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Australian Public Assessment Report for Talimogene Laherparepvec Australian Public Assessment Report for Talimogene Laherparepvec Proprietary Product Name: Imlygic Sponsor: Amgen Australia 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 Imylygic poly-A sequence Amgen Australia PM-2014-03464-1-4 Page 2 of 112 Final 31 May 2016 Therapeutic Goods Administration Contents Common abbreviations _____________________________________________________ 5 Introduction to product submission ______________________________________ 8 Submission details ______________________________________________________________________ 8 Product background ____________________________________________________________________ 8 Regulatory status _____________________________________________________________________ 12 Product Information __________________________________________________________________ 13 II. Quality findings _________________________________________________________ 13 Drug substance (active ingredient) _________________________________________________ 13 Drug product __________________________________________________________________________ 14 Quality summary and conclusions __________________________________________________ 16 III. Nonclinical findings ___________________________________________________ 17 Introduction ___________________________________________________________________________ 17 Pharmacology _________________________________________________________________________ 18 Pharmacokinetics _____________________________________________________________________ 24 Toxicology _____________________________________________________________________________ 26 Nonclinical summary and conclusions _____________________________________________ 35 Nonclinical conclusions and recommendation ____________________________________ 37 IV. Clinical findings ________________________________________________________ 38 Introduction ___________________________________________________________________________ 38 Pharmacokinetics _____________________________________________________________________ 39 Pharmacodynamics ___________________________________________________________________ 40 Dosage selection for the pivotal studies ____________________________________________ 41 Efficacy _________________________________________________________________________________ 42 Safety ___________________________________________________________________________________ 45 First Round Benefit-Risk Assessment ______________________________________________ 50 First round recommendation regarding authorisation ___________________________ 50 Clinical questions _____________________________________________________________________ 51 Second round evaluation of clinical data submitted in response to questions _ 52 Second round benefit-risk assessment _____________________________________________ 52 Second round recommendation regarding authorisation ________________________ 52 V. Pharmacovigilance findings ___________________________________________ 52 Risk management plan _______________________________________________________________ 52 VI. Overall conclusion and risk/benefit assessment__________________ 74 Introduction ___________________________________________________________________________ 74 Quality __________________________________________________________________________________ 74 AusPAR Imylygic poly-A sequence Amgen Australia PM-2014-03464-1-4 Page 3 of 112 Final 31 May 2016 Therapeutic Goods Administration Nonclinical _____________________________________________________________________________ 74 Clinical _________________________________________________________________________________ 75 Risk-benefit analysis __________________________________________________________________ 89 Outcome_______________________________________________________________________________ 111 Attachment 1. Product Information ____________________________________ 111 Attachment 2. Extract from the Clinical Evaluation Report. ________ 111 AusPAR Imylygic poly-A sequence Amgen Australia PM-2014-03464-1-4 Page 4 of 112 Final 31 May 2016 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning ALP Alkaline phosphatase ALQ Above the limit of quantitation ALT Alanine aminotransferase AST Aspartate aminotransferase BLQ Below the limit of quantitation CDMS Clinical data management system CMV Cytomegalovirus Complete response CR CRF Case report form CRO Contract research organization CT Computed tomography CTCAE Common Toxicity Criteria for Adverse Events DLST Dose Level Review Team durable response rate DRR Endpoint Assessment Committee EAC ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group ELISA Enzyme-linked immunosorbent assay EU European Union EUS Endoscopic ultrasound FIH First-in-Human FNI Fine needle injection GCP Good Clinical Practice GM-CSF Granulocyte macrophage colony stimulating factor Genetically modified organism GMO AusPAR Imylygic poly-A sequence Amgen Australia PM-2014-03464-1-4 Page 5 of 112 Final 31 May 2016 Therapeutic Goods Administration Abbreviation Meaning HCMV IE Human cytomegalovirus immediate early promoter hGM-CSF Human granulocyte macrophage colony stimulating factor HIV Human immunodeficiency virus HLA Human lymphocyte antigen HSV Herpes simplex virus HSV-1 Herpes simplex virus, type 1 ICH International Conference on Harmonization Ig Immunoglobulin IRB Institutional review board Intent to treat ITT LDH Lactate dehydrogenase MCHC Mean corpuscular hemoglobin concentration MCV Mean corpuscular volume MedDRA Medical Dictionary for Regulatory Activities MHC Major histocompatibility complex MRI Magnetic resonance imaging OECD Organization for Economic Cooperation and Development OGTR Office of Gene Technology Regulator ORR Objective response rate (=[PR+CR]) OS Overall survival PCR Polymerase chain reaction PD Progressive disease PFU Plaque forming units Partial response PR qPCR Quantitative polymerase chain reaction RECIST Response evaluation criteria in solid tumours SCCHN Squamous cell carcinoma of the head and neck AusPAR Imylygic poly-A sequence Amgen Australia PM-2014-03464-1-4 Page 6 of 112 Final 31 May 2016 Therapeutic Goods Administration Abbreviation Meaning SC Subcutaneous SD Stable disease SD Standard deviation SOC Standard of care TL Talimogene laherparepvec UK United Kingdom ULN Upper limit of normal range US United States WBC White blood cell count WHO World Health Organisation WT Wild-type AusPAR Imylygic poly-A sequence Amgen Australia PM-2014-03464-1-4 Page 7 of 112 Final 31 May 2016 Therapeutic Goods Administration Introduction to product submission Submission details Type of submission: New biological entity Decision: Approved Date of decision: 18 December 2015 Date of entry onto ARTG 21 December 2015 Active ingredient(s): Product name(s): Talimogene laherparepvec Sponsor’s name and ImlygicAmgen Australia Pty Ltd address: Level 7, 123 Epping Road, North
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