Australian Public Assessment Report for pegaspargase Proprietary Product Name: Oncaspar Sponsor: Baxalta Australia September 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 - ONCASPAR – pegaspargase - Baxalta Australia - PM-2016-02333-1-4 – Page 2 of 85 Final 18 September 2018 Therapeutic Goods Administration Contents Common abbreviations _______________________________________________________ 5 I. Introduction to product submission _____________________________________ 8 Submission details ____________________________________________________________________ 8 Product background __________________________________________________________________ 9 Regulatory status _____________________________________________________________________ 9 Product Information_________________________________________________________________ 10 II. Registration time line ___________________________________________________ 10 III. Quality findings __________________________________________________________ 11 Introduction __________________________________________________________________________ 11 Drug product _________________________________________________________________________ 14 IV. Nonclinical findings _____________________________________________________ 18 Introduction __________________________________________________________________________ 18 Pharmacology ________________________________________________________________________ 19 Pharmacokinetics ____________________________________________________________________ 21 Toxicology ____________________________________________________________________________ 22 Comments on the nonclinical safety specification of the Risk Management Plan27 Nonclinical summary and conclusions _____________________________________________ 27 V. Clinical findings ___________________________________________________________ 30 Introduction __________________________________________________________________________ 30 Pharmacokinetics ____________________________________________________________________ 32 Pharmacodynamics__________________________________________________________________ 34 Dosage selection for the pivotal studies ___________________________________________ 36 Efficacy _______________________________________________________________________________ 37 Safety _________________________________________________________________________________ 46 First round benefit-risk assessment _______________________________________________ 52 First round recommendation regarding authorisation ___________________________ 54 VI. Pharmacovigilance findings ___________________________________________ 54 VII. Overall conclusion and risk/benefit assessment _________________ 56 Summary of international regulatory status ______________________________________ 56 Background __________________________________________________________________________ 58 Quality ________________________________________________________________________________ 61 Nonclinical ___________________________________________________________________________ 62 Clinical ________________________________________________________________________________ 62 Risk management plan ______________________________________________________________ 72 Risk-benefit analysis ________________________________________________________________ 73 AusPAR - ONCASPAR – pegaspargase - Baxalta Australia - PM-2016-02333-1-4 – Page 3 of 85 Final 18 September 2018 Therapeutic Goods Administration Outcome ______________________________________________________________________________ 83 Attachment 1. Product Information ______________________________________ 84 Attachment 2. Extract from the Clinical Evaluation Report __________ 84 AusPAR - ONCASPAR – pegaspargase - Baxalta Australia - PM-2016-02333-1-4 – Page 4 of 85 Final 18 September 2018 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning ALL Acute lymphoblastic leukaemia ALP Alkaline phosphatase ALT Alanine aminotransferase aPTT Partial thromboplastin time ARTG Australian Register of Therapeutic Goods AST Aspartate transaminase BFM Berlin Frankfurt Munster BSA Body Surface Area CALGB ALL Cancer and Leukaemia Group B ALL CCG Children’s Cancer Group CNS Central nervous system COG Children’s Oncology Group CR Complete response CSF Cerebrospinal fluid CSR Clinical Study Report DFCI Dana Faber Cancer Institute DI Delayed intensification EFS Event Free Survival EMA European Medicines Agency EPAR European Public Assessment Report ER Exposure ratio FDA Food and Drug Administration GCP Good Clinical Practice GD Gestation day AusPAR - ONCASPAR – pegaspargase - Baxalta Australia - PM-2016-02333-1-4 – Page 5 of 85 Final 18 September 2018 Therapeutic Goods Administration Abbreviation Meaning GRAALL Group for Research on Adult Acute Lymphoblastic Leukaemia Hyper-CVAD Hyper Cyclophosphamide Vincristine Adriamycin (doxorubicin) and Dexamethasone IP Intraperitoneal IPC In-process controls IU International units LOQ Limit of quantitation MRD Minimal residual disease MRHD Maximum recommended human dose MRI Magnetic resonance imaging mTOR Mammalian target of rapamycin MTX Methotrexate NCCN National Comprehensive Cancer Network NOEL No observed effect level NOPHO Nordic Society of Paediatric Haematology and Oncology NZW New Zealand White OS Overall survival PD Progressive disease PEGL PEGL, Pegaspargase, PEG-L-ASNase, PEGylated asparaginase, ASNase Oncaspar Ph Philadelphia chromosome Ph ALL Philadelphia chromosome positive ALL PK Pharmacokinetic PR Partial response PRES Posterior reversible encephalopathy syndrome PSUR Periodic Safety Update Report PTT Partial thromboplastin time AusPAR - ONCASPAR – pegaspargase - Baxalta Australia - PM-2016-02333-1-4 – Page 6 of 85 Final 18 September 2018 Therapeutic Goods Administration Abbreviation Meaning RPLS Reversible posterior leukoencephalopathy syndrome SAS Special Access Scheme SEM Standard error of the mean SLR Systematic Literature Review SOC System Organ Classification SR Standard risk WBC White blood cells AusPAR - ONCASPAR – pegaspargase - Baxalta Australia - PM-2016-02333-1-4 – Page 7 of 85 Final 18 September 2018 Therapeutic Goods Administration I. Introduction to product submission Submission details Type of submission: New biological entity Decision: Approved Date of decision: 19 October 2017 Date of entry onto ARTG: 31 October 2017 ARTG number: 279831 Active ingredient: Pegaspargase Product name: Oncaspar Sponsor’s name and address: Shire Australia Pty Ltd1 Level 39 Grosvenor Place 225 George Street Sydney NSW 2000 Dose form: Solution for injection Strength: 3,750 units / 5 mL Container: vial Pack size: Single vial Approved therapeutic use: Oncaspar is indicated as a component of antineoplastic combination therapy in patients with Acute Lymphoblastic Leukaemia (ALL) Routes of administration: Intravenous infusion or intramuscular (for small volumes).