Australian Public Assessment Report for lonoctocog alfa (rch) Proprietary Product Name: Afstyla Sponsor: CSL Behring Australia Pty Ltd January 2018 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 2018 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 Afstyla Lonoctocog alfa CSR Behring Australia Pty Ltd PM-2015-04357-1-4 Page 2 of 57 Final 23 January 2018 Therapeutic Goods Administration Contents Common abbreviations _______________________________________________________ 5 I. Introduction to product submission _____________________________________ 8 Submission details ____________________________________________________________________ 8 Product background __________________________________________________________________ 9 Regulatory status ____________________________________________________________________ 13 Product Information_________________________________________________________________ 14 II. Registration timeline ____________________________________________________ 14 III. Quality findings __________________________________________________________ 15 Drug substance (active ingredient) ________________________________________________ 15 Drug product _________________________________________________________________________ 15 Biopharmaceutics ___________________________________________________________________ 18 Quality summary and conclusions _________________________________________________ 18 IV. Nonclinical findings _____________________________________________________ 20 Introduction __________________________________________________________________________ 20 Pharmacology ________________________________________________________________________ 20 Pharmacokinetics ____________________________________________________________________ 21 Toxicology ____________________________________________________________________________ 22 Nonclinical summary and conclusions _____________________________________________ 25 V. Clinical findings ___________________________________________________________ 26 Introduction __________________________________________________________________________ 26 Pharmacokinetics ____________________________________________________________________ 28 Pharmacodynamics__________________________________________________________________ 28 Dosage selection for the pivotal studies ___________________________________________ 28 Efficacy _______________________________________________________________________________ 28 Safety _________________________________________________________________________________ 30 First round benefit-risk assessment _______________________________________________ 31 First round recommendation regarding authorisation ___________________________ 32 Clinical questions ____________________________________________________________________ 32 Second round evaluation and second round benefit-risk assessment __________ 32 VI. Pharmacovigilance findings ___________________________________________ 32 Risk management plan ______________________________________________________________ 32 VII. Overall conclusion and risk/benefit assessment _________________ 36 Quality ________________________________________________________________________________ 36 Nonclinical ___________________________________________________________________________ 37 Clinical ________________________________________________________________________________ 38 AusPAR Afstyla Lonoctocog alfa CSR Behring Australia Pty Ltd PM-2015-04357-1-4 Page 3 of 57 Final 23 January 2018 Therapeutic Goods Administration Risk management plan ______________________________________________________________ 46 Risk-benefit analysis ________________________________________________________________ 46 Outcome ______________________________________________________________________________ 55 Attachment 1. Product Information ______________________________________ 56 Attachment 2. Extract from the Clinical Evaluation Report __________ 56 AusPAR Afstyla Lonoctocog alfa CSR Behring Australia Pty Ltd PM-2015-04357-1-4 Page 4 of 57 Final 23 January 2018 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning ABR Annualised bleeding rate ACM Advisory Committee on Medicines ADA Anti-drug antibody AE Adverse event aPTT Activated partial thromboplastin time ARTG Australian Register of Therapeutic Goods ASA Australian Specific Annex AsBR Annualised spontaneous bleeding rate AUC Area under the curve AUC0- Area under the curve from time zero to infinity ∞ BLA Biological License Application BP Blood pressure BU Bethesda unit CER Clinical evaluation report CHO Chinese hamster ovary ChS Chromogenic substrate Cmax Maximal plasma concentration CMI Consumer Medicines Information CNS Central nervous system CTD Common Technical Document DLP Data lock point ECG Electrocardiogram ED Exposure day EMA European Medicines Agency EU European Union AusPAR Afstyla Lonoctocog alfa CSR Behring Australia Pty Ltd PM-2015-04357-1-4 Page 5 of 57 Final 23 January 2018 Therapeutic Goods Administration Abbreviation Meaning EUHASS European Haemophilia Safety Surveillance system FDA Food and Drug Administration FVIII (Coagulation) Factor VIII GLP Good Laboratory Practice ICH International Conference on Harmonisation ITT Intention to treat IU International Units IV Intravenous kDa Kilodalton LFT Liver function test LLOQ Lower limit of quantification MW Molecular weight OS One stage Ph. Eur European Pharmacopoeia PI Product Information PK Pharmacokinetic PP Per protocol PSUR Periodic Safety Update Report PUP Previously untreated patient rDNA Recombinant DNA rFVIII Recombinant human coagulation Factor VIII rFVIIIa Activated rFVIII RMP Risk Management Plan RP-HPLC Reversed phase high performance liquid chromatography SAE Serious adverse event SE-HPLC Size exclusion high performance liquid chromatography AusPAR Afstyla Lonoctocog alfa CSR Behring Australia Pty Ltd PM-2015-04357-1-4 Page 6 of 57 Final 23 January 2018 Therapeutic Goods Administration Abbreviation Meaning SmPC Summary of Product Characteristics t1/2 Half life TEAE Treatment emergent adverse event WFH World Federation on Hemophilia WFI Water for injection US United States AusPAR Afstyla Lonoctocog alfa CSR Behring Australia Pty Ltd PM-2015-04357-1-4 Page 7 of 57 Final 23 January 2018 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New biological entity Decision: Approved Date of decision: 29 March 2017 Date of entry onto ARTG 13 April 2017 Active ingredient: Lonoctocog alfa (rch) Product name: Afstyla Sponsor’s name and address: CSL Behring Australia Pty Ltd 189-209 Camp Road, Broadmeadows, VIC, 3047 Dose form: Powder for injection Strengths: 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 2500 IU, and 3000 IU Container: Vial (glass type I clear) Pack sizes: 1 x single use composite pack containing: 1 x vial (glass type I clear) containing 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU,