17 September 2020 EMA/522604/2020 Corr.1 Committee for Medicinal Products for Human Use (CHMP) Assessment report Velphoro Common name: sucroferric oxyhydroxide Procedure No. EMEA/H/C/002705/X/0020/G 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 An agency of the European Union Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 © European Medicines Agency, 2021. 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. Problem statement ............................................................................................... 8 2.1.1. Disease or condition ........................................................................................... 8 2.1.2. Epidemiology and risk factors, screening tools/prevention ...................................... 8 2.1.3. Biologic features ................................................................................................ 8 2.1.4. Clinical presentation ........................................................................................... 8 2.1.5. Management ..................................................................................................... 8 2.2. Quality aspects .................................................................................................. 10 2.2.1. Introduction .................................................................................................... 10 2.2.2. Active Substance ............................................................................................. 11 2.2.3. Finished Medicinal Product ................................................................................ 11 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............................................................................................. 16 2.3.4. Toxicology ...................................................................................................... 16 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 16 2.3.6. Discussion on non-clinical aspects...................................................................... 16 2.3.7. Conclusion on the non-clinical aspects ................................................................ 16 2.4. Clinical aspects .................................................................................................. 17 2.4.1. Introduction .................................................................................................... 17 2.4.2. Pharmacokinetics............................................................................................. 17 2.4.3. Pharmacodynamics .......................................................................................... 18 2.4.4. Discussion on clinical pharmacology ................................................................... 18 2.4.5. Conclusions on clinical pharmacology ................................................................. 18 2.5. Clinical efficacy .................................................................................................. 18 2.5.1. Dose response studies...................................................................................... 18 2.5.2. Main study ...................................................................................................... 18 2.5.3. Discussion on clinical efficacy ............................................................................ 54 2.5.4. Conclusions on the clinical efficacy ..................................................................... 59 2.6. Clinical safety .................................................................................................... 60 2.6.1. Discussion on clinical safety .............................................................................. 74 2.6.2. Conclusions on the clinical safety ....................................................................... 76 2.7. Risk Management Plan ........................................................................................ 76 2.8. Pharmacovigilance .............................................................................................. 76 2.9. Product information ............................................................................................ 76 2.9.1. User consultation ............................................................................................. 76 Assessment report EMA/522604/2020 Page 2/84 3. Benefit-Risk Balance.............................................................................. 77 3.1. Therapeutic Context ........................................................................................... 77 3.1.1. Disease or condition ......................................................................................... 77 3.1.2. Available therapies and unmet medical need ....................................................... 77 3.1.3. Main clinical studies ......................................................................................... 77 3.2. Favourable effects .............................................................................................. 78 3.3. Uncertainties and limitations about favourable effects ............................................. 78 3.4. Unfavourable effects ........................................................................................... 79 3.5. Uncertainties and limitations about unfavourable effects ......................................... 79 3.6. Effects Table ...................................................................................................... 80 3.7. Benefit-risk assessment and discussion ................................................................. 81 3.7.1. Importance of favourable and unfavourable effects .............................................. 81 3.7.2. Balance of benefits and risks ............................................................................. 82 3.7.3. Additional considerations on the benefit-risk balance ........................................... 82 3.8. Conclusions ....................................................................................................... 82 4. Recommendations ................................................................................. 82 Assessment report EMA/522604/2020 Page 3/84 List of abbreviations Alb albumin ALP alkaline phosphatase ALT alanine aminotransferase APTT activated partial thromboplastin time AST aspartate aminotransferase AUC Area under the concentration-time curve BW body weight Chol cholesterol CKD Chronic kidney disease Cmax Peak plasma concentration Crea creatinine CRF Chronic renal failure CYP Cytochrome P450 DDI Drug-drug interaction DPD Deoxypyrodinoline EMA European Medicines Agency (previously EMEA) ESRD End stage renal disease Epi epithelium FDA Food and Drug Administration GI Gastrointestinal GLP Good Laboratory Practice GMP Good Manufacturing Practice GRAS Generally regarded as safe Hb haemoglobin Hct haematocrit hERG Human ether-a-go-go related gene ICH International Conference on Harmonisation LN lymph node Macroph macrophage MCH mean cell haemoglobin MCHC mean cell haemoglobin concentration MCV mean cell volume Mesen mesenteric m/m Mass per mass NOEL No observed effect level NOAEL No observed adverse effect level PDE Permitted daily exposure Ph. Eur. European Pharmacopoeia Phos phosphate PT prothrombin time PTH Parathyroid hormone RBC red blood cell Retic reticulocyte RES Reticulo-endothelial system SCFA Short-chain fatty acids SG specific gravity Assessment report EMA/522604/2020 Page 4/84 TG triglyceride TIBC total iron binding capacity TIM TNO gastrointestinal model of stomach and small intestine (TIM-1) and large intestine (TIM-2) US United States USP United States Pharmacopoeia Vol Volume Assessment report EMA/522604/2020 Page 5/84 1. Background information on the procedure 1.1. Submission of the dossier Vifor Fresenius Medical Care Renal Pharma France submitted on 20 August 2019 a group of variation(s) consisting of extensions of the marketing authorisation and the following variation: Variation(s) requested Type C.I.6.a C.I.6.a - Change(s) to therapeutic indication(s) - Addition of a new II therapeutic indication or modification of