Reasanz; INN Serelaxin
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22 May 2014 EMA/303748/2014 Committee for Medicinal Products for Human Use (CHMP) Assessment report Reasanz International non-proprietary name: serelaxin Procedure No. EMEA/H/C/002817 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 Product information Name of the medicinal product: Reasanz Applicant: Novartis Europharm Ltd Wimblehurst Road Horsham West Sussex RH12 5AB UNITED KINGDOM Active substance: serelaxin International Nonproprietary Name/Common serelaxin Name: Pharmaco-therapeutic group (ATC Code): C01DX21 Therapeutic indication (as applied for) : Reasanz is indicated for the treatment of acute heart failure and to reduce mortality in patients with acute heart failure. Pharmaceutical form: Concentrate for solution for infusion Strengths: 1 mg/ml Route of administration: Intravenous use Packaging: vial (glass) Package size: 1 vial Assessment report EMA/303748/2014 Page 2/112 Table of contents 1. Background information on the procedure ............................................ 10 1.1. Submission of the dossier .................................................................................... 10 1.2. Steps taken for the assessment of the product ....................................................... 11 Steps taken for the re-examination procedure .............................................................. 12 2. Scientific discussion .............................................................................. 12 2.1. Introduction....................................................................................................... 12 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction .................................................................................................... 14 2.2.2. Active Substance ............................................................................................. 14 2.2.3. Finished Medicinal Product ................................................................................ 15 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 17 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17 2.3. Non-clinical aspects ............................................................................................ 17 2.3.1. Introduction .................................................................................................... 17 2.3.2. Pharmacology ................................................................................................. 18 2.3.3. Pharmacokinetics............................................................................................. 20 2.3.4. Toxicology ...................................................................................................... 22 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 23 2.3.6. Discussion on non-clinical aspects...................................................................... 23 2.3.7. Conclusion on the non-clinical aspects ................................................................ 24 2.4. Clinical aspects .................................................................................................. 24 2.4.1. Introduction .................................................................................................... 24 2.4.2. Pharmacokinetics............................................................................................. 28 2.4.3. Pharmacodynamics .......................................................................................... 31 2.4.4. Discussion on clinical pharmacology ................................................................... 33 Pharmacokinetics ...................................................................................................... 33 Pharmacodynamics ................................................................................................... 34 2.4.5. Conclusions on clinical pharmacology ................................................................. 35 2.5. Clinical efficacy .................................................................................................. 35 2.5.1. Dose response study (Pre-RELAX) ..................................................................... 36 2.5.2. Main study (RELAX-AHF) .................................................................................. 39 2.5.3. Discussion on clinical efficacy ............................................................................ 63 2.5.4. Conclusions on the clinical efficacy ..................................................................... 69 2.6. Clinical safety .................................................................................................... 69 2.6.1. Discussion on clinical safety .............................................................................. 86 2.6.2. Conclusions on the clinical safety ....................................................................... 88 2.7. Pharmacovigilance .............................................................................................. 88 2.8. Risk Management Plan ........................................................................................ 88 2.9. User consultation ............................................................................................... 92 Assessment report EMA/303748/2014 Page 3/112 3. Benefit-Risk Balance ............................................................................. 92 4. Recommendations ................................................................................. 99 5. Re-examination of the CHMP opinion of 23 January 2014 ................... 101 5.1 Detailed grounds for re-examination submitted by the applicant ............................. 101 5.2 Scientific Advisory Group on Cardiovascular Issues (SAG CVS) ................................ 106 5.3 Overall conclusion on grounds for re-examination .................................................. 108 5.4 Recommendations following re-examination ......................................................... 110 Assessment report EMA/303748/2014 Page 4/112 List of abbreviations AA Aldosterone antagonists ACE Angiotensin converting enzyme AE Adverse event AHF Acute Heart Failure AR Assessment report ARB Angiotensin receptor blocker Asp Aspartate, Aspartic acid AUC Area under the concentration-time curve AUC0-t Area under the serum concentration-time curve from time zero to time t, using the linear trapezoidal rule. Concentrations below the LLOQ are set to zero and therefore excluded from the calculation. Actual sample collection times are used. Where 0-t is shown as τ this denotes the AUC under a dosing interval AUCinf Area under the serum concentration-time curve from time zero to infinity. For extrapolation to infinity Clast / λz is used, where Clast is the estimated concentration at the last sample time point above LLOQ from linear regression of the terminal elimination phase BET Bacterial endotoxins test BNP B-type natriuretic peptide BP Blood Pressure bpm beats per minute BUN Blood urea nitrogen C48hr The observed serum concentration at 48 hours after the start of drug administration CBL Chesapeake biological laboratories CBPDE Confirmed Blood Pressure Decrease Event CCU Coronary Care Unit CEC Clinical Endpoint Committee CHF Chronic Heart Failure cGMP Current good manufacturing practice CI Cardiac Index CL Rate of clearance (serum or systemic) CL and CL/F Systemic (or total body) clearance, calculated as Dose / AUCinf following intravenous administration. For extravascular administration where absolute bioavailability is less than 100%, clearance is represented as CL/F Clast Last observed serum concentration CLCR Creatinine clearance Cmax Maximum serum concentration after a single dose CMO Contract manufacturing organisation Assessment report EMA/303748/2014 Page 5/112 CNS Central nervous system CO Cardiac output CPP Critical process parameter CRF Case Report Form CRL Charles River Laboratories Css Steady-state concentration CTD Common technical document CV Coefficient of variation CV Cardiovascular CYP Cytochrome P450 DBP Diastolic Blood Pressure DDI Drug-drug interactions DNA Deoxyribonucleic acid DO Dissolved oxygen DP Drug product DRE Disease-related event DS Drug substance E. coli Escherichia coli ECG Electrocardiogram eGFR Estimated glomerular filtration rate ELISA Enzyme-linked immunosorbent assay EMA European Medicines Agency ERK1/2 Extracellular-signal-regulated kinases ET Endothelin ET-1 Endothelin isoform 1 ETA Endothelial endothelin type A receptor ETB Endothelial endothelin type B receptor FDA Food and Drug Administration GCP Good clinical practice GD Gestational Day GFR Glomerular filtration rate GLP Good Laboratory Practice hERG human Ether-à-go-go-Related Gene HF Heart Failure HR Hazard ratio hs-cTnT High-sensitivity cardiac troponin T IC50 Inhibitory Concentration 50% ICH International conference on harmonisation ICU Intensive Care Unit Assessment report EMA/303748/2014 Page 6/112 IGF Insulin-like growth factor INN International non-proprietary name INSL Insulin-like IPC In-process control Iso-Asp Isoaspartate, isoaspartic