Australian Public Assessment Report for Ixekizumab Proprietary Product Name: Taltz Sponsor: Eli Lilly Australia May 2017 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 2017 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 Taltz Ixekizumab Eli Lilly Australia Pty Ltd PM-2015-01878-1-4 Page 2 of 83 Final 8 May 2017 Therapeutic Goods Administration Contents Common abbreviations _______________________________________________________ 5 I. Introduction to product submission _____________________________________ 8 Submission details ____________________________________________________________________ 8 Product background __________________________________________________________________ 8 Regulatory status _____________________________________________________________________ 9 Product information _________________________________________________________________ 10 II. Quality findings ___________________________________________________________ 10 Drug substance (active ingredient) ________________________________________________ 10 Drug product _________________________________________________________________________ 11 Biopharmaceutics ___________________________________________________________________ 11 Quality summary and conclusions _________________________________________________ 11 III. Nonclinical findings _____________________________________________________ 11 Introduction __________________________________________________________________________ 11 Pharmacology ________________________________________________________________________ 12 Pharmacokinetics ____________________________________________________________________ 14 Toxicology ____________________________________________________________________________ 15 Nonclinical summary and conclusions _____________________________________________ 21 IV. Clinical findings __________________________________________________________ 23 Introduction __________________________________________________________________________ 23 Pharmacokinetics ____________________________________________________________________ 25 Pharmacodynamics__________________________________________________________________ 27 Dosage selection for the pivotal studies ___________________________________________ 30 Efficacy _______________________________________________________________________________ 31 Safety _________________________________________________________________________________ 34 First round benefit-risk assessment _______________________________________________ 40 First round recommendation regarding authorisation ___________________________ 47 Clinical questions ____________________________________________________________________ 47 Second round evaluation of clinical data submitted in response to questions _ 48 Second round benefit-risk assessment ____________________________________________ 49 V. Pharmacovigilance findings ____________________________________________ 49 Risk management plan ______________________________________________________________ 49 VI. Overall conclusion and risk/benefit assessment __________________ 65 Quality ________________________________________________________________________________ 65 Nonclinical ___________________________________________________________________________ 65 Clinical ________________________________________________________________________________ 66 AusPAR Taltz Ixekizumab Eli Lilly Australia Pty Ltd PM-2015-01878-1-4 Page 3 of 83 Final 8 May 2017 Therapeutic Goods Administration Risk management plan ______________________________________________________________ 77 Risk-benefit analysis ________________________________________________________________ 77 Outcome ______________________________________________________________________________ 82 Attachment 1. Product Information ______________________________________ 82 Attachment 2. Extract from the Clinical Evaluation Report __________ 82 AusPAR Taltz Ixekizumab Eli Lilly Australia Pty Ltd PM-2015-01878-1-4 Page 4 of 83 Final 8 May 2017 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning ADA Anti-drug antibody ADR Adverse Drug Reaction AE Adverse event AESI Adverse event of special interest aPTT Actived partial thromboplastin time ARTG Australian Register of Therapeutic Goods ASA Australian Specific Annex ASA Australian Specific Annex AUC Area under the curve BMI Body mass index CER Clinical Evaluation Report CHMP Committee for Medicinal Products for Human Use CHMP Committee for Medicinal Products for Human Use (EU) CIOMS-IX Council for International Organizations of Medical Sciences Working Group IX Cmax Maximum serum concentration Cmax,ss Maximal concentration (steady state) CMH Cochran Mantel Haenszel CNS Central Nervous System CTCAE Common Terminology Criteria for Adverse Events Ctrough.ss Trough concentration at steady state CYP Cytochrome p450 system DLQI Dermatology Life Quality Index EC50 Half maximal effect concentration ELISA Enzyme-linked immunosorbent assay AusPAR Taltz Ixekizumab Eli Lilly Australia Pty Ltd PM-2015-01878-1-4 Page 5 of 83 Final 8 May 2017 Therapeutic Goods Administration Abbreviation Meaning EMA European Medicines Agency Emax Maximum possible effect (efficacy) EU European Union FDA Food and Drug Administration (United States) GCP Good Clinical Practice GLP Good Laboratory Practice GMP Good Manufacturing Practice GVP Good Pharmacovigilance Practices HLT High Level Term ICH International Conference on Harmonisation Ig Immunoglobulin IL Interleukin ILD Interstitial lung disease ISS Integrated Summary of Safety Itch NRS Itch Numeric Rating Scale IV Intravenous KLH Keyhole limpet haemocyanin LOAEL Lowest observable adverse event level MACE Major adverse cardiac event NAb Neutralising antibody NOAEL No observable adverse event level NRI Non-responder imputation PASI Psoriasis Area and Severity Index PCP Pneumocystis pneumonia PD Pharmacodynamic PI Product Information AusPAR Taltz Ixekizumab Eli Lilly Australia Pty Ltd PM-2015-01878-1-4 Page 6 of 83 Final 8 May 2017 Therapeutic Goods Administration Abbreviation Meaning PIP Paediatric Investigation Plan PK Pharmacokinetic PMAB Prescription Medicines Authorisation Branch pMI Placebo multiple imputation PopPK Population pharmacokinetic PSAB Pharmacovigilance and Special Access Branch PT Partial thromboplastin Q2W Every 2 weeks Q4W Every 4 weeks RA Rheumatoid arthritis RMP Risk Management Plan RMP Risk Management Plan SAE Serious Adverse Event SC Subcutaneous SmPC Summary of Product Characteristics sPGA Static Physician’s Global Assessment TE-ADA Treatment-emergent antidrug antibody TEAE Treatment emergent adverse event TGA Therapeutic Goods Administration Tmax Time to maximal serum concentration ULN Upper limit of normal US United States UTI Urinary tract infection Vd Volume of distribution WBC White blood cell AusPAR Taltz Ixekizumab Eli Lilly Australia Pty Ltd PM-2015-01878-1-4 Page 7 of 83 Final 8 May 2017 Therapeutic Goods Administration