Attachment: Extract from Clinical Evaluation: Migalastat
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AusPAR Attachment 2 Extract from the Clinical Evaluation Report for migalastat Proprietary Product Name: Galafold Sponsor: Amicus Therapeutics Pty Ltd First round: September 2016 Second round: February 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-2016-01191-1-3 Extract from the Clinical Evaluation Report for Galafold 2 of 178 Therapeutic Goods Administration Contents List of abbreviations __________________________________________________________ 5 1. Introduction _______________________________________________________________ 9 2. Clinical rationale _________________________________________________________ 9 2.1. Guidance ______________________________________________________________________ 9 3. Contents of the clinical dossier ______________________________________ 10 3.1. Scope of the clinical dossier _______________________________________________ 10 3.2. Paediatric data _____________________________________________________________ 10 3.3. Good clinical practice ______________________________________________________ 11 4. Pharmacokinetics ______________________________________________________ 11 4.1. Studies providing pharmacokinetic data ________________________________ 11 4.2. Summary of pharmacokinetics ___________________________________________ 12 4.3. Evaluator’s conclusions on pharmacokinetics __________________________ 40 5. Pharmacodynamics ____________________________________________________ 44 5.1. Studies providing pharmacodynamic data ______________________________ 44 5.2. Summary of pharmacodynamics _________________________________________ 45 5.3. Evaluator’s conclusions on pharmacodynamics ________________________ 62 6. Dosage selection for the pivotal studies ___________________________ 64 6.1. Rationale ___________________________________________________________________ 64 6.2. Evaluator’s conclusions on dose finding for the pivotal studies _______ 65 7. Clinical efficacy _________________________________________________________ 65 7.1. Studies providing efficacy data ___________________________________________ 65 7.2. Pivotal or main efficacy studies___________________________________________ 66 7.3. Analyses performed across trials: pooled and meta analyses _________ 117 7.4. Evaluator’s conclusions on efficacy _____________________________________ 117 8. Clinical safety __________________________________________________________ 124 8.1. Studies providing safety data ____________________________________________ 124 8.2. Patient exposure __________________________________________________________ 124 8.3. Pivotal Phase III studies – safety data ___________________________________ 125 8.4. Safety issues with the potential for major regulatory impact _________ 134 8.5. Other safety issues ________________________________________________________ 141 8.6. Post-marketing data ______________________________________________________ 147 8.7. Evaluator’s conclusions on safety _______________________________________ 147 9. First round benefit-risk assessment _______________________________ 152 9.1. First round assessment of benefits ______________________________________ 152 Submission PM-2016-01191-1-3 Extract from the Clinical Evaluation Report for Galafold 3 of 178 Therapeutic Goods Administration 9.2. First round assessment of risks _________________________________________ 158 9.3. First round assessment of benefit-risk balance ________________________ 162 10. First round recommendation regarding authorisation ______ 162 11. Clinical questions ___________________________________________________ 163 11.1. General ____________________________________________________________________ 163 11.2. Pharmacokinetics _________________________________________________________ 163 11.3. Pharmacodynamics _______________________________________________________ 164 11.4. Efficacy ____________________________________________________________________ 164 12. Second round evaluation of clinical data _______________________ 165 12.1. General ____________________________________________________________________ 165 12.2. Pharmacokinetics _________________________________________________________ 166 12.3. Pharmacodynamics _______________________________________________________ 172 12.4. Efficacy ____________________________________________________________________ 172 13. Second round benefit-risk assessment _________________________ 176 13.1. Second round assessment of benefits ___________________________________ 176 13.2. Second round assessment of risks_______________________________________ 176 13.3. Second round assessment of benefit-risk balance _____________________ 176 14. Second round recommendation regarding authorisation ___ 176 15. References ___________________________________________________________ 176 Submission PM-2016-01191-1-3 Extract from the Clinical Evaluation Report for Galafold 4 of 178 Therapeutic Goods Administration List of abbreviations Abbreviation Meaning -Gal A alpha-galactosidase A ACMα Advisory Committee on Medicines ADME absorption, distribution, metabolism, and excretion AT1001 migalastat HCl ACEI angiotensin-converting enzyme inhibitor AE adverse event ARB angiotensin-receptor blocker AUC area under the concentration-time curve AUC 0-24 area under the concentration-time curve from time zero to 24 hours AUC 0-48 area under the concentration-time curve from time zero to 48 hours AUC 0-t area under the concentration-time curve from time zero to time t AUC 0- area under the concentration-time curve from time zero (pre-dose) BID ∞ twice daily BPI Brief Pain Inventory CKD chronic kidney disease CI confidence interval CLcr creatinine clearance Cmax maximum observed concentration CMI Consumer Medicines Information Cmin minimal observed concentration CYP450 cytochrome P450 ECG electrocardiogram ECHO echocardiography eGFR estimated glomerular filtration rate eGFR CKD- estimated glomerular filtration rate based on the Chronic Submission PM-2016-01191-1-3 Extract from the Clinical Evaluation Report for Galafold 5 of 178 Therapeutic Goods Administration Abbreviation Meaning EPI Kidney Disease Epidemiology Collaboration equation eGFR MDRD estimated glomerular filtration rate based on the Modification of Diet in Renal Disease equation EMA European Medicines Agency ERT enzyme replacement therapy FDA Food and Drug Administration (US) GAA Acid -glucosidase GFR glomerularα filtration rate GL-3 globotriaosylceramide GLA gene -Gal A GCP Good encodingClinical Practice α GLP Good Laboratory Practice GSRS Gastrointestinal Symptoms Rating Scale HCl hydrochloride HEK human embryonic kidney hR301Q - mouse model of Fabry disease that expresses a human mutant - Gal A Tg/KO Gal A transgene (R301Q, found in Fabry disease) on a mouse α Gla knockout background α hERG human ether-a-go-go related gene IAR infusion-associated reaction IC interstitial capillary IC 50 half maximal inhibitory concentration ICH International Conference on Harmonisation ITT intent to treat IV Intravenous Ki dissociation constant for binding