30 January 2020 EMA/CHMP/70703/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Givlaari International non-proprietary name: givosiran Procedure No. EMEA/H/C/004775/0000 Note Assessment report as adopted 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 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ..................................................................................... 7 1.2. Steps taken for the assessment of the product ........................................................ 9 2. Scientific discussion .............................................................................. 11 2.1. Problem statement ............................................................................................. 11 2.1.1. Disease or condition ........................................................................................ 11 2.1.2. Epidemiology and risk factors ........................................................................... 11 2.1.3. Aetiology and pathogenesis .............................................................................. 11 2.1.4. Clinical presentation, diagnosis and stage/prognosis ............................................ 12 2.1.5. Management ................................................................................................... 12 2.2. Quality aspects .................................................................................................. 14 2.2.1. Introduction.................................................................................................... 14 2.2.2. Active Substance ............................................................................................. 14 General information .................................................................................................. 14 Manufacture, characterisation and process controls ....................................................... 16 Specification ............................................................................................................ 18 Stability................................................................................................................... 19 2.2.3. Finished Medicinal Product ................................................................................ 19 Description of the product and Pharmaceutical development .......................................... 19 Manufacture of the product and process controls .......................................................... 22 Product specification ................................................................................................. 22 Stability of the product .............................................................................................. 23 Adventitious agents .................................................................................................. 24 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 24 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 ............................................................................................ 25 2.3.1. Introduction.................................................................................................... 25 2.3.2. Pharmacology ................................................................................................. 25 2.3.3. Pharmacokinetics ............................................................................................ 30 2.3.4. Toxicology ...................................................................................................... 39 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 45 2.3.6. Discussion on non-clinical aspects ..................................................................... 46 2.3.7. Conclusion on the non-clinical aspects ............................................................... 47 2.4. Clinical aspects .................................................................................................. 48 2.4.1. Introduction.................................................................................................... 48 2.4.2. Pharmacokinetics ............................................................................................ 49 2.4.3. Pharmacodynamics .......................................................................................... 54 2.4.4. Discussion on clinical pharmacology ................................................................... 56 2.4.5. Conclusions on clinical pharmacology ................................................................. 57 Assessment report EMA/CHMP/70703/2020 Page 2/101 2.5. Clinical efficacy .................................................................................................. 58 2.5.1. Dose response studies ..................................................................................... 58 2.5.2. Main study ..................................................................................................... 59 2.5.3. Discussion on clinical efficacy ............................................................................ 78 2.5.4. Conclusions on the clinical efficacy .................................................................... 81 2.6. Clinical safety .................................................................................................... 81 2.6.1. Discussion on clinical safety .............................................................................. 87 2.6.2. Conclusions on the clinical safety ...................................................................... 88 2.7. Risk Management Plan ........................................................................................ 88 2.8. Pharmacovigilance ............................................................................................. 94 2.9. New Active Substance ........................................................................................ 94 2.10. Product information .......................................................................................... 95 2.10.1. User consultation ........................................................................................... 95 2.10.2. Additional monitoring ..................................................................................... 95 3. Benefit-Risk Balance ............................................................................. 95 3.1. Therapeutic Context ........................................................................................... 95 3.1.1. Disease or condition ........................................................................................ 95 3.1.2. Available therapies and unmet medical need ....................................................... 96 3.1.3. Main clinical studies ......................................................................................... 96 3.2. Favourable effects .............................................................................................. 96 3.3. Uncertainties and limitations about favourable effects ............................................. 97 3.4. Unfavourable effects ........................................................................................... 97 3.5. Uncertainties and limitations about unfavourable effects ......................................... 98 3.6. Effects Table ...................................................................................................... 98 3.7. Benefit-risk assessment and discussion ................................................................. 99 3.7.1. Importance of favourable and unfavourable effects .............................................. 99 3.7.2. Balance of benefits and risks .......................................................................... 100 3.8. Conclusions ..................................................................................................... 100 4. Recommendations ............................................................................... 100 Assessment report EMA/CHMP/70703/2020 Page 3/101 List of abbreviations AAR Annualized attack rate ADA Anti-drug antibodies ADP ALAD-deficient porphyria AE Adverse events Af 2ʹ-fluoroadenosine AHP Acute hepatic porphyria AIP Acute intermittent porphyria ALA Aminolevulinic acid ALAD Aminolevulinic acid dehydratase ALAS1 Aminolevulinate synthase 1 ALT Alanine aminotransferase Am 2ʹ-O-methyladenosine ANCOVA Analysis of covariance AS Atomic Spectroscopy ASGPR Asialoglycoprotein receptor AST Aspartate aminotransferase AX Anion Exchange BPI-SF Brief Pain Inventory (Short Form) BMI Body mass index cERD circulating extracellular RNA detection Cf 2ʹ-fluorocytidine CHE Chronic high excreters CKD Chronic kidney disease CLR Clearance Cm 2ʹ-O-methylcytidine CPP Critical process parameter CPV Continuous process verification CQA Critical quality attribute DMT 4,4'-dimethoxy trityl DS Drug substance eGFR Estimated