Australian Public Assessment for Lipegfilgrastim (Rbe)
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Australian Public Assessment Report for Lipegfilgrastim (rbe) Proprietary Product Name: Lonquex Sponsor: Teva Pharma Australia Pty Ltd February 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 Lonquex Lipegfilgrastim (rbe) Teva Pharma Australia Pty Ltd, PM- 2014-03142-1-4 Page 2 of 60 Final 23 February 2016 Therapeutic Goods Administration Contents Common abbreviations _______________________________________________________ 5 I. Introduction to product submission _____________________________________ 9 Submission details ____________________________________________________________________ 9 Product background __________________________________________________________________ 9 Regulatory status ____________________________________________________________________ 10 Product Information_________________________________________________________________ 11 II. Quality findings ___________________________________________________________ 12 Drug substance (active ingredient) ________________________________________________ 12 Drug product _________________________________________________________________________ 13 Biopharmaceutics ___________________________________________________________________ 14 Quality summary and conclusions _________________________________________________ 14 III. Nonclinical findings _____________________________________________________ 15 Introduction __________________________________________________________________________ 15 Pharmacology ________________________________________________________________________ 15 Pharmacokinetics ____________________________________________________________________ 16 Pharmacokinetic drug interactions ________________________________________________ 17 Toxicology ____________________________________________________________________________ 17 Nonclinical summary and conclusions _____________________________________________ 21 Nonclinical conclusions and recommendation ____________________________________ 22 IV. Clinical findings __________________________________________________________ 22 Introduction __________________________________________________________________________ 22 Pharmacokinetics ____________________________________________________________________ 24 Pharmacodynamics__________________________________________________________________ 26 Dosage selection for the pivotal studies ___________________________________________ 28 Efficacy _______________________________________________________________________________ 31 Safety _________________________________________________________________________________ 32 First round benefit-risk assessment _______________________________________________ 34 First Round Recommendation Regarding Authorisation _________________________ 34 Clinical Questions ____________________________________________________________________ 35 Second Round Evaluation of clinical data submitted in response to questions_ 36 Second round recommendation regarding authorisation ________________________ 36 V. Pharmacovigilance findings ____________________________________________ 36 Risk management plan ______________________________________________________________ 36 VI. Overall conclusion and risk/benefit assessment __________________ 47 Quality ________________________________________________________________________________ 47 AusPAR Lonquex Lipegfilgrastim (rbe) Teva Pharma Australia Pty Ltd, PM- 2014-03142-1-4 Page 3 of 60 Final 23 February 2016 Therapeutic Goods Administration Nonclinical ___________________________________________________________________________ 47 Clinical ________________________________________________________________________________ 47 Risk management plan ______________________________________________________________ 55 Risk-benefit analysis ________________________________________________________________ 55 Outcome ______________________________________________________________________________ 59 Attachment 1. Product Information ______________________________________ 59 Attachment 2. Extract from the Clinical Evaluation Report __________ 59 AusPAR Lonquex Lipegfilgrastim (rbe) Teva Pharma Australia Pty Ltd, PM- 2014-03142-1-4 Page 4 of 60 Final 23 February 2016 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning γ-GT -glutamyl-transferase ADA γAnti-drug-antibody AE Adverse Event ALAT Alanine aminotransferase ALP Alkaline phosphatase ALT Alanine aminotransferase ANC Absolute neutrophil count ANOVA Analysis of variance aPPT Activated partial thromboplastin time ASAT Aspartate aminotransferase ATC Anatomical therapeutic chemical AUC Area under the curve AUC0-t Area under the curve from the time of dosing to the time of the last observation AUClast Area under the curve from the time of dosing to the last measurable concentration AUC0-∞ Area under the curve from the time of dosing extrapolated to infinity, based on the last observed concentration BW Body weight CHMP Committee of Human Medicinal Products CI Confidence interval CK Creatine kinase CL Total body clearance Cmax Highest observed plasma concentration CML Chronic myelogenous leukemia CPA/CTX Cyclophosphamide CYP450 Cytochrome P450 DNA Deoxyribonucleic acid AusPAR Lonquex Lipegfilgrastim (rbe) Teva Pharma Australia Pty Ltd, PM- 2014-03142-1-4 Page 5 of 60 Final 23 February 2016 Therapeutic Goods Administration Abbreviation Meaning DNS Duration of severe neutropenia DPF Dose proportion factor EC70 Effective concentration of drug substances that lead to a 70% viability of the NFS-60 cells ECG Electrocardiography ECL Electro-chemiluminescence EMA European Medicines Agency EORTC European Organisation for Research and Treatment of Cancer FN Febrile neutropenia G-CSF Granulocyte colony stimulating factor GalNAc N-Acetylgalactosamine GD Gestation day GLDH Glutamate-dehydrogenase HCT Haematocrit HD High dose HGB Haemoglobin content IA Intra-arterial IgG Immunoglobulin G IgM Immunoglobulin M IM Intramuscular IP Intraperitoneal ISS Integrated Summary of Safety ITT Intent-to-Treat IV Intravenous LC/MS/MS Liquid chromatography/tandem mass spectrometry LD Low dose LDH Lactate dehydrogenase LDS Loading-dye sample buffer LI Lobularity index LLOD Lower limit of detection AusPAR Lonquex Lipegfilgrastim (rbe) Teva Pharma Australia Pty Ltd, PM- 2014-03142-1-4 Page 6 of 60 Final 23 February 2016 Therapeutic Goods Administration Abbreviation Meaning LLOQ Lower limit of quantification LOD Limit of detection LLOQ Limit of quantification LPS Lipoplysaccharides LS Least square MCH Mean corpuscular haemoglobin MCHC Mean corpuscular haemoglobin concentration MCV Mean corpuscular volume MD Medium dose MedDRA Medical Dictionary for Regulatory Activities MFI Median fluorescent intensity mPEG Methoxypolyethylene glycol MSR Minimal significant ratio NFS60 Mouse myelogenous leukaemia cell line adapted to respond to recombinant G-CSF (lipegfilgrastim/Neulasta)