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Parsabiv H-3995 15 September 2016 EMA/664198/2016 Committee for Medicinal Products for Human Use (CHMP) Assessment report Parsabiv International non-proprietary name: etelcalcetide Procedure No. EMEA/H/C/003995/0000 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 © European Medicines Agency, 2016. 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 ........................................................ 7 2. Scientific discussion ................................................................................ 8 2.1. Introduction ........................................................................................................ 8 2.1.1. Problem statement ............................................................................................ 8 2.1.2. About the product ............................................................................................. 9 2.2. Quality aspects .................................................................................................... 9 2.2.1. Introduction...................................................................................................... 9 2.2.2. Active Substance ............................................................................................. 10 General information .................................................................................................. 10 Manufacture, characterisation and process controls ....................................................... 10 Specification ............................................................................................................ 11 Stability................................................................................................................... 12 2.2.3. Finished Medicinal Product ................................................................................ 12 Manufacture of the product and process controls .......................................................... 13 Product specification ................................................................................................. 13 Stability of the product .............................................................................................. 14 Adventitious agents .................................................................................................. 15 2.2.4. Discussion on chemical, pharmaceutical and biological aspects.............................. 15 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 15 2.2.6. Recommendations for future quality development ............................................... 15 2.3. Non-clinical aspects ............................................................................................ 15 2.3.1. Introduction.................................................................................................... 15 2.3.2. Pharmacology ................................................................................................. 15 2.3.3. Pharmacokinetics ............................................................................................ 17 2.3.4. Toxicology ...................................................................................................... 20 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 23 2.3.6. Discussion on non-clinical aspects ..................................................................... 23 2.3.7. Conclusion on non-clinical aspects ..................................................................... 25 2.4. Clinical aspects .................................................................................................. 25 2.4.1. Introduction.................................................................................................... 25 2.4.2. Pharmacokinetics ............................................................................................ 26 2.4.3. Pharmacodynamics .......................................................................................... 28 2.4.4. Discussion on clinical pharmacology ................................................................... 32 2.4.5. Conclusions on clinical pharmacology ................................................................. 32 2.5. Clinical efficacy .................................................................................................. 33 2.5.1. Dose response studies ..................................................................................... 33 2.5.2. Main studies ................................................................................................... 33 2.5.3. Discussion on clinical efficacy ............................................................................ 55 Assessment report EMA/664198/2016 Page 2/98 2.5.4. Conclusions on clinical efficacy .......................................................................... 60 2.6. Clinical safety .................................................................................................... 61 2.6.1. Discussion on clinical safety .............................................................................. 80 2.6.2. Conclusions on clinical safety ............................................................................ 83 2.7. Risk Management Plan ........................................................................................ 83 2.8. Pharmacovigilance ............................................................................................. 87 2.9. Product information ............................................................................................ 87 2.9.1. User consultation ............................................................................................ 87 2.9.2. Additional monitoring ....................................................................................... 87 3. Benefit-Risk Balance ............................................................................. 87 Discussion on the benefit-risk assessment ................................................................... 95 4. Recommendations ................................................................................. 97 Assessment report EMA/664198/2016 Page 3/98 List of abbreviations ADME absorption, distribution, metabolism, excretion AMG 416 Etelcalcetide AUC area under the concentration-time curve BDC bile duct cannulated BSAP bone specific alkaline phosphatase CaSR calcium-sensing receptor cCA corrected calcium cCa x P corrected calcium-phosphorus product CI confidence interval CKD Chronic Kidney Disease CMH Cochran-Mantel-Haenszel CPP Critical process parameter CQA Critical quality attribute CTX collagen C-telopeptide DOPPS Dialysis Outcomes and Practice Patterns Study EAP efficacy assessment period EC European Commission EMA European Medicines Agency ERA-EDTA European Renal Association–European Dialysis and Transplant Association ESRD end-stage renal disease EU European Union EVOLVE EValuation Of Cinacalcet Therapy to Lower CardioVascular Events, Study 20050182 FGF-23 fibroblast growth factor-23 FMEA Failure mode effects analysis FMoc Fluorenylmethyloxycarbonyl GC Gas Chromatography GLP Good Laboratory Practice GMP Good Manufacturing Practice HPLC High performance liquid chromatography SHPT Secondary Hyperparathyroidism IC Ion chromatography ICH International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use IPC In-process control ICP-MS Inductively coupled plasma mass spectrometry IV Intravenous JP Japanese Pharmacopoeia KDIGO Kidney Disease: Improving Global Outcomes KDOQI Kidney Disease Outcome Quality Initiative KF Karl Fischer titration LE Long Evans MedDRA Medical Dictionary for Regulatory Activities NMR Nuclear Magnetic Resonance NOAEL no observed adverse effect level NOE Nuclear Overhauser Effect P Phosphorus Ph. Eur. European Pharmacopoeia PIP Paediatric Investigation Plan Assessment report EMA/664198/2016 Page 4/98 PK Pharmacokinetics PRO patient reported outcome PTG parathyroid gland PTH parathyroid hormone PVC Poly vinyl chloride QbD Quality by design QD once daily QTc corrected QT interval QTcF Fridericia-corrected QT interval RH Relative Humidity RTU ready to use SAP statistical analysis plan SAPC serum albumin peptide conjugate SC Subcutaneous SD Sprague Dawley SD standard deviation SE standard error SmPC Summary of Product Characteristics SMQ Standardized Medical Dictionary for Regulatory Activities Queries TFA trifluoroacetic acid TIW three times a week TK Toxicokinetics USP United States Pharmacopoeia UV/Vis Ultraviolet/visible spectroscopy WFI Water for injections Assessment report EMA/664198/2016 Page 5/98 1. Background information on the procedure 1.1. Submission of the dossier The applicant Amgen Europe B.V. submitted on 2 September 2015 an application for Marketing Authorisation to the European Medicines Agency (EMA) for Parsabiv, through the centralised procedure under Article 3(2)(a) of
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