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Proprietary Product Name: Biktarvy Sponsor: Gilead Sciences Australian Public Assessment Report for Bictegravir / Emtricitabine / Tenofovir alafenamide Proprietary Product Name: Biktarvy Sponsor: Gilead Sciences August 2019 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 2019 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 - Biktarvy - Bictegravir / emtricitabine / tenofovir alafenamide - Gilead Sciences - PM-2017- Page 2 of 88 02454-1-2 - FINAL 1 August 2019 Therapeutic Goods Administration Contents Common abbreviations _____________________________________________________ 5 I. Introduction to product submission __________________________________ 10 Submission details ___________________________________________________________________ 10 Product background _________________________________________________________________ 11 Regulatory status ____________________________________________________________________ 11 Product Information_________________________________________________________________ 12 II. Registration time line __________________________________________________ 12 III. Quality findings ________________________________________________________ 13 Introduction __________________________________________________________________________ 13 Drug substances (active ingredients) ______________________________________________ 13 Drug product _________________________________________________________________________ 15 Biopharmaceutics ___________________________________________________________________ 15 Quality summary and conclusions _________________________________________________ 16 IV. Nonclinical findings ___________________________________________________ 17 Introduction __________________________________________________________________________ 17 Pharmacology ________________________________________________________________________ 17 Pharmacokinetics ____________________________________________________________________ 20 Toxicology ____________________________________________________________________________ 22 Nonclinical summary and conclusions _____________________________________________ 26 V. Clinical findings _________________________________________________________ 28 Introduction __________________________________________________________________________ 28 Pharmacokinetics ____________________________________________________________________ 33 Pharmacodynamics__________________________________________________________________ 38 Dosage selection for the pivotal studies ___________________________________________ 39 Efficacy _______________________________________________________________________________ 40 Safety _________________________________________________________________________________ 41 First round benefit-risk assessment _______________________________________________ 56 First round recommendation regarding authorisation ___________________________ 58 Clinical questions and second round evaluation __________________________________ 58 Second round benefit-risk assessment ____________________________________________ 60 VI. Pharmacovigilance findings __________________________________________ 60 Risk management plan ______________________________________________________________ 60 VII. Overall conclusion and risk/benefit assessment _________________ 62 Introduction __________________________________________________________________________ 62 Quality ________________________________________________________________________________ 63 AusPAR - Biktarvy - Bictegravir / emtricitabine / tenofovir alafenamide - Gilead Sciences - PM-2017- Page 3 of 88 02454-1-2 - FINAL 1 August 2019 Therapeutic Goods Administration Nonclinical ___________________________________________________________________________ 63 Clinical ________________________________________________________________________________ 64 Risk management plan ______________________________________________________________ 78 Risk-benefit analysis ________________________________________________________________ 78 Outcome ______________________________________________________________________________ 87 Attachment 1. Product Information _____________________________________ 87 AusPAR - Biktarvy - Bictegravir / emtricitabine / tenofovir alafenamide - Gilead Sciences - PM-2017- Page 4 of 88 02454-1-2 - FINAL 1 August 2019 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning (14C) Carbon-14 3TC Lamivudine ABC Abacavir ADME Absorption, distribution, metabolism and excretion ADR Adverse drug reaction AE Adverse event AIDS Acquired immunodeficiency syndrome ALT Alanine aminotransferase ART Antiretroviral therapy ARV Antiretroviral AST Aspartate aminotransferase ATV Atazanavir AUCinf Area under the plasma concentration versus time curve extrapolated to infinite time AUClast Area under the plasma concentration versus time curve from time zero to the last quantifiable concentration B/F/TAF Fixed dose combination of bictegravir 50 mg (B)/emtricitabine 200 mg (F)/tenofovir alafenamide 25 mg (TAF) BCRP Breast cancer resistance protein BCS Biopharmaceutics Classification System BIC Bictegravir (GS-9883) CD4 Cluster determinant 4 CHMP Committee for Medicinal Products for Human Use CI Confidence interval CL/F Apparent oral clearance after administration of the drug Cmax Maximum observed concentration of drug AusPAR - Biktarvy - Bictegravir / emtricitabine / tenofovir alafenamide - Gilead Sciences - PM-2017- Page 5 of 88 02454-1-2 - FINAL 1 August 2019 Therapeutic Goods Administration Abbreviation Meaning COBI Cobicistat Ctau Observed drug concentration at the end of the dosing interval CV Coefficient of variation CYP Cytochrome P450 D1 Duration of the depot compartment DAVG11 Time-weighted average change from baseline to study Day 11 DB Double-blind (treatment period) DDI Drug-drug interaction DILI Drug induced liver injury DNA Deoxyribonucleic acid DRV Darunavir DTG Dolutegravir DVY Emtricitabine/Tenofovir alafenamide (Descovy) E/C/F/TAF elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (coformulated; Genvoya) EC50 Half-maximal effective concentration ECG Electrocardiogram eGFR Estimated glomerular filtration rate eGFRCG Estimated glomerular filtration rate calculated using the Cockcroft-Gault equation F/TAF Emtricitabine/tenofovir alafenamide (Descovy) FDA Food and Drug Administration FDC Fixed dose combination FTC Emtricitabine (Emtriva) GCP Good Clinical Practice GFR Glomerular filtration rate GGT Gamma glutamyl transferase AusPAR - Biktarvy - Bictegravir / emtricitabine / tenofovir alafenamide - Gilead Sciences - PM-2017- Page 6 of 88 02454-1-2 - FINAL 1 August 2019 Therapeutic Goods Administration Abbreviation Meaning GI Gastrointestinal GLP Good Laboratory Practice GLP-1 Glucagon-like peptide 1 GLSM Geometric least squares mean HBV Hepatitis B virus HCV Hepatitis C virus HIV Human immunodeficiency virus HIV-1 Human immunodeficiency virus type 1 ICH International Conference on Harmonisation INSTI Integrase strand-transfer
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