AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Brexpiprazole Proprietary Product Name: Rexulti Sponsor: Lundbeck Australia Pty Ltd First round CER: October 2016 Second round CER: January 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 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 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]>. Submission PM-2016-00905-1-1 Extract from the Clinical Evaluation Report for Rexulti Brexpiprazole Page 2 of 88 Lundbeck Australia Pty Ltd Therapeutic Goods Administration Contents List of common abbreviations_______________________________________________ 5 1. Introduction _____________________________________________________________ 8 1.1. Submission type ________________________________________________________________ 8 1.2. Drug class and therapeutic indication ________________________________________ 8 1.3. Dosage forms and strengths __________________________________________________ 8 1.4. Dosage and administration ____________________________________________________ 8 2. Clinical rationale _______________________________________________________ 8 2.1. Background _____________________________________________________________________ 8 2.2. Clinical rationale _______________________________________________________________ 9 2.3. Formulation development___________________________________________________ 10 2.4. Evaluator’s commentary on the background information ________________ 10 3. Contents of the clinical dossier_____________________________________ 10 3.1. Scope of the clinical dossier _________________________________________________ 10 3.2. Paediatric data _______________________________________________________________ 11 3.3. Good clinical practice ________________________________________________________ 11 3.4. Evaluator’s commentary on the clinical dossier ___________________________ 11 4. Pharmacokinetics ____________________________________________________ 11 4.1. Studies providing pharmacokinetic information __________________________ 11 4.2. Summary of pharmacokinetics _____________________________________________ 14 4.3. Evaluator’s overall conclusions on pharmacokinetics ____________________ 28 5. Pharmacodynamics __________________________________________________ 29 5.1. Studies providing pharmacodynamic information ________________________ 29 5.2. Summary of pharmacodynamics ___________________________________________ 29 5.3. Evaluator’s overall conclusions on pharmacodynamics __________________ 33 6. Dosage selection for the pivotal studies __________________________ 34 6.1. Pharmacokinetics and pharmacodynamics: dose finding studies________ 34 6.2. Phase II dose finding studies ________________________________________________ 34 6.3. Phase III pivotal studies investigating more than one dose regimen ____ 34 6.4. Evaluator’s conclusions on dose finding for the pivotal studies _________ 35 7. Clinical efficacy _______________________________________________________ 35 7.1. Studies providing evaluable efficacy data __________________________________ 35 7.2. Pivotal or main efficacy studies _____________________________________________ 35 7.3. Other efficacy studies ________________________________________________________ 50 7.4. Analyses performed across trials: pooled and meta analyses ____________ 56 Submission PM-2016-00905-1-1 Extract from the Clinical Evaluation Report for Rexulti Brexpiprazole Page 3 of 88 Lundbeck Australia Pty Ltd Therapeutic Goods Administration 7.5. Evaluator’s conclusions on clinical efficacy ________________________________ 59 8. Clinical safety__________________________________________________________ 60 8.1. Studies providing evaluable safety data ____________________________________ 60 8.2. Studies that assessed safety as the sole primary outcome ________________ 62 8.3. Patient exposure _____________________________________________________________ 62 8.4. Adverse events _______________________________________________________________ 64 8.5. Evaluation of issues with possible regulatory impact _____________________ 71 8.6. Other safety issues ___________________________________________________________ 79 8.7. Post-marketing experience__________________________________________________ 79 8.8. Evaluator’s overall conclusions on clinical safety _________________________ 80 9. First round benefit-risk assessment ______________________________ 81 9.1. First round assessment of benefits _________________________________________ 81 9.2. First round assessment of risks _____________________________________________ 82 9.3. First round assessment of benefit-risk balance ___________________________ 82 10. First round recommendation regarding authorisation ________ 82 11. Clinical questions _____________________________________________________ 83 11.1. Pharmacokinetics __________________________________________________________ 83 11.2. Pharmacodynamics ________________________________________________________ 83 11.3. Efficacy ______________________________________________________________________ 83 11.4. Safety ________________________________________________________________________ 83 11.5. PI and CMI ___________________________________________________________________ 83 11.6. Additional expert input ____________________________________________________ 84 12. Second round evaluation of clinical data submitted in response to questions ______________________________________________________________________ 84 12.1. Pharmacokinetics __________________________________________________________ 84 12.2. Pharmacodynamics ________________________________________________________ 84 12.3. Efficacy ______________________________________________________________________ 85 12.4. Safety ________________________________________________________________________ 85 12.5. PI/CMI _______________________________________________________________________ 86 13. Second round benefit-risk assessment ___________________________ 86 13.1. Second round assessment of benefits _____________________________________ 86 13.2. Second round assessment of risks ________________________________________ 86 13.3. Second round assessment of benefit-risk balance _______________________ 86 14. Second round recommendation regarding authorisation ____ 86 15. References _____________________________________________________________ 87 Submission PM-2016-00905-1-1 Extract from the Clinical Evaluation Report for Rexulti Brexpiprazole Page 4 of 88 Lundbeck Australia Pty Ltd Therapeutic Goods Administration List of common abbreviations Abbreviation Meaning 5-HT Serotonin ADHD Attention deficit hyperactivity disorder AE Adverse event AIMS Abnormal Involuntary Movement Scale ANCOVA Analysis of covariance AUC0-24 Area under the concentration-time curve from time zero to 24 hours AUCt Area under the concentration-time curve during a dosing interval at steady state AUC Area under the concentration-time curve from time zero to infinity BARS∞ Barnes Akathisia Rating Scale BRCP Breast cancer resistance protein CGI-I Clinical Global Impression - Improvement Scale CGI-S Clinical Global Impression