AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Eliglustat (as tartrate) Proprietary Product Name: Cerdelga Sponsor: Sanofi-Aventis Australia Pty Ltd First round evaluation: 28 April 2014 Second round evaluation: 28 August 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-2013-03651-1-3 Extract from the Clinical Evaluation Report for Eliglustat (as tartrate) Page 2 of 165 Cerdelga Therapeutic Goods Administration Contents List of commonly used abbreviations _____________________________________ 5 1. Introduction ____________________________________________________________ 10 1.1. Clinical rationale ___________________________________________________________ 10 1.2. Orphan drug designation __________________________________________________ 11 1.3. Guidance ____________________________________________________________________ 11 2. Contents of the clinical dossier ______________________________________ 11 2.1. Scope of the clinical dossier _______________________________________________ 11 2.2. Paediatric data _____________________________________________________________ 12 2.3. Good clinical practice ______________________________________________________ 12 3. Pharmacokinetics______________________________________________________ 12 3.1. Studies providing clinical pharmacology data ___________________________ 12 3.2. Summary of pharmacokinetics ___________________________________________ 17 4. Pharmacodynamics ___________________________________________________ 44 4.1. Biomarker studies _________________________________________________________ 44 4.2. QT interval (ECG) studies _________________________________________________ 45 4.3. PK/PD relationship between efficacy and PK parameters _____________ 49 4.4. Evaluator's overall conclusions on pharmacodynamics ________________ 56 5. Dosage selection for the pivotal studies ___________________________ 57 6. Clinical efficacy _________________________________________________________ 58 6.1. Pivotal efficacy studies ____________________________________________________ 58 6.2. Supportive efficacy study _________________________________________________ 84 6.3. Efficacy in sub-groups _____________________________________________________ 88 6.4. Evaluator's conclusion on clinical efficacy for GD1 _____________________ 88 7. Clinical safety ___________________________________________________________ 95 7.1. Studies providing evaluable safety data _________________________________ 95 7.2. Exposure ___________________________________________________________________ 96 7.3. Demographics ______________________________________________________________ 97 7.4. Adverse events _____________________________________________________________ 98 7.5. Laboratory tests __________________________________________________________ 108 7.6. Other safety assessments ________________________________________________ 112 7.7. Safety issues in special groups ___________________________________________ 113 7.8. Post-marketing data ______________________________________________________ 114 7.9. Evaluator's overall conclusions on clinical safety ______________________ 115 8. First round benefit-risk assessment ______________________________ 120 Submission PM-2013-03651-1-3 Extract from the Clinical Evaluation Report for Eliglustat (as tartrate) Page 3 of 165 Cerdelga Therapeutic Goods Administration 8.1. First round assessment of benefits ______________________________________ 120 8.2. First round assessment of risks _________________________________________ 122 8.3. First round assessment of benefit-risk balance ________________________ 125 9. First round recommendation regarding authorisation _______ 126 9.1. GD1 patients who are treatment-naive _________________________________ 126 9.2. GD1 patients stabilized on ERT prior to switching to eliglustat ______ 126 10. Clinical questions __________________________________________________ 128 10.1. Clinical questions _________________________________________________________ 128 11. Second round evaluation of clinical data submitted in response to questions ___________________________________________________________________ 130 11.1. Pharmacokinetics _________________________________________________________ 130 11.2. Efficacy ____________________________________________________________________ 146 11.3. Safety ______________________________________________________________________ 152 11.4. ENGAGE - Evaluation of 78-week results memo report _______________ 154 12. Second round benefit-risk assessment ________________________ 157 12.1. Second round assessment of benefits ___________________________________ 157 12.2. Second round assessment of risks _______________________________________ 163 12.3. Second round assessment of benefit-risk balance _____________________ 163 13. Second round recommendation regarding authorisation __ 164 14. References __________________________________________________________ 164 Submission PM-2013-03651-1-3 Extract from the Clinical Evaluation Report for Eliglustat (as tartrate) Page 4 of 165 Cerdelga Therapeutic Goods Administration List of commonly used abbreviations Abbreviation Meaning AE Adverse event Ae Amount excreted ALB Albumin ALP Alkaline phosphatase ALT Alanine aminotransferase ANCOVA Analysis of covariance ANOVA Analysis of variance AST Aspartate aminotransferase AUC(0-4h) Area under the plasma concentration versus time curve from time zero to 4 hours post-dose AUC(0-12h) Area under the plasma concentration versus time curve from time zero to 12 hours post-dose AUC(0-24h) Area under the plasma concentration versus time curve from time zero to 24 hours post-dose AUC(0- Area under the plasma concentration versus time curve from time zero extrapolated to infinity AUCinf[∞])(0-last) Area under the plasma concentration time curve from time zero to the time of the last concentration above the lower limit of quantification AUC(0-tau) Area under the plasma concentration over the dosing interval BCRP Breast cancer resistance protein BD Twice daily BMB Bone marrow burden BMD Bone mineral density BMI Body mass index BPI Brief Pain Inventory BQL Below quantifiable levels Submission PM-2013-03651-1-3 Extract from the Clinical Evaluation Report for Eliglustat (as tartrate) Page 5 of 165 Cerdelga Therapeutic Goods Administration BSEP Bile salt export pump CCL18 Chemokine CC motif ligand 18 CHMP Committee for Human Medicinal Products CI Confidence interval CL Total body clearance CL/F Apparent total body clearance CLr Renal clearance Cmax Maximum observed plasma concentration CNS Central nervous system CRCL Creatinine clearance CRF Case report form CSR Clinical study report Ctrough Trough plasma concentration CV Coefficient of variation CYP Cytochrome P450 CYP3A Cytochrome P450 3A subfamily (including 3A4, 3A5, and 3A7) DDI Drug-drug interaction DLT Dose-limiting toxicity DMC Data Monitoring Committee DS3 Gaucher Disease Severity Scoring System during repeat dosing DXA Dual energy X-ray absorptiometry ECG Electrocardiogram