26 March 2020 EMA/200482/2020 Committee for Medicinal Products for Human Use (CHMP) Committee for Advanced Therapies (CAT) Assessment report Zolgensma International non-proprietary name: onasemnogene abeparvovec Procedure No. EMEA/H/C/004750/0000 Note The CAT Assessment report has been endorsed 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, 2020. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 6 1.1. Submission of the dossier ...................................................................................... 6 1.2. Steps taken for the assessment of the product ......................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Problem statement ............................................................................................. 10 2.1.1. Disease or condition ......................................................................................... 10 2.1.2. Epidemiology .................................................................................................. 11 2.1.3. Biologic features .............................................................................................. 11 2.1.4. Clinical presentation and diagnosis .................................................................... 12 2.1.5. Management ................................................................................................... 13 2.2. Quality aspects .................................................................................................. 14 2.2.1. Introduction .................................................................................................... 14 2.2.2. Active Substance ............................................................................................. 14 2.2.1. Finished Medicinal Product ................................................................................ 18 2.2.2. Discussion on chemical, pharmaceutical and biological aspects .............................. 23 2.2.3. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 24 2.2.4. Recommendation(s) for future quality development ............................................. 25 2.3. Non-clinical aspects ............................................................................................ 26 2.3.1. Pharmacology ................................................................................................. 26 2.3.2. Pharmacokinetics............................................................................................. 32 2.3.3. Toxicology ...................................................................................................... 35 2.3.4. Ecotoxicity/environmental risk assessment ......................................................... 43 2.3.5. Discussion on the non-clinical aspects ................................................................ 49 2.3.6. Conclusion on non-clinical aspects ..................................................................... 54 2.4. Clinical aspects .................................................................................................. 55 2.4.1. Introduction .................................................................................................... 55 2.4.2. Pharmacokinetics............................................................................................. 59 2.4.3. Pharmacodynamics .......................................................................................... 60 2.4.4. Discussion on clinical pharmacology ................................................................... 63 2.4.5. Conclusions on clinical pharmacology ................................................................. 64 2.5. Clinical efficacy .................................................................................................. 65 2.5.1. Dose finding ................................................................................................... 65 2.5.2. Main studies ................................................................................................... 65 2.5.3. Supportive studies ........................................................................................... 78 2.5.4. Discussion on clinical efficacy ............................................................................ 96 2.5.5. Conclusions on the clinical efficacy ................................................................... 102 2.6. Clinical safety .................................................................................................. 103 2.6.1. Discussion on clinical safety ............................................................................ 125 2.6.2. Conclusions on the clinical safety ..................................................................... 128 2.7. Risk Management Plan ...................................................................................... 132 2.8. Pharmacovigilance ............................................................................................ 133 2.9. New Active Substance ....................................................................................... 133 2.10. Product information ........................................................................................ 133 2.10.1. User consultation ......................................................................................... 133 EMA/200482/2020 Page 2/150 2.10.2. Labelling exemptions .................................................................................... 134 2.10.3. Additional monitoring ................................................................................... 134 3. Benefit risk assessment ....................................................................... 134 3.1. Therapeutic Context ......................................................................................... 134 3.1.1. Disease or condition ....................................................................................... 134 3.1.2. Available therapies and unmet medical need ..................................................... 135 3.1.3. Main clinical studies ....................................................................................... 135 3.2. Favourable effects ............................................................................................ 136 3.3. Uncertainties and limitations about favourable effects ........................................... 138 3.4. Unfavourable effects ......................................................................................... 139 3.5. Uncertainties and limitations about unfavourable effects ....................................... 140 3.6. Effects Table .................................................................................................... 140 3.7. Co-primary endpoint: proportion of patients achieving independent sitting .............. 141 3.8. Benefit-risk assessment and discussion ............................................................... 142 3.8.1. Importance of favourable and unfavourable effects ............................................ 142 3.8.2. Balance of benefits and risks ........................................................................... 144 3.8.3. Additional considerations ................................................................................ 145 3.9. Conclusions ..................................................................................................... 148 4. Recommendations ............................................................................... 148 EMA/200482/2020 Page 3/150 List of abbreviations Abbreviation Definition AAV adeno-associated virus AAV9 adeno-associated virus serotype 9 ACTIVE-mini Ability Captured Through Interactive Video Evaluation – mini ADaM Analysis Data Model AE adverse event ALT alanine aminotransferase AST aspartate aminotransferase ASO antisense oligonucleotide BiPAP bi-level positive airway pressure CDISC Clinical Data Interchange Standards Consortium CHOP-INTEND Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders CMAP compound motor action potential CMV cytomegalovirus CSF cerebrospinal fluid CSR clinical study report ddPCR droplet digital polymerase chain reaction DILI drug-induced liver injury DSMB Data Safety Monitoring Board ECAS efficacy completer analysis set ECG electrocardiogram EES efficacy evaluable set EIM electrical impedance myography EMA European Medicines Agency EU European Union FAS full analysis set FDA Food and Drug Administration GMP Good Manufacturing Practice ICD-10 10th Revision of the International Classification of Diseases and Related Health Problems ICH International Council for Harmonization IQR interquartile range IRB Institutional Review. Board Inspections IT intrathecal ITR inverted terminal repeats ITT intent-to-treat IV intravenous LOCF last observation carried forward LS least squares Max maximum Min minimum mITT modified intent-to-treat MMRM mixed model repeated measure mRNA messenger ribonucleic acid MUNE motor unit number