Australian Public Assessment Report for Evolocumab (rch) Proprietary Product Name: Repatha Sponsor: Amgen Australia Pty Ltd May 2016 Therapeutic Goods Administration About the Therapeutic Goods Administration (TGA) • The Therapeutic Goods Administration (TGA) is part of the Australian Government Department of Health and is responsible for regulating medicines and medical devices. • The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance) when necessary. • The work of the TGA is based on applying scientific and clinical expertise to decision- making, to ensure that the benefits to consumers outweigh any risks associated with the use of medicines and medical devices. • The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. TGA investigates reports received by it to determine any necessary regulatory action. • To report a problem with a medicine or medical device, please see the information on the TGA website <https://www.tga.gov.au>. About AusPARs • An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. • An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2016 This work is copyright. You may reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the TGA Copyright Officer, Therapeutic Goods Administration, PO Box 100, Woden ACT 2606 or emailed to <[email protected]>. AusPAR Repatha Evolocumab (rch) Amgen Australia Pty Ltd PM-2014-03144-1-3 Page 2 of 112 Final 3 May 2016 Therapeutic Goods Administration Contents Common abbreviations _______________________________________________________ 5 I. Introduction to product submission ___________________________________ 10 Submission details ___________________________________________________________________ 10 Product background _________________________________________________________________ 11 Regulatory status ____________________________________________________________________ 13 Product Information_________________________________________________________________ 13 II. Quality findings ___________________________________________________________ 13 Drug substance (active ingredient) ________________________________________________ 13 Drug product _________________________________________________________________________ 15 Biopharmaceutics ___________________________________________________________________ 15 Quality summary and conclusions _________________________________________________ 15 III. Nonclinical findings _____________________________________________________ 15 Introduction __________________________________________________________________________ 15 Pharmacology ________________________________________________________________________ 15 Pharmacokinetics ____________________________________________________________________ 25 Toxicology ____________________________________________________________________________ 26 Nonclinical summary ________________________________________________________________ 32 Nonclinical conclusions _____________________________________________________________ 35 IV. Clinical findings __________________________________________________________ 35 Introduction __________________________________________________________________________ 36 Pharmacokinetics ____________________________________________________________________ 39 Pharmacodynamics__________________________________________________________________ 43 Dosage selection for the pivotal studies ___________________________________________ 44 Efficacy _______________________________________________________________________________ 45 Evaluator's conclusions on clinical efficacy _______________________________________ 46 Safety _________________________________________________________________________________ 54 V. Pharmacovigilance findings ____________________________________________ 65 Risk management plan ______________________________________________________________ 65 VI. Overall conclusion and risk/benefit assessment __________________ 74 Quality ________________________________________________________________________________ 74 Nonclinical ___________________________________________________________________________ 74 Clinical ________________________________________________________________________________ 75 Risk management plan ______________________________________________________________ 93 Risk-benefit analysis ________________________________________________________________ 93 Outcome ____________________________________________________________________________ 110 AusPAR Repatha Evolocumab (rch) Amgen Australia Pty Ltd PM-2014-03144-1-3 Page 3 of 112 Final 3 May 2016 Therapeutic Goods Administration Attachment 1. Product Information _____________________________________111 Attachment 2. Extract from the Clinical Evaluation Report _________111 AusPAR Repatha Evolocumab (rch) Amgen Australia Pty Ltd PM-2014-03144-1-3 Page 4 of 112 Final 3 May 2016 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning ACC American College of Cardiology ACTH Adrenocorticotropic hormone AE Adverse event AHA American Heart Association AI/Pen Auto injector/pen ALP Alkaline phosphatase ALT Alanine aminotransferase AMD Automated mini-doser ANCOVA Analysis of covariance ApoA1 Apolipoprotein A1 ApoB Apolipoprotein B AST Aspartate aminotransferase AUC Area under the curve BP Blood pressure CABG Coronary artery bypass graft CAS Completer analysis set CBC Complete blood count CEC Clinical endpoint committee CETP Cholesterylester transfer protein CHD Coronary heart disease CK Creatine kinase Cmax Maximal concentration CMH Cochran-Mantel Haenszel statistical test for categorical variables CRP C-reactive protein CSR Clinical study report AusPAR Repatha Evolocumab (rch) Amgen Australia Pty Ltd PM-2014-03144-1-3 Page 5 of 112 Final 3 May 2016 Therapeutic Goods Administration Abbreviation Meaning CTCAE NCI Common Terminology Criteria for AEs CVS Cardiovascular system CVD Cardiovascular disease DBP Diastolic blood pressure DILI Drug-induced liver injury DMC Data monitoring committee EAS European atherosclerosis committee ECG Electrocardiogram eCRF Electronic case report form eGFR Estimated glomerular filtration rate EOS End of study (for individual subject) EU European Union EvoMab Evolocumab FAS Full analysis set FDA Food and Drug Administration FH Familial hypercholesterolaemia FSH Follicle-stimulating hormone GCP Good Clinical Practice HbA1c Haemoglobin A1c HeFH Heterozygous familial hypercholesterolaemia HCV Hepatitis C virus HDL-C High density lipoprotein cholesterol HLGT High level group term HoFH Homozygous familial hypercholesterolaemia HR Heart Rate hsCRP High sensitivity CRP AusPAR Repatha Evolocumab (rch) Amgen Australia Pty Ltd PM-2014-03144-1-3 Page 6 of 112 Final 3 May 2016 Therapeutic Goods Administration Abbreviation Meaning IBG Independent Biostatistical Group ICH International Conference on Harmonization IEAAS Integrated expansion all-IP period analysis set IECAS Integrated extension SOC-controlled period analysis set IEC/IRB Independent Ethics Committee / Institutional Review Board INR International normalized ratio IP Investigational product IPAS Integrated parent analysis set iSAP Integrated statistical analysis plan ISE Integrated summary of efficacy ISS Integrated summary of safety IVRS/IWRS Interactive Voice Response System/Interactive Web Response System IV Intravenous LDH Lactate dehydrogenase LDL-C Low-density lipoprotein cholesterol LDLR LDL receptor LH Luteinizing hormone LLN Lower limit of normal LLOQ Lower limit of quantitation LOCF Last observation carried forward Lp(a) Lipoprotein(a) LS Least squares LSM Least squares mean MAS Monotherapy analysis set MedDRA Medical dictionary for regulatory activities AusPAR Repatha Evolocumab (rch) Amgen Australia Pty Ltd PM-2014-03144-1-3 Page 7 of 112 Final 3 May 2016 Therapeutic Goods Administration Abbreviation Meaning NCEP ATP III National Cholesterol Education Program Adult Treatment Panel III NYA New York Heart Association PCI Percutaneous coronary intervention PCSK9 Proprotein convertase subtilisin/kexin