AusPAR Attachment 2 Extract from the Clinical Evaluation Report for Nusinersen Proprietary Product Name: Spinraza Sponsor: Biogen Australia Pty Ltd First round evaluation 9 June 2017 Second round evaluation 31 July 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]>. Extract from the Clinical Evaluation Report for SPINRAZA - nusinersen (as heptadecasodium) - Page 2 of 128 Biogen Australia Pty Ltd - Submission PM-2016-04042-1-3 – FINAL 13 August 2018 Therapeutic Goods Administration Contents 1. List of abbreviations _____________________________________________________ 5 2. Introduction _____________________________________________________________ 12 2.1. Submission type ___________________________________________________________ 12 2.2. Drug class and therapeutic indication ___________________________________ 12 2.3. Dosage forms and strengths ______________________________________________ 13 2.4. Dosage and administration _______________________________________________ 13 3. Clinical rationale _______________________________________________________ 13 3.1. Information on the condition being treated _____________________________ 14 3.2. Current treatment options ________________________________________________ 16 3.3. Clinical rationale ___________________________________________________________ 16 3.4. Formulation ________________________________________________________________ 17 3.5. Guidance ____________________________________________________________________ 17 3.6. Evaluator’s commentary on the background information______________ 17 4. Contents of the clinical dossier ______________________________________ 17 4.1. Scope of the clinical dossier _______________________________________________ 17 4.2. Paediatric data _____________________________________________________________ 19 4.3. Good clinical practice ______________________________________________________ 20 4.4. Evaluator’s commentary on the clinical dossier ________________________ 20 5. Pharmacokinetics ______________________________________________________ 20 5.1. Studies providing pharmacokinetic information ________________________ 20 5.2. Summary of pharmacokinetics ___________________________________________ 21 6. Pharmacodynamics ____________________________________________________ 29 6.1. Studies providing pharmacodynamic information ______________________ 29 6.2. Summary of pharmacodynamics _________________________________________ 29 6.3. Evaluator’s overall conclusions on pharmacodynamics ________________ 31 7. Dosage selection for the pivotal studies ___________________________ 31 7.1. Pharmacokinetics and pharmacodynamics: dose finding studies _____ 31 7.2. Evaluator’s conclusions on dose finding for the pivotal studies _______ 31 8. Clinical efficacy _________________________________________________________ 31 8.1. Studies providing evaluable efficacy data _______________________________ 31 8.2. Pivotal or main efficacy studies___________________________________________ 32 8.3. Other efficacy studies _____________________________________________________ 53 8.4. Analyses performed across trials: pooled and meta analyses __________ 58 8.5. Evaluator’s conclusions on clinical efficacy ______________________________ 58 Extract from the Clinical Evaluation Report for SPINRAZA - nusinersen (as heptadecasodium) - Page 3 of 128 Biogen Australia Pty Ltd - Submission PM-2016-04042-1-3 – FINAL 13 August 2018 Therapeutic Goods Administration 9. Clinical safety ___________________________________________________________ 59 9.1. Studies providing evaluable safety data _________________________________ 59 9.2. Studies that assessed safety as the sole primary outcome _____________ 64 9.3. Patient exposure ___________________________________________________________ 64 9.4. Adverse events _____________________________________________________________ 67 9.5. Evaluation of issues with possible regulatory impact __________________ 73 9.6. Other safety issues _________________________________________________________ 80 9.7. Evaluator’s overall conclusions on clinical safety _______________________ 82 10. First round benefit-risk assessment _____________________________ 84 10.1. First round assessment of benefits _______________________________________ 84 10.2. First round assessment of risks __________________________________________ 85 10.3. First round assessment of benefit-risk balance _________________________ 87 11. First round recommendation regarding authorisation _______ 88 12. Clinical questions ____________________________________________________ 88 12.1. Clinical questions __________________________________________________________ 88 13. Second round evaluation of clinical data submitted in response to questions ______________________________________________________________________ 89 13.1. Overseas regulatory status update _______________________________________ 89 13.2. Sponsor’s responses to clinical questions _______________________________ 90 14. Second round benefit-risk assessment _________________________ 122 14.1. Second round assessment of benefits ___________________________________ 122 14.2. Second round assessment of risks_______________________________________ 123 14.3. Second round assessment of benefit-risk balance _____________________ 124 15. Second round recommendation regarding authorisation ___ 125 16. References ___________________________________________________________ 125 Extract from the Clinical Evaluation Report for SPINRAZA - nusinersen (as heptadecasodium) - Page 4 of 128 Biogen Australia Pty Ltd - Submission PM-2016-04042-1-3 – FINAL 13 August 2018 Therapeutic Goods Administration 1. List of abbreviations Abbreviation Meaning 6MWT Six-Minute Walk Test aCSF Artificial cerebrospinal fluid preparation ACN Acetonitrile ADA Anti-drug antibody ADP N2-Acetyl-2,6-Diaminopurine ADR Adverse Drug Reaction AEs Adverse Events AhR aryl hydrocarbon receptor AMPA 3-(3-Acetyl-4-methylpyrimidin-2-one-6-yl)-2-aminoimidazole Amu Atomic mass unit AON Antisense oligonucleotide API Active pharmaceutical ingredient ASO Antisense oligonucleotide AUC Area under the concentration-time curve BCRP Breast Cancer Resistance Protein BiPAP Bi-level positive airway pressure BLAST Basic Local Alignment Search Tool BLQ Below the limit of quantitation BSEP Bile Salt Export Pump BWT Body weight CAPA Corrective and preventive actions CAR Constitutive androstane receptor CFU Colony forming unit CCP Critical controlled parameters Extract from the Clinical Evaluation Report for SPINRAZA - nusinersen (as heptadecasodium) - Page 5 of 128 Biogen Australia Pty Ltd - Submission PM-2016-04042-1-3 – FINAL 13 August 2018 Therapeutic Goods Administration Abbreviation Meaning CHMP Committee for Medicinal Products for Human Use CHOP Children’s Hospital of Philadelphia Infant Test for Neuromuscular INTEND Disease CIPC Critical in-process controls CIPT Critical in-process tests CK Creatine kinase CLr Renal clearance CMAP Compound muscle action potential CNET 3-N-cyanoethylthymine impurities