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Extract from the Clinical Evaluation Report for Secukinumab (Rch) AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Secukinumab (rch) Proprietary Product Name: Cosentyx Sponsor: Novartis Pharmaceuticals Australia Pty Ltd CER Report: 23 April 2014 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 the Extract from the Clinical Evaluation Report • This document provides a more detailed evaluation of the clinical findings, extracted from the Clinical Evaluation Report (CER) prepared by the TGA. This extract does not include sections from the CER regarding product documentation or post market activities. • The words [Information redacted], where they appear in this document, indicate that confidential information has been deleted. • For the most recent Product Information (PI), please refer to the TGA website <https://www.tga.gov.au/product-information-pi>. Copyright © Commonwealth of Australia 2015 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]>. Submission PM-2013-04153-1-4 Extract from the Clinical Evaluation Report for Cosentyx Page 2 of 150 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Background _____________________________________________________________ 11 2. Clinical rationale _______________________________________________________ 11 3. Contents of the clinical dossier ______________________________________ 12 3.1. Scope of the clinical dossier _______________________________________________ 12 3.2. Paediatric data _____________________________________________________________ 12 3.3. Good clinical practice ______________________________________________________ 13 4. Pharmacokinetics ______________________________________________________ 13 4.1. Studies providing pharmacokinetic data ________________________________ 13 4.2. Summary of pharmacokinetics ___________________________________________ 15 4.3. Evaluator’s overall conclusions on pharmacokinetics __________________ 21 5. Pharmacodynamics ____________________________________________________ 23 5.1. Studies providing pharmacodynamic data ______________________________ 23 5.2. Summary of pharmacodynamics _________________________________________ 23 5.3. Evaluator’s overall conclusions on pharmacodynamics ________________ 30 6. Dosage selection for the pivotal studies ___________________________ 33 7. Clinical efficacy _________________________________________________________ 36 7.1. Pivotal efficacy studies ____________________________________________________ 37 7.2. Other efficacy studies _____________________________________________________ 76 7.3. Analyses performed across trials (pooled analyses and meta-analyses)88 7.4. Evaluator’s conclusions on clinical efficacy ______________________________ 96 8. Clinical safety ___________________________________________________________ 98 8.1. Studies providing evaluable safety data _________________________________ 98 8.2. Pivotal studies that assessed safety as a primary outcome ___________ 102 8.3. Dose-response and non-pivotal efficacy studies _______________________ 102 8.4. Adverse events ____________________________________________________________ 104 8.5. Laboratory tests __________________________________________________________ 115 8.6. Post-marketing experience ______________________________________________ 130 8.7. Safety issues with the potential for major regulatory impact _________ 130 8.8. Other safety issues ________________________________________________________ 136 8.9. Evaluator’s overall conclusions on clinical safety ______________________ 140 9. First round benefit-risk assessment _______________________________ 143 9.1. First round assessment of benefits ______________________________________ 143 9.2. First round assessment of risks _________________________________________ 144 Submission PM-2013-04153-1-4 Extract from the Clinical Evaluation Report for Cosentyx Page 3 of 150 Therapeutic Goods Administration 9.3. First round assessment of benefit-risk balance ________________________ 144 10. First round recommendation regarding authorisation ______ 146 11. Clinical questions ___________________________________________________ 146 11.1. Pharmacokinetics up to here ____________________________________________ 146 11.2. Pharmacodynamics _______________________________________________________ 147 11.3. Efficacy ____________________________________________________________________ 147 11.4. Safety ______________________________________________________________________ 147 12. Second round evaluation of clinical data submitted in response to questions _____________________________________________________________________ 147 13. Second round benefit-risk assessment _________________________ 147 14. Second round recommendation regarding authorisation ___ 148 15. References ___________________________________________________________ 148 Submission PM-2013-04153-1-4 Extract from the Clinical Evaluation Report for Cosentyx Page 4 of 150 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning ACR American College of Rheumatology ADA anti-drug-antibodies ADR adverse drug reaction AE Adverse Event AI autoinjector/pen AIN457 secukinumab ALP alkaline phosphatase ALT alanine aminotransferase ANCOVA analysis of covariance AS ankylosing spondylitis AST aspartate aminotransferase AUC0-t area under the serum concentration-time curve from time zero to time t, using the log-linear trapezoidal rule AUCinf area under the serum concentration-time curve from time zero to infinity AUClast area under the drug serum concentration-time curve (time 0 to the last measurable concentration sampling time). AV atrioventricular b.i.d twice a day BA bioavailability BE bioequivalence BMI body mass index BSA body surface area Cav average concentration CCV cardiovascular/cerebrovascular Submission PM-2013-04153-1-4 Extract from the Clinical Evaluation Report for Cosentyx Page 5 of 150 Therapeutic Goods Administration Abbreviation Meaning CD3G T-cell surface glycoprotein CD3 gamma chain CHO Chinese hamster ovary CL plasma or serum clearance, calculated as dose/AUCinf after an i.v. dose CL/F the apparent systemic (or total body) clearance from plasma (or serum or blood) following extravascular administration [volume / time] Cmax maximum serum concentration after a single dose CMH Cochran-Mantel-Haenszel CMI Confidence Interval Cmin pre-dose concentration CRF case report/record form CSR clinical study report CTCAE Common Terminology Criteria for Adverse Events CV coefficient of variation CYP cytochrome DDI drug-drug interaction DILI drug-induced liver injury DLQI Dermatology Life Quality Index dPGA dynamic Physician’s Global Assessment ECG electrocardiogram ECL electrochemiluminescence EFD embryo foetal development ELISA enzyme-linked immunosorbent assay EMA European Medicines Agency EQ-5D EuroQOL 5-Dimension Health Questionnaire F fraction of the dose systemically available Submission PM-2013-04153-1-4 Extract from the Clinical Evaluation Report for Cosentyx Page 6 of 150 Therapeutic Goods Administration Abbreviation Meaning FAS Full Analysis Set FDA United States Food and Drug Administration FI fixed interval dosing GCP Good Clinical Practice GGT gamma-glutamyltransferase HA health authority HAQ-DI Health Assessment Questionnaire-Disability Index hBD-2 human beta defensin-2 HBsAg hepatitis B surface antigen HLT high level term HRQoL health-related quality of life HAS human serum albumin hsCRP high sensitivity C-reactive protein i.v. intravenous(ly) IA interim analysis IBD inflammatory bowel disease Ig immunoglobulin IGA Investigator’s Global Assessment IGA mod IGA scale used in part of the Phase II program, 6-point scale 2007 IGA mod IGA scale
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