73 2.10. GMO / Environmental risk assessment............................................................... 73 3. Benefit-Risk Balance.............................................................................. 81 4. Initial Recommendations June 2011 ..................................................... 85 5. Re-examination of the CHMP opinion..................................................... 86 6. CAT assessment following the EC Request to CHMP dated 30 January 2012 ................................................................................................................ 104 6.1. Background information ...................................................................................104 6.2. Assessment of the answer provided by the applicant ............................................104 Clinical safety data in the restricted patient population................................................116authorised 7. Overall CAT and CHMP discussion on the restricted patient population117 8. Pharmacovigilance .............................................................................. 122 8.1. User consultation ............................................................................................129 8.2. GMO / Environmental risk assessment................................................................129longer 9. CAT BENEFIT-RISK BALANCE...............................................................no 130 10. CHMP BENEFIT-RISK BALANCE .......................................................... 134 11. CHMP Final Recommendation July 2012 ............................................ 139 product Medicinal Assessment report EMA/882900/2011 Page 3/147 List of abbreviations AAV adeno-associated virus AAV1 adeno-associated virus serotype 1 AAV2 adeno-associated virus serotype 2 AMT Amsterdam Molecular Therapeutics bp base pairs BVDV Bovine viral diarrhoea virus, BWP Biotechnology Working Party CAL Cells at limit of or beyond the maximum level used for production cap capsid CAT Committee for Advanced Therapy Medicinal Products CHMP Committee for Human Medicinal Products CM chylomicrons CMV cytomegalovirus CPK creatine phosphokinase CPV Canine Parvovirus CSA ciclosporin A CYP cytochrome P450 DNA deoxyribonucleic acid DP Drug Product DS Drug Substance authorised ELISA Enzyme Linked Immunosorbant Assay EMCV Encephalomyocarditis Virus EMEA/EMA European Medicines Agency ERA Environmental Risk Assessment gDNA genomic DNA gc genome copies GFP Green Fluorescent Protein GCP Good Clinical Practice longer GD Gestation Day GLP Good Laboratory Practice GMP Good Manufacturing Practice GTWP Gene Therapy Working Party no HBx Hepatitis B Protein X HDL high-density lipoprotein HDL-C high-density lipoprotein cholesterol HR Homologous Repeats ICH International Conference on Harmonisation ICU intensive care unit IM intramuscular INN International Nonproprietary Name ip infectious particles ITRs inverted terminal repeatsproduct IV intravenous LAM-PCR Linear Amplification-Mediated PCR LDL Low Density Lipoproteins LOD limit of detection LoI List of outstanding issues LOQ limit of quantification LoQ List of questions LPL lipoprotein lipase gene LPL lipoprotein lipase LPLD lipoprotein lipase deficiency LPL-/- Medicinal homozygous lipop rotein lipase deficient LPL+/- heterozygous lipoprotein lipase deficient LTFU Long-Term Follow Up MCB Master Cell Bank MMF mycophenolate mofetil MOI multiplicity of infection MSV Master Seed Virus n number N/A not applicable Assessment report EMA/882900/2011 Page 4/147 NGS Next Generation Sequencing NOAEL non-observable-adverse-effect level ORF open reading frame PBS phosphate buffer solution PETG Polyethylene Terephthalate Copolyester Ph. Eur. European Pharmacopoeia PP CM post-prandial chylomicronemia PRE Post Transcriptional Regulatory Elements PRV Pseudorabies Virus QC quality control Q-PCR quantitative Polymerase Chain Reaction QPPV Qualified Person for Pharmacovigilance rc replication competent rep replicase RMP Risk Management