Australian Public Assessment Report for Odomzo
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Australian Public Assessment Report for Odomzo Proprietary Product Name: Sonidegib Sponsor: Novartis Pharmaceuticals Australia Pty Ltd November 2019 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 AusPARs • An Australian Public Assessment Report (AusPAR) provides information about the evaluation of a prescription medicine and the considerations that led the TGA to approve or not approve a prescription medicine submission. • AusPARs are prepared and published by the TGA. • An AusPAR is prepared for submissions that relate to new chemical entities, generic medicines, major variations and extensions of indications. • An AusPAR is a static document; it provides information that relates to a submission at a particular point in time. • A new AusPAR will be developed to reflect changes to indications and/or major variations to a prescription medicine subject to evaluation by the TGA. Copyright © Commonwealth of Australia 2019 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]>. AusPAR Odomzo sonidegib Novartis Pharmaceuticals Australia Pty Ltd PM-2014-01865-1-4 - FINAL Page 2 of 92 27 November 2019 Therapeutic Goods Administration Contents Common abbreviations _____________________________________________________ 5 I. Introduction to product submission ____________________________________ 9 Submission details ____________________________________________________________________ 9 Product background _________________________________________________________________ 10 Regulatory status ____________________________________________________________________ 11 Product Information_________________________________________________________________ 11 II. Registration time line __________________________________________________ 11 III. Quality findings ________________________________________________________ 12 Drug substance (active ingredient) ________________________________________________ 12 Drug product _________________________________________________________________________ 13 Quality summary and conclusions _________________________________________________ 13 Biopharmaceutics ___________________________________________________________________ 14 IV. Nonclinical findings ___________________________________________________ 14 Introduction __________________________________________________________________________ 14 Pharmacology ________________________________________________________________________ 14 Toxicity _______________________________________________________________________________ 19 Nonclinical summary and conclusions _____________________________________________ 24 V. Clinical findings _________________________________________________________ 27 Introduction __________________________________________________________________________ 27 Pharmacokinetics ____________________________________________________________________ 28 Pharmacodynamics__________________________________________________________________ 36 Dosage selection for the pivotal studies ___________________________________________ 38 Efficacy _______________________________________________________________________________ 39 Safety _________________________________________________________________________________ 43 First round benefit-risk assessment _______________________________________________ 58 First round recommendation regarding authorisation ___________________________ 62 Clinical questions and second round evaluation __________________________________ 63 Second round benefit-risk assessment ____________________________________________ 79 Second round recommendation regarding authorisation ________________________ 79 VI. Pharmacovigilance findings __________________________________________ 80 Risk management plan ______________________________________________________________ 80 VII. Overall conclusion and risk/benefit assessment _________________ 82 Quality ________________________________________________________________________________ 82 Nonclinical ___________________________________________________________________________ 82 Clinical ________________________________________________________________________________ 83 AusPAR Odomzo sonidegib Novartis Pharmaceuticals Australia Pty Ltd PM-2014-01865-1-4 - FINAL Page 3 of 92 27 November 2019 Therapeutic Goods Administration Risk management plan ______________________________________________________________ 89 Risk-benefit analysis ________________________________________________________________ 89 Outcome ______________________________________________________________________________ 90 Attachment 1. Product Information _____________________________________ 91 AusPAR Odomzo sonidegib Novartis Pharmaceuticals Australia Pty Ltd PM-2014-01865-1-4 - FINAL Page 4 of 92 27 November 2019 Therapeutic Goods Administration Common abbreviations Abbreviation Meaning AAN Australian Approved Name ACM Advisory Committee on Medicines ADME Absorption, distribution, metabolism and excretion AE Adverse event ALT Alanine aminotransferase ARTG Australian Register of Therapeutic Goods AST Aspartate transaminase AUC Area under the plasma concentration-time curve AUC0-24h Area under the plasma concentration-time curve from time zero to 24 hours AUC0- Area under the plasma concentration-time curve from time zero ∞ to infinity AUC(last) Area under the plasma concentration-time curve calculated to the time of the last quantifiable concentration BCC Basal cell carcinoma BCRP Breast cancer resistance protein BCS Biopharmaceutics classification system bd Twice daily BLRM Bayesian logistic regression model CER Clinical evaluation report CHMP Committee on Medicinal Products for Human Use (EMA/EU) CI Confidence interval CK (CPK) Creatine kinase (creatinine phosphokinase) CL/F Apparent plasma clearance after oral administration Cmax Maximum plasma concentration Cmin Trough plasma concentration CNS Central nervous system AusPAR Odomzo sonidegib Novartis Pharmaceuticals Australia Pty Ltd PM-2014-01865-1-4 - FINAL Page 5 of 92 27 November 2019 Therapeutic Goods Administration Abbreviation Meaning CPMP Committee for Proprietary Medicinal Products (EMA/EU) CR Complete response CRR Complete response rate CSR Clinical study report CT Computerised tomography CTCAE Common Technical Criteria Adverse Event CV Coefficient of variation CYP Cytochrome P450 DDI Drug-drug interaction DLT Dose limiting toxicity DoR Duration of objective tumour response ECG Electrocardiogram EMA European Medicines Agency EU European Union F Bioavailability FAS Full analysis set FDA Food and Drug Administration (US) FMI Final marketing image GLP Good Laboratory Practice Hh Hedgehog ICH International Conference on Harmonisation IEC Independent Ethics Committee IRC Independent Review Committee IV Intravenous laBCC Locally advanced basal cell carcinoma LDE225 Sonidegib AusPAR Odomzo sonidegib Novartis Pharmaceuticals Australia Pty Ltd PM-2014-01865-1-4 - FINAL Page 6 of 92 27 November 2019 Therapeutic Goods Administration Abbreviation Meaning mBCC Metastatic basal cell carcinoma MedDRA Medical Dictionary for Regulatory Activities mRECIST Modified Response Evaluation Criteria in Solid Tumors MRI Magnetic resonance imaging MRP2 Multi-resistance protein 2 MTD Maximum tolerated dose NBCCS Nevoid basal cell carcinoma syndrome NE Not-estimable NMSC Non melanoma skin cancer OAT Organic anion transporter OATP Organic anion transporting polypeptide OCT Organic cation transporter ORR Objective response rate OS Overall survival PD Pharmacodynamic(s) pEAS Primary efficacy analysis set PFS Progression free survival P-gp P-glycoprotein pH Negative logarithm of hydrogen ion concentration PK Pharmacokinetic(s) PK/PD Pharmacokinetic(s)/pharmacodynamic(s) PPI