21 April 2017 EMA/31226/2017 Committee for Medicinal Products for Human Use (CHMP) Assessment report Brineura International non-proprietary name: cerliponase alfa Procedure No. EMEA/H/C/004065/0000 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 5520 Send a question via our website www.ema.europa.eu/contact An agency of the European Union 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 ........................................................ 7 2. Scientific discussion ................................................................................ 9 2.1. Problem statement ............................................................................................... 9 2.1.1. Disease or condition .......................................................................................... 9 2.1.2. Epidemiology .................................................................................................... 9 2.1.3. Biologic features, aetiology and pathogenesis ....................................................... 9 2.1.4. Clinical presentation, diagnosis and stage/prognosis ............................................ 10 2.1.5. Management ................................................................................................... 10 2.2. About the product .............................................................................................. 10 2.3. Quality aspects .................................................................................................. 11 2.3.1. Introduction.................................................................................................... 11 2.4. Active Substance ............................................................................................... 11 2.4.1. Finished Medicinal Product ................................................................................ 14 2.4.2. Discussion on chemical, pharmaceutical and biological aspects.............................. 17 2.4.3. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17 2.4.4. Recommendation(s) for future quality development ............................................. 18 2.5. Non-clinical aspects ............................................................................................ 18 2.5.1. Introduction.................................................................................................... 18 2.5.2. Pharmacology ................................................................................................. 18 2.5.3. Pharmacokinetics ............................................................................................ 19 2.5.4. Toxicology ...................................................................................................... 20 2.5.5. Ecotoxicity/environmental risk assessment ......................................................... 21 2.5.6. Discussion on non-clinical aspects ..................................................................... 21 2.5.7. Conclusion on the non-clinical aspects ............................................................... 23 2.6. Clinical aspects .................................................................................................. 23 2.6.1. Introduction.................................................................................................... 23 2.6.2. Pharmacokinetics ............................................................................................ 24 2.6.3. Pharmacodynamics .......................................................................................... 25 2.6.4. Discussion on clinical pharmacology ................................................................... 26 2.6.5. Conclusions on clinical pharmacology ................................................................. 26 2.7. Clinical efficacy .................................................................................................. 27 2.7.1. Dose response study........................................................................................ 27 2.7.2. Main study ..................................................................................................... 27 2.7.3. Discussion on clinical efficacy ............................................................................ 57 2.7.4. Conclusions on the clinical efficacy .................................................................... 63 2.8. Clinical safety .................................................................................................... 64 2.8.1. Discussion on clinical safety .............................................................................. 72 2.8.2. Conclusions on the clinical safety ...................................................................... 76 2.9. Risk Management Plan ........................................................................................ 77 Assessment report EMA/312226/2017 Page 2/95 2.10. Pharmacovigilance ............................................................................................ 79 2.11. New Active Substance ....................................................................................... 79 2.12. Product information .......................................................................................... 79 2.12.1. User consultation ........................................................................................... 79 2.12.2. Labelling exemptions ..................................................................................... 79 2.12.3. Additional monitoring ..................................................................................... 79 3. Benefit-Risk Balance ............................................................................. 80 3.1. Therapeutic Context ........................................................................................... 80 3.1.1. Disease or condition ........................................................................................ 80 3.1.2. Available therapies and unmet medical need ....................................................... 80 3.1.3. Main clinical studies ......................................................................................... 80 3.2. Favourable effects .............................................................................................. 81 3.3. Uncertainties and limitations about favourable effects ............................................. 82 3.4. Unfavourable effects ........................................................................................... 83 3.5. Uncertainties and limitations about unfavourable effects ......................................... 84 3.6. Effects Table ...................................................................................................... 85 3.7. Benefit-risk assessment and discussion ................................................................. 89 3.7.1. Importance of favourable and unfavourable effects .............................................. 89 3.7.2. Balance of benefits and risks ............................................................................ 90 3.7.3. Additional considerations on the benefit-risk balance ........................................... 90 3.8. Conclusions ....................................................................................................... 91 4. Recommendations ................................................................................. 91 Assessment report EMA/312226/2017 Page 3/95 List of abbreviations ADA Anti-drug antibodies ADE Acceptable daily exposure AE Adverse event API Active pharmaceutical ingredient BBB Blood brain barrier BMN 190 Recombinant human tripeptidyl peptidase-1 CE-LIF Capillary electrophoresis with laser induced fluorescence CFS Cerebrospinal fluid CHO Chinese Hamster Ovary CHOP CHO proteins, host cell proteins CI-M6PR Cation-independent mannose-6-phosphate receptor CLN2 Classical late infantile CLN2, cLINCL, or Jansky-Bielschowsky disease CQA Critical quality attributes CRF Case report form CSF Cerebrospinal fluid CSR Clinical study report CT Computed tomography CTCAE Common Terminology Criteria for Adverse Events CZE-LIF Capillary Zone Electrophoresis/Laser-Induced Fluorescence Detection DBP Diastolic blood pressure DMC Data Monitoring Committee DP Drug product DS Drug substance EOPC End of Production Cells ERT Enzyme replacement therapy FBDS Formulated bulk drug substance FS Flushing solution HCCF Harvested cell culture fluid HIC Hydrophobic interaction chromatography HIPAA Health Insurance Portability and Accountability Act HTST High-Temperature-Short-Time ICF Informed consent form ICV Intracerebroventricular IEC Independent Ethics Committee IgE Immunoglobulin E ICP-MS Inductively coupled plasma mass spectrometry ICP-OES Inductively coupled plasma optical emission spectrometry IM Intramuscular IND Investigational New Drug (application) IRB Institutional Review Board cIEF Capillary Isoelectric Focusing IT-C Intrathecal-cisternal IT-L Intrathecal-lumbar ITT Intent-to-treat IVC Intracerebroventricularly LCA Limit of in vitro cell age Assessment report EMA/312226/2017