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(EMDAC) June 20, 2017 EMDAC Background document Victoza (liraglutide) - LEADER FDA Briefing Document Endocrinologic and Metabolic Drugs Advisory Committee Meeting (EMDAC) June 20, 2017 The committee will discuss a supplemental new drug application for VICTOZA (liraglutide) injection (NDA 022341), sponsored by Novo Nordisk, for the proposed additional indication of; as an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non- fatal stroke) in adults with type 2 diabetes mellitus and high cardiovascular risk. 1 EMDAC Background document Victoza (liraglutide) - LEADER The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought the discussion of a supplemental new drug application for VICTOZA (liraglutide) injection (NDA 022341), sponsored by Novo Nordisk, for the proposed additional indication of; as an adjunct to standard treatment of cardiovascular risk factors to reduce the risk of major adverse cardiovascular events (cardiovascular death, non- fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and high cardiovascular risk, to this Advisory Committee in order to gain the Committee’s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting. 2 EMDAC Background document Victoza (liraglutide) - LEADER Table of Contents Table of Contents ............................................................................................................................ 3 Abbreviations .................................................................................................................................. 4 Executive Summary ........................................................................................................................ 6 Draft Points to Consider................................................................................................................ 10 Introduction and Background ....................................................................................................... 11 NONCLINICAL SUMMARY...................................................................................................... 16 CLINICAL AND STATISTICAL EFFICACY SUMMARY ...................................................... 23 LEADER- Design and Methods ............................................................................................... 23 LEADER - results ..................................................................................................................... 26 Subject Demographics ....................................................................................................................................... 26 Subject Disposition ............................................................................................................................................ 32 Traditional CV risk factors ................................................................................................................................. 44 Microvascular endpoints .................................................................................................................................... 49 CLINICAL SAFETY (NON-THYROID) SUMMARY .............................................................. 57 Methods..................................................................................................................................... 57 Identification, Categorization, and Evaluation of Adverse Events..................................................................... 57 Routine Clinical Testing .................................................................................................................................... 59 Targeted Safety Issues .............................................................................................................. 60 Neoplasms .......................................................................................................................................................... 60 Pancreatitis ......................................................................................................................................................... 84 Acute Gallstone Disease .................................................................................................................................... 95 Hypoglycemia .................................................................................................................................................. 101 Renal Safety ..................................................................................................................................................... 106 Hepatic Safety .................................................................................................................................................. 110 Immunogenicity ............................................................................................................................................... 113 Eye Disorders ................................................................................................................................................... 117 Diabetic Foot Ulcers ........................................................................................................................................ 118 Other Safety Explorations ................................................................................................................................ 120 CLINICAL SAFETY SUMMARY: MEDULLARY THYROID CANCER ............................ 124 ONCOLOGY CONSULT: PANCREATIC CANCER .............................................................. 129 OPHTHALMOLOGY CONSULT: RETINOPATHY ............................................................... 134 EPIDEMIOLOGY SUMMARY ................................................................................................. 141 PHARMACOVIGILANCE SUMMARY .................................................................................. 146 Appendix 1. EAC definitions ...................................................................................................... 147 Appendix 2. Clinical Narratives ................................................................................................. 156 Selected Examples of Non-Cardiovascular Death Adjudicator Classification ................................................. 156 Renal Deaths (Liraglutide-Treated Subjects) ................................................................................................... 157 Hepatic Events (Liraglutide-Treated Patients) ................................................................................................. 160 Patients on Liraglutide with ‘Immune Complex Disease’ (by MedDRA Search) SAEs ................................. 165 ‘Blindness’ SAEs/MESIs in Liraglutide-Treated Patients ............................................................................... 166 3 EMDAC Background document Victoza (liraglutide) - LEADER Abbreviations ACCORD Action to Control Cardiovascular Risk in ICH Intracranial hemorrhage Diabetes ACEI Angiotensin-Converting Enzyme Inhibitor ICU Intensive care unit ACR Albumin to Creatinine Ratio IND Investigational new drug ACTH Adrenocorticotropic hormone IPMN Intraductal papillary mucinous neoplasm ADA American Diabetes Association ISR Injection site reactions ADVANCE Action in Diabetes and Vascular Disease ISS Integrated summary of safety AE Adverse Event ITA Italy AJCC American Joint Committee on Cancer ITT Intention to treat Afib Atrial fibrillation KOR Korea AHA American Heart Association LDL Low Density Lipoprotein Cholesterol AKI Acute kidney injury LLN Lower limit of normal ALT Alanine Aminotransferase LLQ Lower limit of quantification AML Acute myeloid leukemia LOCF Last observation carried forward ARB Angiotensin II Receptor Blocker LVH Left ventricular hypertrophy ARF Acute renal failure MACE Major Adverse Cardiovascular Events ASA Acetylsalicylic acid MedDRA Medical Dictionary for Regulatory Activities AST Aspartate Aminotransferase MDRD Modification of Diet in Renal Disease AUS Australia MEK mitogen activated protein kinase AUT Austria MEN 2 multiple endocrine neoplasia type 2 BEL Belgium MESI Medical event of special interest BMI Body Mass Index MI Myocardial Infarction BRA Brazil MRI Magnetic resonance imaging BRCA BReast CAncer genes MSOF Multisystem organ failure CABG Coronary Artery Bypass Graft MTC Medullary thyroid cancer CA Cancer CAD Coronary Artery Disease MVA Motor vehicle accident CAN Canada N Number CEA Carcinoembryonic antigen NAACC North American Association of Central Cancer
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